Kliegman: Nelson Textbook of Pediatrics, 18th ed.

Copyright 2007 Saunders, An Imprint of Elsevier Chapter 195 Salmonella Zulfiqar Ahmed Bhutta Salmonellosis is a common and widely distributed food-borne disease that is a global major public health problem affecting millions of individuals with significant mortality. Salmonellae live in the intestinal tracts of warm- and cold-blooded animals. Some species are ubiquitous, whereas others are specifically adapted to a particular host. The recent sequencing of the Salmonella enterica serovar Typhi (previously called Salmonella typhi) and Salmonella typhimurium genomes has indicated almost 95% genetic homology between the organisms. However, the clinical diseases caused by the 2 organisms differ considerably, which appears to be related to several unique clusters of genes known as pathogenicity islands. Salmonella causes 2 clinical syndromes in humans: a gastroenteritis that is usually self-limited, and typhoid fever that is a relatively severe systemic illness classically caused by S. typhi. Nontyphoidal strains of Salmonella can also cause a severe bacteremic illness in some circumstances. The nomenclature of Salmonella reflects the species name Salmonella enterica with a number of serovars. Salmonella nomenclature has undergone considerable alterations. The original taxonomy was based on clinical syndromes (S. typhi, S. choleraesuis, S. paratyphi). With adoption of serologic analysis, a Salmonella species was defined subsequently as a group of related fermentation phage-type with the result that each Salmonella serovar was considered as a species in itself. Although simplistic, using this classification until 2004 resulted in identification of 2,501 serovars of Salmonella, which led to the need for further categorization to aid communication between scientists, public health officials, and the public. All Salmonella serovars form a single DNA hybridization group: a single species composed of 7 subspecies. The current nomenclature with the species name Salmonella enterica was adopted with several subspecies, IVI ( Table 195-1 ). Each subspecies contains various serotypes defined by the O and H antigens. To further simplify the nomenclature for physicians and epidemiologists, the common serovars' names are kept for subspecies I strains, which represent >99.5% of the Salmonella strains isolated from humans and other warmblooded animals.

TABLE 195-1 -- Salmonella Nomenclature TRADITIONAL USAGE FORMAL NAME S. typhi S. dublin S. typhimurium S. enterica[*] subsp. enterica ser. Typhi S. enterica subsp. enterica ser. Dublin S. enterica subsp. enterica ser.

CDC DESIGNATION S. ser. Typhi S. ser. Dublin S. ser. Typhimurium

TRADITIONAL USAGE S. choleraesuis S. marina

FORMAL NAME Typhimurium S. enterica subsp. enterica ser. Choleraesuis S. enterica subsp. houtenae ser. Marina

CDC DESIGNATION S. ser. Choleraesuis S. ser. Marina

CDC, Centers for Disease Control and Prevention;subsp, subspecies; ser., serovar.
* Some authorities prefer S. choleraesuis or S. enteritidis rather than enterica to describe the species.

195.1 Nontyphoidal Salmonellosis

ETIOLOGY.

Salmonellae are motile, nonsporulating, nonencapsulated, gram-negative rods that grow aerobically and are capable of facultative anaerobic growth. They are resistant to many physical agents but can be killed by heating to 130F (54.4C) for 1 hr or 140F (60C) 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 family Enterobacteriaceae, Salmonella possesses somatic O antigens and flagellar H antigens. With the exception of a few serotypes that affect only 1 or a few animal species, such as S. dublin in cattle and S. choleraesuis in pigs, most serotypes have a broad host spectrum. Typically, such strains cause gastroenteritis that is often uncomplicated and does not need treatment, but can be severe in the young, the elderly, and patients with weakened immunity. The causes are typically S. Enteritidis (S. enterica serotype Enteritidis) and S. Typhimurium (S. enterica serotype Typhimurium), the 2 most important serotypes for salmonellosis transmitted from animals to humans.
EPIDEMIOLOGY.

Salmonellosis constitutes a major public health burden and represents a significant cost to society in many countries. It is estimated that, in the United States alone, an estimated 1.4 million nontyphoidal Salmonella infections results in 168,000 physician visits, 15,000 hospitalizations, and 580 deaths annually. The total cost associated with Salmonella infections is estimated at $3 billion annually in the United States. While there is little information on its epidemiology and the burden of Salmonella gastroenteritis from developing countries, Salmonella infections are recognized as major causes of childhood diarrheal illness. With the growing burden of HIV infections and malnutrition in Africa, there is a growing interest in the importance of nontyphoidal Salmonella bacteremias in children and adults. Nontyphoidal Salmonella infections have a worldwide distribution with an incidence proportional to the standards of hygiene, sanitation, availability of safe water, and food preparation practices. In the developed world, the incidence of Salmonella infections and outbreaks has increased several-fold over the past few decades, which may be related to modern practices of mass food production that increase the potential for epidemics. Salmonella gastroenteritis accounts for over half of all episodes of bacterial diarrhea in the United States, with incidence peaks at the extreme of ages, among young infants and the

