Salmonella infections occur worldwide. Acute gastroenteritis, the most frequent presentation, is usually self-limited, although bacteremia and focal extraintestinal infections may develop, especially in immunocompromised patients. The latter group has become more important and complex because of the increasing number of children who are compromised because of acquired immunodeficiency syndrome (AIDS), organ transplant, or chemotherapy. Enteric fever, a severe systemic disease typically caused by Salmonella typhi, is found mainly in developing countries, but it is seen elsewhere because of international travel.
ETIOLOGY. Salmonella is a genus that belongs to the family Enterobacteriaceae and contains three species: S. typhi, S. choleraesuis, and S. enteritidis. The former two species have one serotype each, but S. enteritidis contains more than 1800 distinct serotypes. For convenience, serotypes are sometimes artificially identified as if they were Salmonella species (e.g., S. typhimurium).
Salmonellae are motile, nonsporulating, nonencapsulated, gram-negative rods. Most strains ferment glucose, mannose, and mannitol to produce acid and gas, but they do not ferment lactose or sucrose. S. typhi does not produce gas. Salmonella organisms grow aerobically and are capable of facultative anaerobic growth. They are resistant to many physical agents but can be killed by heating to 130º F (54.4º C) for 1 hr or 140º F (60º C) for 15 min. They remain viable at ambient or reduced temperatures for days and may survive for weeks in sewage, dried foodstuffs, pharmaceutical agents, and fecal material. Like other members of the Enterobacteriaceae, Salmonella possesses somatic O antigens and flagellar H antigens. The O antigens are the heat-stable lipopolysaccharide components of cell wall; the H antigens are heat-labile proteins that can be present in phase 1 or 2. The Kauffmann-White scheme commonly used to classify salmonellae serotypes is based on O and H antigens. Serotyping is important clinically because certain serotypes tend to be associated with specific clinical syndromes and because the detection of an unusual serotype is sometimes epidemiologically useful. Another antigen is a virulence (Vi) capsular polysaccharide present on S. typhi and rarely found on strains of S. paratyphi C (S. hirschfeldii).
These classification schemes are based on biochemical or serologic reactions. Molecular technology has enabled classification at the gene level. DNA hybridizations have proven that all Salmonella organisms are closely related genetically as a single species with six subgroups; most isolates causing human or animal disease belong to subgroup 1.
EPIDEMIOLOGY.
About 50,000 cases of culture-proven salmonellosis, approximately 98% of which are caused by nontyphoidal salmonellae, are reported annually in the United States
Salmonella infections occur with highest frequency in the warm months, July through November in the United States United States include S. typhimurium, S. enteritidis, S. heidelberg, and S. newport .
The major reservoir of nontyphoidal salmonellae is infected animals, which constitute the principal source of human disease. Infected animals are often asymptomatic. Salmonella organisms have been isolated from many animals, including poultry (i.e., chickens, turkeys, ducks), sheep, cows, pigs, pets, and birds. Animal-to-animal transmission may occur. Animal feeds containing fish meal or bone meal contaminated with Salmonella are an important source of infection for animals. Moreover, subtherapeutic concentrations of antibiotics are often added to animal feed. Such practices promote the emergence of antibiotic-resistant bacteria, including Salmonella, in the gut flora of the animals. During slaughtering, these gut organisms may contaminate the meat, which is subsequently consumed by humans. Data suggest that animal antibiotic exposure may be responsible for antibiotic-resistant Salmonella infections in man.
Studies of outbreaks have enabled the collection of numeric data regarding the sources of human salmonellosis. Poultry and poultry products (mainly eggs) caused about half of the common-source outbreaks. Foods containing raw or undercooked eggs (e.g., Caesar salad, egg-dipped bread, homemade eggnog) are of special importance. Salmonella infections in chickens increase the risk for contamination of eggs. Salmonellae can contaminate the shell surface, penetrate the egg, or be transmitted from an ovarian infection directly to the egg yolk. Salmonella serotypes have been isolated in as many as 50% of poultry, 16% of pork, 5% of beef, and 40% of frozen egg products purchased in retail stores. Meats, especially beef and pork, caused about 13% of the outbreaks, and raw or powdered milk and dairy products were the source of about 5% of the outbreaks. Food product–related outbreaks are often caused by contaminated equipment in processing plants or infected food handlers. Pets, especially turtles, caused about 3% of the outbreaks.
The estimated number of bacteria that must be ingested to cause symptomatic disease in healthy adults is 106–108 Salmonella organisms. In infants and in persons with certain underlying conditions, the inoculum size that can produce disease is smaller. Because of the relatively high inoculum size of Salmonella infection, ingestion of contaminated food, in which the organisms can multiply, is a major source of human infection. Unlike S. typhi, infection with nontyphoidal salmonellae by contaminated water is infrequent. Because of the high infecting dose, person-to-person transmission by direct fecal-oral spread is unusual but can occur, especially in young children who are not yet toilet-trained and do not maintain proper hygiene. Perinatal transmission during vaginal delivery has been reported.
Nosocomial infections have been related to contaminated medical instruments (particularly endoscopes) and diagnostic or pharmacologic preparations, particularly those of animal origin (e.g., pancreatic extracts, pituitary extracts, bile salts, pepsin, gelatin, vitamins, carmine dye). Foodborne nosocomial transmission is also possible. Hospitalized patients are at increased risk of severe and complicated Salmonella infections. Intravenous transmission by platelet transfusion has been reported.
After infection, nontyphoidal salmonellae are excreted in feces for a median of 5 wk. In young children and in individuals with symptomatic infections, the excretion period is longer. Prolonged carriage of Salmonella organisms is rare in healthy children but has been reported in those with underlying immune deficiency. During the period of Salmonella excretion, the individual may infect others, directly by the fecal-oral route or indirectly by contaminating foods. If one household member becomes infected, the probability that another will also become infected is about 60%.
PATHOLOGY.
Enterocolitis is the typical disorder caused by nontyphoidal Salmonella infection. Findings include diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses. Although Salmonella organisms are capable of penetrating the intestinal mucosa, neither destruction of epithelial cells nor production of ulcers is usually seen. Intestinal inflammation, with polymorphonuclear leukocytes and macrophages, usually involves the lamina propria. Underlying intestinal lymphoid tissue and mesenteric lymph nodes enlarge and may develop small areas of necrosis. Such lymphoid hypertrophy may cause interference with the blood supply to the gut mucosa. Hyperplasia of the reticuloendothelial system is seen also within the liver and spleen. If bacteremia develops, it may lead to localized infection and suppuration (with polymorphonuclear leukocyte response) of almost any organ.
PATHOGENESIS. The development of disease after infection with Salmonella depends on the number of infecting organisms, on their virulence traits, and on several host defense factors. Ingested Salmonella organisms reach the stomach, where acidity is the first protective barrier. The acidity inhibits multiplication of the salmonellae, and when gastric pH reaches 2.0, most organisms are rapidly killed. Achlorhydria, buffering medications, rapid gastric emptying after gastrectomy or gastroenterostomy, and a large inoculum enable viable organisms to reach the small intestine. Neonates and young infants have hypochlorhydria and rapid gastric emptying, which contribute to their increased vulnerability to symptomatic salmonellosis. Because the transit time through the stomach is faster for drinks than for foods, a lower inoculum may cause disease in waterborne infection.
In the small and large intestines, salmonellae have to compete with normal bacterial flora to multiply and cause disease; prior antibiotic therapy disrupts this competitive relationship. Decreased intestinal motility due to anatomic causes or medications increases the contact time of the ingested salmonellae with the mucosa and the likelihood of symptomatic disease. After multiplication within the lumen, the organisms penetrate the mucosa, typically at the distal part of the ileum and the proximal part of the colon, with subsequent localization in the Peyer patches. The penetration process includes specific attachment to the luminal surface of epithelial cells, internalization into the cell by receptor-mediated endocytosis, cytoplasmic translocation of the infected endosome to the basal epithelial membrane, and release of the salmonellae in the lamina propria. The role of cytotoxins, which are produced by most salmonellae, is uncertain. Penetration usually occurs without destroying epithelial cells, and ulcers are not produced.