elderly. While most human infections have been caused by S. enterica serovar Enteritidis, its prevalence has reduced over the past decade, with S. enterica serovar Typhimurium overtaking it in some countries. This rise in Salmonella infections in many parts of the world over the past 3 decades may also be related to intensive animal husbandry practices, which selectively promote the rise of certain strains, especially drug-resistant varieties that emerge in response to antimicrobial usage in food animals. Although this may be related to selective pressure from the use of antimicrobials, there may be other factors such as the rise of strains with a selective propensity to develop resistance and virulence. It appears that multidrug-resistant strains of Salmonella are more virulent than susceptible strains, and that poorer outcome does not simply relate to the empirical choice of an ineffective antibiotic delaying treatment response. Strains of multidrug-resistant Salmonella such as S. Typhimurium phage type DT104 harbor a genomic island that contains many of the drug resistance genes. It is feasible that these integrons also contain genes that express virulence factors. The global spread of multidrugresistant S. Typhimurium phage type DT104 in animals and humans in recent years may be related to the growing use of antimicrobials and also facilitated by international and national trade of infected animals. There are several risk factors associated with outbreaks of Salmonella infections. Animals constitute the principal source of human nontyphoidal Salmonella disease, and cases have occurred where individuals have had contact with infected animals, including domestic animals such as cats, dogs, reptiles, pet rodents, and amphibians. Specific serotypes may be associated with particular animal hosts; children with S. enterica serovar Marina typically have exposure to pet lizards. Domestic animals probably acquire the infection in the same way as humans through consumption of contaminated raw meat, poultry, or poultry-derived products. Animal feeds containing fishmeal 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 to promote growth. Such practices promote the emergence of antibiotic-resistant bacteria, including Salmonella, in the gut flora of the animals, with subsequent contamination of their meat. There is strong evidence to link resistance of S. Typhimurium to fluoroquinolones to its use in animal feeds. While animal-toanimal transmission can occur, most infected animals are asymptomatic. Salmonella infections in chickens increase the risk for contamination of eggs, and both poultry and eggs are associated with almost half of the common-source outbreaks. Food productrelated outbreaks are often caused by contaminated equipment in processing plants or infected food handlers. While almost 80% of Salmonella infections are discrete, outbreaks can pose an inordinate burden on public health systems. This may be a particular risk in schools. In an evaluation of a consecutive 604 outbreaks of food-borne disease in schools, Salmonella was the most commonly identified pathogen, accounting for 36% of outbreak reports with a known etiology. In 55% of outbreaks, specific food vehicles of transmission were epidemiologically identified and included foods containing poultry (18.6%), salads (6.0%), Mexican-style food (6.0%), beef (5.7%), and dairy products excluding ice cream (5.0%). The most commonly reported food preparation practices that contributed to these school-related outbreaks were improper food storage and holding temperatures and food contaminated by a food handler. In addition to the effect of antibiotic use in animal feeds, the relationship of Salmonella infections to prior antibiotic use among children in the previous month is well recognized.

This increased risk for infection in people who have received antibiotics for an unrelated reason may be related to alterations in gut microbial ecology, predisposing them to colonization and infection with antibiotic-resistant Salmonella isolates. These resistant strains of Salmonella are also more virulent. It is estimated that antimicrobial resistance in Salmonella may result in about 30,000 additional Salmonella infections, leading to about 300 hospitalizations and 10 deaths. Given the ubiquitous nature of the organism, nosocomial infections with nontyphoidal Salmonella strains can also occur through contaminated equipment and diagnostic or pharmacologic preparations, particularly those of animal origin (pancreatic extracts, pituitary extracts, bile salts). Hospitalized children are at increased risk for severe and complicated Salmonella infections, especially with drug-resistant organisms.
PATHOGENESIS.

The estimated number of bacteria that must be ingested to cause symptomatic disease in healthy adults is 106108 Salmonella organisms. The gastric acidity inhibits multiplication of the salmonellae, and most organisms are rapidly killed at gastric pH 2.0. 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. In infants who typically take fluids, the inoculum size that can produce disease is also comparatively smaller because of faster transit through the stomach. Once they reach the small and large intestine, the ability of Salmonella organisms to multiply and cause infection depends on the infecting dose as well as competition with normal flora. Prior antibiotic therapy may alter this relationship, as might factors such as co-administration of antimotility agents. The typical intestinal mucosal response to nontyphoidal Salmonella infection is an enterocolitis with diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses. Salmonella organisms are capable of penetrating the intestinal mucosa, although destruction of epithelial cells and ulcers are usually not found. 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 also found within the liver and spleen. If bacteremia develops, it may lead to localized infection and suppuration in almost any organ. Salmonella species invade epithelial cells in vitro by a process of bacterial-mediated endocytosis, involving cytoskeletal rearrangement, disruption of the epithelial cell brush border, and the subsequent formation of membrane ruffles. An adherent and invasive phenotype of S. enterica is activated under conditions similar to those found in the human small intestine (high osmolarity, low oxygen). The invasive phenotype is mediated, in part, by Salmonella pathogenicity island 1 (SPI-1), a 40 kb region that encodes regulator proteins (HilA), a type III secretion system (TTSS) that delivers bacterial proteins from the salmonella cytosol into the host cell, and several effector proteins that induce changes within the host cell and promote bacterial uptake.

Although S. Typhimurium can cause systemic disease in humans, intestinal infection usually results in a localized enteritis that is associated with a secretory response in the intestinal epithelium, as well as induction of the secretion of interleukin 8 (IL-8) from the basolateral surface and other epithelial pathogen-elicited chemo-attractants toward the apical surface, which direct the recruitment and transmigration of neutrophils into the gut lumen, thus preventing the systemic spread of the bacteria ( Fig. 195-1 ).

Figure 195-1 Pathogenesis of Salmonella gastroenteritis. (Adapted from Santos RL, Tsolis RM, Bumler AJ, et al: Pathogenesis of Salmonella-induced enteritis. Braz J Med Biol Res 2003;36[1]:312.)