Heat-labile, cholera-like enterotoxin is produced by many Salmonella isolates. This toxin and the prostaglandins that are produced locally increase cyclic adenosine monophosphate levels within intestinal crypts, causing a net efflux of electrolytes and water into the intestinal lumen.
Genes code for adherence to epithelial cells, invasion of epithelial cells, a cholera toxin–like enterotoxin, spread beyond the Peyer patches to mesenteric lymph nodes, intracellular growth in the liver and spleen, survival in macrophages, serum resistance, and complement resistance. Some of these traits are shared by all salmonellae, but others are serotype restricted. These virulence traits have been defined in tissue culture and murine models; it is likely that clinical features of human Salmonella infection will eventually be related to specific DNA sequences.
With most diarrhea-associated nontyphoidal salmonelloses, the infection does not extend beyond the lamina propria and the local lymphatics. S. dublin and S. choleraesuis rapidly invade the bloodstream with little or no intestinal involvement. Specific virulence genes are related to the ability to cause bacteremia. These genes are found significantly more often in strains of S. typhimurium isolated from the blood than the feces of humans. Bacteremia, however, is theoretically possible with any Salmonella strain, especially in individuals with reduced host defenses. An impaired reticuloendothelial or cellular immune response is important. Children with chronic granulomatous disease, other white cell disorders, and AIDS are at increased risk. Children with sickle cell disease are prone to Salmonella septicemia and osteomyelitis. The numerous infarcted areas in the gastrointestinal tract, bones, and reticuloendothelial system may initially permit organisms greater access to the circulation from the intestine and then furnish an optimal environment for localization. The decreased phagocytic and opsonizing capacity of patients with sickle cell disease also contributes to the high infection rate.
Chronic infection is associated with cholelithiasis, Schistosoma mansoni hepatosplenic involvement, and urinary tract Schistosoma hematobium infection. Localized infections are more common in areas with impaired local defenses (e.g., effusions, tumors, hematomas).
CLINICAL MANIFESTATIONS. Several distinct clinical syndromes can develop in children infected with nontyphoidal Salmonella, depending on host factors and the specific serotype involved.
Acute Gastroenteritis. This is the most common clinical presentation. After an incubation period of 6–72 hr (mean, 24 hr), there is an abrupt onset of nausea, vomiting, and crampy abdominal pain primarily in the periumbilical area and right lower quadrant, followed by mild to severe watery diarrhea and sometimes by dysenteric diarrhea, containing blood and mucus. Moderate fever of 101–102º F (38.5–39º C) affects about 70% of patients. Some children develop severe disease with high fever, headache, drowsiness, confusion, meningismus, seizures, and abdominal distention. Abdominal examination reveals some tenderness. The stool, which is usually not bloody, typically contains a moderate number of polymorphonuclear leukocytes and occult blood. Mild leukocytosis may be detected. Symptoms subside within 2–7 days in healthy children; fatalities are rare.
Hemocolitis in salmonellosis
In certain high-risk groups, the course of Salmonella gastroenteritis is distinct. Neonates, young infants, and children with primary or secondary immune deficiency may have symptoms persisting for several weeks. In patients with AIDS, the infection may become widespread and overwhelming, causing multisystem involvement, septic shock, and death. In patients with inflammatory bowel disease, especially active ulcerative colitis, Salmonella gastroenteritis may cause invasion of the bowel with rapid development of toxic megacolon, systemic toxicity, and death. Patients with schistosomiasis have increased susceptibility to salmonellosis and exhibit persistence of infection unless the schistosomiasis is also treated. Salmonella organisms are able to multiply within the schistosomes, where they are protected from antibiotics.
Bacteremia. Transient bacteremia during nontyphoidal Salmonella gastroenteritis is thought to occur in 1–5% of patients. The precise incidence is unclear, because blood cultures often are not obtained from patients with Salmonella gastroenteritis, especially those who are not hospitalized, and because most studies are retrospective. Salmonella bacteremia is associated with fever, chills, and often with a toxic appearance. Bacteremia has been documented, however, in afebrile, well-looking children, especially neonates. Prolonged or intermittent bacteremia is associated with low-grade fever, anorexia, weight loss, diaphoresis, and myalgias. Children with certain underlying conditions who have Salmonella gastroenteritis are at increased risk of bacteremia, which may lead to extraintestinal infection. Recurrent Salmonella septicemia is one of the criteria for diagnosing AIDS according to the Centers for Disease Control and Prevention (CDC) case definition. In these patients, recurrent septicemia appears despite antibiotic therapy, often with a negative stool culture for Salmonella and sometimes with no identifiable focus of infection. Prolonged or recurrent bacteremia is also seen in patients with schistosomiasis. Hemolytic anemias, malaria, and bartonellosis are associated with an increased risk of bacteremia, presumably because of reticuloendothelial system dysfunction. In pregnancy, Salmonella septicemia and fetal loss have been reported. S. typhimurium is the most common serotype causing Salmonella bacteremia in the United States
Extraintestinal Focal Infections. After salmonellae have entered the blood stream, they have a unique capability to metastasize and cause a focal, suppurative infection of almost any organ. Sites of pre-existing abnormalities are typically involved. The most common focal infections involve the skeletal system, meninges, and intravascular sites. Salmonella is a common cause of osteomyelitis in children with sickle cell disease. Salmonella osteomyelitis and suppurative arthritis also occur in sites of previous trauma or skeletal prosthesis. Reactive arthritis may follow Salmonella gastroenteritis, usually in children with the HLA-B27 antigen. Meningitis appears mainly in infants. Patients usually present with little or no fever and minimal symptoms, but rapid deterioration, a high mortality rate (~50%), and neurologic sequelae occur despite appropriate antibiotic therapy. Salmonella meningitis occurs also in patients with AIDS, for whom the mortality rate is more than 50%, and relapse and brain abscesses can occur. Persistent bacteremia suggests endocarditis, arteritis, or an infected aneurysm. The serotypes causing most extraintestinal focal infections are S. typhimurium and S. choleraesuis.
Asymptomatic Infection. Asymptomatic fecal excretion of salmonellae after infection with these organisms has been documented, for instance, as part of an outbreak investigation. The precise incidence is unclear. After clinical recovery from Salmonella gastroenteritis, asymptomatic fecal excretion of salmonellae occurs for several weeks. A chronic carrier state is defined as asymptomatic excretion of Salmonella organisms for more than 1 yr. Although the carrier state does occur after nontyphoidal salmonellosis, it is rare (<1%), and it develops especially in patients with biliary tract disease. The only significance of asymptomatic fecal excretion of nontyphoidal Salmonella is the potential transmission of the infection to other individuals.
DIAGNOSIS.
Definitive diagnosis of the various clinical syndromes is still based on culturing and subsequent identification of Salmonella organisms. In children with gastroenteritis, cultures of stools have higher yields than rectal swabs. In patients with sites of local suppuration, aspirated specimens should be used for Gram staining and culture. Salmonella organisms grow well on nonselective or enriched media, such as blood agar, chocolate agar, or nutrient broth. Normally sterile body fluids (e.g., cerebrospinal fluid, joint fluid, urine) can be cultured on any of these. For specimens normally containing bacterial flora (e.g., stools), selective media, such as MacConkey, XLD, bismuth sulfite (BBL) or Salmonella-Shigella (SS) agar, which inhibit the growth of normal flora, should be used.
Several methods are being developed to answer the need for rapid diagnosis. Two tests, based on latex agglutination and fluorescence, are commercially available for the rapid diagnosis of Salmonella colonies growing in stool culture enrichment broth or culture plates. Clinical experience is limited. Alternatively, chromosomal fragments that are unique to the genus Salmonella have been employed as DNA probes to detect Salmonella species. The method is still experimental and needs evaluation with clinical specimens. Serologic assay for detecting antibodies against S. typhimurium and S. enteritidis has been reported, but clinical usefulness is still unclear.