Shortly following invasion of the gut epithelium, invasive Salmonella organisms encounter macrophages within the gut-associated lymphoid tissue. The interaction between Salmonella and macrophages results in alteration in the expression of a number of host genes, including those encoding proinflammatory mediators (inducible nitric oxide synthase [iNOS], chemokines, IL-1b), receptors or adhesion molecules (tumor necrosis factor- receptor [TNF-

R], CD40, intercellular adhesion molecule 1 [ICAM-1]), and anti-inflammatory mediators (transforming growth factor-1 and -2 [TGF-1 and -2]). Other upregulated genes include those involved in cell death or apoptosis (intestinal epithelial cell protease, TNF-R1, Fas) and transcription factors (Egr-1, IRF-1). S. Typhimurium can induce rapid macrophage death in vitro, which is dependent on the host cell protein caspase-1 and mediated by the SPI-1 effector SipB. Intracellular S. Typhimurium is found within specialized Salmonella organisms containing vacuoles that have diverged from the normal endocytic pathway. This ability to survive within monocytes/macrophages is essential for S. Typhimurium to establish a systemic infection in the mouse. The mucosal pro-inflammatory response to S. Typhimurium infection and the subsequent recruitment of phagocytic cells to the site may also facilitate systemic spread of the bacteria. Some virulence traits are shared by all salmonellae, but others are serotype restricted. These virulence traits have been defined in tissue culture and murine models, and 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. 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 in the feces of humans. Both S. dublin and S. choleraesuis have a greater propensity to rapidly invade the bloodstream with little or no intestinal involvement. The development of disease after infection with Salmonella depends on the number of infecting organisms, their virulence traits, and several host defense factors. Various host factors may also affect the development of specific complications or clinical syndromes ( Table 195-2 ).

TABLE 195-2 -- Host Factors and Conditions Predisposing to the Development of Systemic Disease with Non-typhoidal Salmonella Strains Neonates and young infants (3 mo of age) HIV/AIDS Other immune deficiencies and chronic granulomatous disease Immunosuppressive and corticosteroid therapy Malignancies, especially leukemia and lymphoma Hemolytic anemia, including sickle cell disease, malaria, and bartonellosis Collagen vascular disease Inflammatory bowel disease Achlorhydria or antacid medication use Impaired intestinal motility Schistosomiasis, malaria Malnutrition

Bacteremia, however, is possible with any Salmonella serotype, especially in individuals with reduced host defenses, and especially in those with altered reticuloendothelial or cellular

immune function. Thus, children with HIV infection, chronic granulomatous disease, and leukemia are more likely to develop bacteremia after Salmonella infection, although the majority of children with Salmonella bacteremia in Africa are HIV negative. Children with Schistosoma mansoni infection and hepatosplenic involvement as well as chronic malarial anemia are also at a greater risk for developing chronic salmonellosis. Children with sickle cell disease are at increased risk for Salmonella septicemia and osteomyelitis. This may be related to the presence of numerous infarcted areas in the gastrointestinal tract, bones, and reticuloendothelial system as well as reduced phagocytic and opsonizing capacity of patients, which allows the organism to flourish. Some inherited defects such as IL-12 deficiency (IL-12 receptor 1 chain deficiency, IL-12 p40 subunit deletion) are associated with increased risk for Salmonella infections, suggesting a key role for IL-12 in the clearance of Salmonella. IL-12 is produced by activated macrophages and is a potent inducer of interferon- by natural killer cells and T lymphocytes. Given the putative protective role of IL-12 against malarial infection, Salmonella infection of phagocytes may secondarily affect IL-12 production and thus produce a vicious cycle of chronic malaria and salmonella co-infection.
CLINICAL MANIFESTATIONS. Acute Enteritis.

The most common clinical presentation of salmonellosis is with acute enteritis. After an incubation period of 672 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 diarrhea containing blood and mucus. A large proportion of children are febrile, although younger infants may exhibit a normal or subnormal temperature. Symptoms usually subside within 27 days in healthy children and fatalities are rare. However, some children develop severe disease with a septicemia-like picture (high fever, headache, drowsiness, confusion, meningismus, seizures, abdominal distention). The stool typically contains a moderate number of polymorphonuclear leukocytes and occult blood. Mild leukocytosis may be detected.
Bacteremia.

Although the precise incidence of bacteremia following Salmonella gastroenteritis is unclear, transient bacteremia can occur in 15% of children with Salmonella diarrhea. While bacteremia can occur with minimal associated symptoms in newborns and very young infants, in older infants it typically follows gastroenteritis and can be associated with fever, chills, and septic shock. In patients with AIDS, recurrent septicemia appears despite antibiotic therapy, often with a negative stool culture for Salmonella and sometimes with no identifiable focus of infection. Nontyphoidal Salmonella gastrointestinal infections commonly cause bacteremia in developing countries. High rates of invasive disease with S. Typhimurium and S. Enteritides reported from Africa (3870% of isolates) suggest an association with HIV infections and malaria.
Extraintestinal Focal Infections.

Following bacteremia, salmonellae have the propensity to seed and cause focal suppurative infection of many organs. The most common focal infections involve the skeletal system,

meninges, and intravascular sites and sites of pre-existing abnormalities; areas of bone infarction as in sickle cell disease; or bone prostheses. Although meningeal infection is less common than bacteremia, Salmonella infections are also associated with focal intracranial infections. The peak incidence of Salmonella meningitis is in infancy and may be associated with a florid clinical course, high mortality, and neurologic sequelae.
COMPLICATIONS.

Salmonella gastroenteritis can be associated with acute dehydration and complications resulting from delayed presentation and inadequate treatment. Bacteremia in younger infants and immunocompromised individuals can have serious consequences and potentially fatal outcomes. Salmonella organisms can seed many organ systems, leading to intracranial infections (meningitis, focal brain abscesses) as well as osteomyelitis in children with sickle cell disease. Reactive arthritis may follow Salmonella gastroenteritis, usually in adolescents with HLA-B27 antigen. In certain high-risk groups, especially those with impaired immunity, the course of Salmonella gastroenteritis may be more complicated. Neonates, infants <6 mo of age, and children with primary or secondary immune deficiency may have symptoms persisting for several weeks. The course of illness and complications may also be affected by coexisting pathologies. In children with AIDS, the infection frequently becomes widespread and overwhelming, causing multisystem involvement, septic shock, and death. In patients with inflammatory bowel disease, especially active ulcerative colitis, Salmonella gastroenteritis may be potentially fatal, with rapid development of toxic megacolon, bacterial translocation, and sepsis. In children with schistosomiasis, the Salmonella may persist and multiply within schistosomes, leading to chronic infection unless the schistosomiasis is effectively treated. Prolonged or intermittent bacteremia is associated with low-grade fever, anorexia, weight loss, diaphoresis, and myalgias, and may occur in children with underlying problems and reticulo-endothelial system dysfunction such as hemolytic anemia or malaria.
DIAGNOSIS.