DIFFERENTIAL DIAGNOSIS.
Salmonella gastroenteritis should be differentiated from other bacterial, viral, and parasitic causes of diarrhea. The presentation of inflammatory diarrhea with moderate fever should be particularly differentiated from Shigella, enteroinvasive Escherichia coli, Yersinia enterocolitica, and Clostridium difficile infections. Rotavirus infections in infants can mimic Salmonella enterocolitis. Etiologic diagnosis on the basis of the clinical picture is not possible. Epidemiologic data may be helpful. If abdominal pain and tenderness are severe, appendicitis, perforated viscus, and ulcerative colitis merit consideration in the differential diagnosis.
PREVENTION.
Chlorinated water, proper sanitary systems, and adequate food hygiene practices are necessary to prevent nontyphoidal salmonellosis in humans. Handwashing is of paramount importance in controlling person-to-person transmission by means of food. In hospitalized patients, enteric precautions should be used for the duration of illness. Individuals with symptomatic or asymptomatic excretion of Salmonella strains should be excluded from activities that involve food preparation or child care until repeated stool cultures are negative. Promotion of breast-feeding may reduce infection, especially in developing communities.
Control of the transmission of Salmonella infections to humans requires control of the infection in the animal reservoir, judicious use of antibiotics in dairy and livestock farming, prevention of contamination of foodstuffs prepared from animals, and use of appropriate standards in food processing in commercial and private kitchens. Whenever cooking practices prevent food from reaching a temperature greater than 150º F (65.5º C) for more than 12 min, salmonellosis may be transmitted. Because large outbreaks are often related to mass food production, it should be recognized that contamination of just one piece of machinery used in food processing may cause an outbreak; meticulous cleaning of the equipment is essential. No vaccine against nontyphoidal Salmonella infections is available.
TREATMENT.
Proper therapy depends on the specific clinical presentation of Salmonella infection. Assessment of the hydration status, correction of dehydration and electrolyte disturbances, and supportive care (see Chapter 60) are the most important aspects of managing Salmonella gastroenteritis in children. Antimotility agents prolong intestinal transit time and are thought to increase the risk of invasion; they should not be used when salmonellosis is suspected. In patients with gastroenteritis, antimicrobial agents do not shorten the clinical course, nor do they eliminate fecal excretion of Salmonella. By suppressing normal intestinal flora, antimicrobial agents may prolong the excretion of Salmonella and increase the risk of creating the chronic carrier state. Antibiotics therefore are not indicated routinely in treating Salmonella gastroenteritis. They should be used in young infants and other children who are at increased risk of a disseminated disease and in those with a severe or protracted course.
Children with bacteremia or extraintestinal focal Salmonella infections should receive antimicrobial therapy. Ampicillin (200 mg/kg/24 hr in four divided doses) is efficacious and used to be the drug of choice; trimethoprim-sulfamethoxazole (TMP-SMX; 10–50 mg/kg/24 hr in two divided doses) and chloramphenicol (75 mg/kg/24 hr in four divided doses) are also effective. Because of the increasing worldwide antibiotic resistance of Salmonella strains, it is necessary to perform susceptibility tests on all human isolates. About 20% of Salmonella isolates in the United States
The duration of antimicrobial therapy is 10–14 days in children with bacteremia, 4–6 wks for acute osteomyelitis, and 4 wk for meningitis. In a child with a focal suppurative process, surgical drainage is necessary in addition to antibiotic treatment. Surgical intervention is often necessary in intravascular Salmonella infections (e.g., repair of aneurysm, replacement of valve) and in cases of chronic osteomyelitis.
PROGNOSIS. Complete recovery is the rule in healthy children who develop Salmonella gastroenteritis. Young infants and immunocompromised patients often have systemic involvement, a prolonged course, and complications. The prognosis is poor for children with Salmonella meningitis (~50% mortality rate) or endocarditis.
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