There are few clinical features that are specific to Salmonella gastroenteritis and allow differentiation from other bacterial causes of diarrhea. Definitive diagnosis of Salmonella infection is based on clinical correlation of the presentation and culturing and subsequent identification of Salmonella organisms from feces or other body fluids. In children with gastroenteritis, cultures of stools have higher yields than rectal swabs. In children with nontyphoidal Salmonella gastroenteritis, prolonged fever lasting 5 days or more and young age should be recognized as risk factors closely associated with development of bacteremia. In patients with sites of local suppuration, aspirated specimens should be Gram stained and cultured. Salmonella organisms grow well on nonselective or enriched media, such as blood agar, chocolate agar, or nutrient broth, but stool specimens containing mixed bacterial flora require selective media such as MacConkey, xylose-lysine-deoxycholate (XLD), bismuth sulfite (BBL), or Salmonella-Shigella (SS) agar for isolation. Although other rapid diagnostic methods, such as latex agglutination and immunofluorescence, have been developed for rapid diagnosis of Salmonella in cultures, there are few comparable tests for rapid serologic detection. Polymerase chain reaction (PCR) techniques may offer a rapid alternative to classic cultures but are as yet not in widespread use in clinical settings.

TREATMENT.

Appropriate therapy relates to the specific clinical presentation of Salmonella infection. In children with gastroenteritis, rapid clinical assessment, correction of dehydration and electrolyte disturbances, and supportive care are key (see Chapters 55 and 337 ). Antibiotics are not generally recommended for the treatment of Salmonella gastroenteritis because they may suppress normal intestinal flora and prolong the excretion of Salmonella and the remote risk for creating the chronic carrier state (usually in adults). However, given the risk for bacteremia in infants (<3 mo of age) and that of disseminated infection in high-risk groups with immune compromise (HIV, malignancies, immunosuppressive therapy, immunodeficiency states), these children must receive an appropriate antibiotic empirically until culture results are available ( Table 195-3 ). The strain of S. Typhimurium phage type DT104 is usually resistant to 5 drugs: ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. An increasing proportion of S. Typhimurium phage type DT104 isolates also have reduced susceptibility to fluoroquinolones. Given the higher mortality associated with multidrug-resistant Salmonella infections, it is necessary to perform susceptibility tests on all human isolates. Infections with suspected drug-resistant Salmonella should be closely monitored and treated with appropriate antimicrobial therapy.

TABLE 195-3 -- Treatment of Salmonella Gastroenteritis DOSE AND DURATION OF ORGANISM AND INDICATION TREATMENT Salmonella infections in infants <3 mo of age, immunocompromised persons Cefotaxime 100200 mg/kg/day every 6 hr for 514 days or Ceftriaxone 75 mg/kg/day once daily for 7 days or Ampicillin 100 mg/kg/day every 6 hr for 7 days or Chloramphenicol 15 mg/kg/day divided every 6 hr PO for 510 days
PROGNOSIS.

Most healthy children with Salmonella gastroenteritis recover fully. However, malnourished children and those who do not receive optimal supportive treatment (see Chapters 55 and 337 ) are at risk for developing prolonged diarrhea and complications. Young infants and immunocompromised patients often have systemic involvement, a prolonged course, and extraintestinal foci. In particular, children with HIV infection and Salmonella infections can have a florid course. After infection, nontyphoidal salmonellae are excreted in feces for a median of 5 wk. However, after clinical recovery from Salmonella gastroenteritis, asymptomatic fecal excretion of the organism may occur for several months, particularly in younger children or

those treated with antibiotics. A prolonged carrier state after nontyphoidal salmonellosis is rare (<1%), but may be seen in children with biliary tract disease and cholelithiasis following chronic hemolysis. 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.
PREVENTION.

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 ( Table 195-4 ). Because large outbreaks are often related to mass food production, it should be recognized that contamination of just 1 piece of machinery used in food processing may cause an outbreak; meticulous cleaning of equipment is essential. Clean water supply and education in handwashing and food preparation and storage is critical to reducing person-to-person transmission. Salmonella may remain viable when cooking practices prevent food from reaching a temperature greater than 150F (65.5C) for >12 min. Parents should be advised of the risk of reptiles as pets in households with young infants.

TABLE 195-4 -- Recommendations for Preventing Transmission of Salmonella from Reptiles and Amphibians to Humans Pet store owners, health care providers, and veterinarians should provide information to owners and potential purchasers of reptiles and amphibians about the risks for and prevention of salmonellosis from these pets. Persons at increased risk for infection or serious complications from salmonellosis (e.g., children aged <5 yr and immunocompromised persons) should avoid contact with reptiles and amphibians and any items that have been in contact with reptiles and amphibians. Reptiles and amphibians should be kept out of households that include children aged <5 yr or immunocompromised persons. A family expecting a child should remove any pet reptile or amphibian from the home before the infant arrives. Reptiles and amphibians should not be allowed in child-care centers. Persons always should wash their hands thoroughly with soap and water after handling reptiles and amphibians or their cages. Reptiles and amphibians should not be allowed to roam freely throughout a home or living area. Pet reptiles and amphibians should be kept out of kitchens and other food preparation areas. Kitchen sinks should not be used to bathe reptiles and amphibians or to wash their dishes, cages, or aquariums. If bathtubs are used for these purposes, they should be cleaned thoroughly and disinfected with bleach. Reptiles and amphibians in public settings (e.g., zoos and exhibits) should be kept from direct or indirect contact with patrons except in designated animal contact areas equipped with adequate handwashing facilities. Food and drink should not be allowed

in animal contact areas. From the Centers for Disease Control and Prevention: Reptile-associated salmonellosis Selected states, 19982002. MMWR2003;52:12061210.

In contrast to developed countries, relatively little is known about the transmission of nontyphoidal Salmonella infections in developing countries, and it is likely that person-toperson transmission may be relatively more important in some settings. Although some vaccines have been used in animals, no human vaccine against nontyphoidal Salmonella infections is currently available. Infections should be reported to public health authorities so that outbreaks can be recognized and investigated. Given the rapid rise of antimicrobial resistance among Salmonella isolates, it is imperative that there is rigorous regulation of the use of antimicrobials in animal feeds.
195.2 Enteric Fever (Typhoid Fever)

Enteric fever (more commonly termed typhoid fever) remains endemic in many developing countries. Given the ease of modern travel, cases are regularly reported from most developed countries, usually from returning travelers.
ETIOLOGY.

Typhoid fever is caused by Salmonella enterica serovar Typhi (S. Typhi), a gram-negative bacterium. A very similar but often less severe disease is caused by S. Paratyphi A and rarely by S. Paratyphi B (Schotmulleri) and S. Paratyphi C (Hirschfeldii). The ratio of disease caused by S. Typhi to that caused by S. Paratyphi is about 10 to 1, although the proportion of S. Paratyphi infections is increasing in some parts of the world. Although S. Typhi shares many genes with Escherichia coli and at least 95% with S. Typhimurium, there are several unique gene clusters known as pathogenicity islands and others that have been acquired during evolution. The inactivation of single genes, as well as the acquisition or loss of single genes or large islands of DNA, may have contributed to host adaptation and restriction of S. Typhi. One of the most specific genes is for the polysaccharide capsule Vi. This is present in about 90% of all freshly isolated S. Typhi and has a protective effect against the bactericidal action of the serum of infected patients.
EPIDEMIOLOGY.

It is currently estimated that over 21.7 million typhoid cases occur annually, with the vast majority of cases in Asia, with over 200,000 deaths. Additionally, an estimated 5.4 million cases occur due to paratyphoid. Given the paucity of microbiological facilities in developing countries, these figures may be more representative of the clinical syndrome rather than culture-proven disease. In most developing countries, the incidence of typhoid fever is <15 cases per 100,000 population, with most cases occurring in travelers or isolated cases of exposure to carriers. In contrast, the incidence may vary considerably in the developing world, with estimated rates ranging from 1001,000 cases per 100,000 population. There may also be differences in the age distribution and population at risk. Population-based studies from south Asia also indicate that, contrary to previous views, the age-specific incidence of

typhoid may be highest in children <5 yr of age, with comparatively higher rates of complications and hospitalization. Typhoid fever has been notable for the emergence of drug resistance. Following sporadic outbreaks of chloramphenicol-resistant typhoid, many strains of S. Typhi have developed plasmid-mediated multidrug resistance to all 3 of the primary antimicrobials: ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. Chromosomally acquired quinolone resistance in S. Typhi has been described in various parts of Asia and may be a consequence of widespread and indiscriminate use of these agents. S. Typhi is highly adapted to infection of human beings to the point that it has lost the ability to cause transmissible disease in other animals. The discovery of the large number of pseudogenes in S. Typhi suggests that the genome of this pathogen has undergone degeneration to facilitate a specialized association with human beings. Thus, direct or indirect contact with an infected person (sick or chronic carrier) is a prerequisite for infection. Ingestion of foods or water contaminated with S. Typhi from human feces is the most common mode of transmission, although water-borne outbreaks due to poor sanitation or contamination can occur in developing countries. In other parts of the world, oysters and other shellfish cultivated in water contaminated by sewage or the use of night soil as fertilizer may also cause infection.
PATHOGENESIS.

The disease occurs by the ingestion of the organism, and a variety of sources of fecal contamination have been reported, including street foods and contamination of water reservoirs. Human volunteer experiments established an infecting dose of about 105109 organisms with an incubation period ranging from 4 to 14 days, depending on the inoculating dose of viable bacteria. After ingestion, S. Typhi organisms are thought to invade the body through the gut mucosa in the terminal ileum, possibly through specialized antigen-sampling cells, known as M cells, that overlie gut-associated lymphoid tissues, through enterocytes, or via a paracellular route. S. Typhi crosses the intestinal mucosal barrier after attachment to the microvilli by an intricate mechanism involving membrane ruffling, actin rearrangement, and internalization in an intracellular vacuole. After passing through the intestinal mucosa, S. Typhi organisms enter the mesenteric lymphoid system, and then pass into the bloodstream via the lymphatics. This primary bacteremia is usually symptomless, and blood cultures are frequently negative at this stage of the disease. The blood-borne bacteria are disseminated throughout the body and are thought to colonize the organs of the reticulo-endothelial system, where they may replicate within macrophages. After a period of bacterial replication, S. Typhi organisms are shed back into the blood, causing a secondary bacteremia, which coincides with the onset of clinical symptoms and marks the end of the incubation period ( Fig. 195-2 ).

Figure 195-2 Pathogenesis of typhoid fever. (Adapted from Richens J: Typhoid fever. In Cohen J, Powderly WG, Opal SM [editors]: Infectious Diseases, 2nd ed. London, Mosby, 2004, pp 15611566.)

In vitro studies with human cell lines have shown qualitative and quantitative differences in the epithelial cell response to S. Typhi and S. Typhimurium with regard to cytokine and chemokine secretion. Thus, by avoiding the triggering of an early inflammatory response in the gut, S. Typhi could instead colonize deeper tissues and organ systems. Infection with S. Typhi produces an inflammatory response in the deeper mucosal layers and underlying lymphoid tissue with hyperplasia of Peyer patches, and subsequent necrosis and sloughing of overlying epithelium with ulceration. The ulcers can bleed but usually heal without scarring or stricture formation. The inflammatory lesion may occasionally penetrate the muscularis and serosa of the intestine and produce perforation. The mesenteric lymph nodes, liver, and spleen are hyperemic and generally reveal areas of focal necrosis as well. A mononuclear response may be seen in the bone marrow in association with areas of focal necrosis. The morphologic changes of S. Typhi infection are less prominent in infants compared with older children and adults. In particular, in contrast to adults with typhoid, despite bacterial multiplication in the gall bladder wall, inflammation is both focal and mild. It is thought that several virulence genes, including the SPI-2 TTSS, may be necessary for the virulence properties and ability to cause systemic infection. The surface Vi (virulence)

polysaccharide capsular antigen found in S. Typhi interferes with phagocytosis by preventing the binding of C3 to the surface of the bacterium. The ability of organisms to survive within macrophages after phagocytosis is an important virulence trait encoded by the phoP regulon; it may be related to metabolic effects on host cells. The occasional occurrence of diarrhea may be explained by the presence of a toxin related to cholera toxin and E. coli heat-labile enterotoxin. The clinical syndrome of fever and systemic symptoms is produced by a release of pro-inflammatory cytokines (IL-6, IL-1, and TNF-) from the infected cells. In addition to the virulence of the infecting organisms, host factors and immunity may also play an important role in predisposition to infection. There is an association between susceptibility to typhoid fever and human genes within the major histocompatability complex class II and class III loci. Patients who are infected with HIV are at significantly increased risk for clinical infection with S. Typhi and S. Paratyphi. Similarly patients with Helicobacter pylori infection also have an increased risk for acquiring typhoid fever.
CLINICAL FEATURES.

The incubation period of typhoid fever is usually 714 days but is also dependent on the infecting dose (range 330 days). The clinical presentation varies from a mild illness with low-grade fever, malaise, and slight dry cough to a severe clinical picture with abdominal discomfort and multiple complications. Many factors influence the severity and overall clinical outcome of the infection. They include the duration of illness before the initiation of appropriate therapy, choice of antimicrobial treatment, age, previous exposure or vaccination history, virulence of the bacterial strain, quantity of inoculum ingested, and several host factors affecting immune status. The presentation of typhoid fever may also differ according to age. Although data from South America and other parts of Africa suggest that typhoid may present as a mild illness in young children, this may vary in different parts of the world. There is emerging evidence from south Asia that the presentation of typhoid may be more dramatic in children <5 yr of age, with comparatively higher rates of complications and hospitalization. Diarrhea, toxicity, and complications such as disseminated intravascular complications are also more common in infancy, with higher case fatality rates. However, some of the other features and complications of typhoid fever seen in adults, such as relative bradycardia, neurologic manifestations, and gastrointestinal bleeding, are rare. Typhoid fever usually presents with high-grade fever with a wide variety of associated features such as generalized myalgia, abdominal pain, hepatosplenomegaly, abdominal pain, and anorexia ( Table 195-5 ). In children, diarrhea may be present in the earlier stages of the illness and may be followed by constipation. In the absence of localizing signs, the early stage of the disease may be difficult to differentiate from other endemic diseases such as malaria or dengue fever. The fever may rise gradually, but the classic stepladder rise of fever is relatively rare. In about 25% of cases, a macular or maculopapular rash (rose spots) may be visible around the 7th10th day of the illness, and lesions may appear in crops of 1015 on the lower chest and abdomen and last 23 days ( Fig. 195-3 ). These lesions may be difficult to see in dark-skinned children. Patients managed as outpatients will present with fever (99%) but have less emesis, diarrhea, hepatomegaly, splenomegaly, and myalgias than hospitalized patients.

TABLE 195-5 -- Common Clinical Features of Typhoid Fever in Children[*] High-grade fever 95% Coated tongue Anorexia Vomiting Hepatomegaly Diarrhea Toxicity Abdominal pain Pallor Splenomegaly Constipation Headache Jaundice Obtundation Ileus 76% 70% 39% 37% 36% 29% 21% 20% 17% 7% 4% 2% 2% 1%

Intestinal perforation 0.5%

* Karachi, Pakistan, from 2,000 children.

Figure 195-3 A, A rose spot in a volunteer with experimental typhoid fever. B, A small cluster of rose spots is usually located on the abdomen. These lesions may be difficult to identify, especially in dark-skinned people. (From Huang DB, DuPont HL: Problem pathogens: Extra-intestinal complications of Salmonella enterica serotype Typhi infection. Lancet Infect Dis 2005;5: 341348.)

The presentation of typhoid fever may be tempered by coexisting morbidities and early administration of antibiotics. In malaria-endemic areas and in parts of the world where schistosomiasis is common, the presentation of typhoid may also be atypical. It is also recognized that multidrug-resistant S. Typhi infection is a more severe clinical illness with higher rates of toxicity, complications, and case fatality rates, which may be related to the increased virulence as well as higher number of circulating bacteria. These findings may have implications for treatment algorithms, especially in endemic areas with high rates of multidrug-resistant typhoid.

If no complications occur, the symptoms and physical findings gradually resolve within 24 wk; however, the illness may be associated with malnutrition in a number of affected children. Although enteric fever caused by S. Paratyphi organisms has been classically regarded as a milder illness, recent reports of infections with drug-resistant isolates indicate that paratyphoid fever may also be severe, with significant morbidity and complications.
COMPLICATIONS.

Although altered liver function is found in many patients with enteric fever, clinically significant hepatitis, jaundice, and cholecystitis are relatively rare and may be associated with higher rates of adverse outcome. Intestinal hemorrhage (<1%) and perforation (0.51%) is infrequent among children. Intestinal perforation may be preceded by a marked increase in abdominal pain (usually in the right lower quadrant), tenderness, vomiting, and features of peritonitis. Intestinal perforation and peritonitis may be accompanied by a sudden rise in pulse rate, hypotension, marked abdominal tenderness and guarding, and subsequent abdominal rigidity. A rising white blood cell count with a left shift and free air on abdominal radiographs may be seen in such cases. Rare complications include toxic myocarditis, which may manifest by arrhythmias, sinoatrial block, or cardiogenic shock ( Table 195-6 ). Neurologic complications are also relatively uncommon among children and may include delirium, psychosis, increased intracranial pressure, acute cerebellar ataxia, chorea, deafness, and Guillain-Barr syndrome. Although case fatality rates may be higher with neurologic manifestations, recovery usually occurs with no sequelae. Other reported complications include fatal bone marrow necrosis, disseminated intravascular coagulation (DIC), hemolytic uremic syndrome, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis.

TABLE 195-6 -- Extraintestinal Infectious Complications of Typhoid Fever Caused by Salmonella enterica Serotype Typhi ORGAN SYSTEM INVOLVED PREVALENCE RISK FACTORS COMPLICATIONS Central nervous 335% system Residence in endemic region, malignancy, endocarditis, congenital heart disease, paranasal sinus infections, pulmonary infections, meningitis, trauma, surgery, and osteomyelitis of the skull Cardiac abnormalities e.g., existing valvular abnormalities, rheumatic heart disease, or congenital heart defects Residence in endemic region, past pulmonary Encephalopathy, cerebral edema, subdural empyema, cerebral abscess, meningitis, ventriculitis, transient parkinsonism, motor neuron disorders, ataxia, seizures, Guillain-Barr syndrome, psychosis Endocarditis, myocarditis, pericarditis, arteritis, congestive heart failure

Cardiovascular 15% system

Pulmonary system

16%

Pneumonia, empyema, bronchopleural fistula

ORGAN SYSTEM INVOLVED

PREVALENCE

RISK FACTORS infection, sickle cell anaemia, alcohol abuse, diabetes, HIV infection

COMPLICATIONS

Bone and joint

<1%

Sickle cell anaemia, diabetes, systemic lupus erythematosus, lymphoma, liver disease, previous surgery or trauma, those at extremes of age, and steroid use Residence in endemic region, pyogenic infections, intravenous drug use, splenic trauma, HIV, haemoglobinopathy Urinary tract, pelvic pathology, and systemic abnormalities

Osteomyelitis, septic arthritis

Hepatobiliary system

126%

Cholecystitis, hepatitis, hepatic abscesses, splenic abscess, peritonitis, paralytic ileus Urinary tract infection, renal abscess, pelvic infections, testicular abscess, prostatitis, epididymitis Psoas abscess, gluteal abscess, cutaneous vasculitis

Genitourinary system

<1%

Soft tissue infections

At least 17 cases Diabetes reported in the English-language literature

At least 5 cases Haemophagocytosis reported in the syndrome English-language literature From Huang DB, DuPont HL: Problem pathogens: Extra-intestinal complications of Salmonella enterica serotype Typhi infection. Lancet Infect Dis 2005;5:341348.

Haematologic

The propensity to become a carrier follows the epidemiology of gall bladder disease, increasing with age and antibiotic resistance of the prevalent strains. Although limited data are available, in general, rates of chronic carriage are lower in children than adults.
DIAGNOSIS.

The mainstay of the diagnosis of typhoid fever is a positive culture from the blood or another anatomic site. Results of blood cultures are positive in 4060% of the patients seen early in the course of the disease, and stool and urine cultures become positive after the 1st wk. The stool culture result is also occasionally positive during the incubation period. However, the sensitivity of blood cultures in diagnosing typhoid fever in many parts of the developing world is limited as widespread antibiotic prescribing may render bacteriologic confirmation

difficult. Although bone marrow cultures may increase the likelihood of bacteriologic confirmation of typhoid, these are difficult to obtain and relatively invasive. Other laboratory investigations are nonspecific. While blood leukocyte counts are frequently low in relation to the fever and toxicity, but there is a wide range in counts; in younger children leukocytosis is a common association and may reach 20,00025,000/mm3. Thrombocytopenia may be a marker of severe illness and accompany DIC. While liver function test results may be deranged, significant hepatic dysfunction is rare. The classic Widal test measures antibodies against O and H antigens of S. Typhi but lacks sensitivity and specificity in endemic areas. Because many false-positive and false-negative results occur, diagnosis of typhoid fever by Widal test alone is prone to error. Other relatively newer diagnostic tests using monoclonal antibodies have been developed that directly detect S. Typhispecific antigens in the serum or S. Typhi Vi antigen in the urine. However, few have proved sufficiently robust in large-scale evaluations. A nested PCR using H1-d primers has been used to amplify specific genes of S. Typhi in the blood of patients, and given the low level of bacteremia in enteric fever, is a promising means of making a rapid diagnosis. Despite these new developments, in much of the developing world the mainstay of diagnosis of typhoid remains clinical, and several diagnostic algorithms have been evaluated in endemic areas.
DIFFERENTIAL DIAGNOSIS.

In endemic areas, typhoid fever may mimic many common febrile illnesses without localizing signs. In children with multisystem features, the early stages of enteric fever may be confused with alternative conditions such as acute gastroenteritis, bronchitis, or bronchopneumonia. Subsequently, the differential diagnosis includes malaria; sepsis with other bacterial pathogens; infections caused by intracellular microorganisms, such as tuberculosis, brucellosis, tularemia, leptospirosis, and rickettsial diseases; and viral infections such as Dengue fever, acute hepatitis, and infectious mononucleosis.
TREATMENT.

An early diagnosis of typhoid fever and institution of appropriate treatment is essential. The vast majority of children with typhoid can be managed at home with oral antibiotics and close medical follow-up for complications or failure to respond to therapy. Patients with persistent vomiting, severe diarrhea, and abdominal distension may require hospitalization and parenteral antibiotic therapy. There are general principles of management of typhoid. Adequate rest, hydration, and attention are important to correct fluid-electrolyte imbalance. Antipyretic therapy (acetaminophen 120750 mg every 46 hr PO) should be provided as required. A soft, easily digestible diet should be continued unless the patient has abdominal distention or ileus. Antibiotic therapy is critical to minimize complications ( Table 195-7 ). It has been suggested that traditional therapy with either chloramphenicol or amoxicillin is associated with relapse rates of 515% and 48%, respectively, whereas the quinolones and 3rd generation cephalosporins are associated with higher cure rates. The antibiotic treatment of typhoid fever in children is also influenced by the prevalence of antimicrobial resistance. Over the past 2 decades, emergence of multidrug-resistant strains of S. Typhi (i.e., isolates fully resis tant to amoxicillin, trimethoprim-sulfamethoxazole, and chloramphenicol) has necessitated treatment

with fluoroquinolones, which are the antimicrobial drug of choice for treatment of salmonellosis in adults, or cephalosporins. The emergence of resistance to quinolones has placed tremendous pressure on public health systems, as therapeutic options are limited.

TABLE 195-7 -- Treatment of Typhoid Fever in Children ALTERNATIVE EFFECTIVE OPTIMAL THERAPY DRUGS SUSCEPTIBILIT Y Antibiotic Fully sensitive Daily Dose (mg/kg/day Day ) s Antibiotic Daily Dose (mg/kg/day Day ) s 5 7[*]

UNCOMPLICATED TYPHOID FEVER Chloramphenic 5075 ol 14 Fluoroquinolon 15 21 e, e.g., ofloxacin or ciprofloxacin 14 57 Azithromycin 7 14 7 10 14 14 Fluoroquinolon 15 e, e.g., ofloxacin or ciprofloxacin 10 14 Cefixime Cefixime 810 1520 20 7 7 14 7 14

Amoxicillin

75100

Multidrug resistant Fluoroquinolon 15 e or cefixime 1520 Quinolone resistant[] Azithromycin or 810 ceftriaxone 75 SEVERE TYPHOID FEVER Fully sensitive Ampicillin or ceftriaxone 100

6075 Multidrug resistant Fluoroquinolon 15 e Quinolone resistant Ceftriaxone 6075

10 14 10 Ceftriaxone or 14 cefotaxime 60 80 10 14

10 Fluoroquinolon 2030 14 14 e Modified from World Health Organization: Treatment of typhoid fever. Background document: the diagnosis, prevention and treatment of typhoid fever. Communicable Disease Surveillance and Response Vaccines and Biologicals: World Health Organization. Geneva, 2003. pp. 1923. [Available from URL: www.who.int/entity/vaccine_research/documents/en/typhoid_diagnosis.pdf ]
* A 3 day course is also effective, particularly for epidemic containment.

 The optimum treatment for quinolone-resistant typhoid fever has not been determined. Azithromycin, 3rd generation

cephalosporins, or high-dose fluoroquinolones for 1014 days are effective.

While it has been suggested that, like adults, children with typhoid should also be treated with fluoroquinolones, others have questioned this approach on the basis of the potential development of further resistance to fluoroquinolones and the fact that quinolones are still not approved for widespread use in children. A Cochrane review of the treatment of typhoid fever also indicates that there is little evidence to support the carte blanche administration of fluoroquinolones to all cases of typhoid. Relapse with all antibiotics may occur in 15% of previously treated patients. In addition to antibiotics, the importance of supportive treatment and maintenance of appropriate fluid and electrolyte balance must be underscored. Although additional treatment with dexamethasone (3 mg/kg for the initial dose, followed by 1 mg/kg every 6 hr for 48 hr) has been recommended among severely ill patients with shock, obtundation, stupor, or coma, this must only be done under strict controlled conditions and supervision, and signs of abdominal complications may be masked.
PROGNOSIS.

The prognosis for a patient with enteric fever depends on the rapidity of diagnosis and institution of appropriate antibiotic therapy. Other factors include the age of the patient, general state of health and nutrition, causative Salmonella serotype, and appearance of complications. Infants and children with underlying malnutrition and those infected with multidrug-resistant isolates are at higher risk for adverse outcomes. Despite appropriate therapy, 24% of infected children may relapse after initial clinical response to treatment. Individuals who excrete S. Typhi for 3 mo after infection are regarded as chronic carriers. However, the risk for becoming a carrier is low in children and increases with age, but in general is <2% for all infected children. Children with schistosomiasis can develop a chronic urinary carrier state.
PREVENTION.

Of the major risk factors for outbreaks of typhoid, contamination of water supplies with sewage is the most important. During outbreaks, therefore, a combination of central chlorination as well as domestic water purification are important. In endemic situations, consumption of street foods, especially ice cream and cut fruit has been recognized as an important risk factor. The human-to-human spread by chronic carriers is also important, and attempts should therefore be made to target food handlers and high-risk groups for S. Typhi carriage screening. Once identified, chronic carriers must be counseled as to the risk for disease transmission and given advice on handwashing and preventive strategies. The classic heat-inactivated whole cell vaccine is associated with an unacceptably high rate of side effects and has been largely withdrawn from public health use. Globally, 2 vaccines are currently available for potential use in children. An oral, live-attenuated preparation of the Ty21a strain of S. Typhi has been shown to have good efficacy (6782%) for up to 5 years. Significant adverse effects are rare. The Vi capsular polysaccharide can be used in people 2 yr of age. It is given as a single intramuscular dose, with a booster every 2 yr and has a

protective efficacy of 7080%. The vaccines are currently recommended for traveling into endemic areas, but a few countries have introduced large-scale vaccination strategies. Given the age spectrum and distribution of cases in south Asia, it is important that strategies for vaccinating preschool children be explored. The recent Vi-conjugate vaccine has been shown to have a protective efficacy exceeding 90% in younger children and may offer protection in parts of the world where a large proportion of preschool children are at risk for the disease. Email to Colleague Print Version Copyright 2008 Elsevier Inc. All rights reserved. - www.mdconsult.com