Salmonellosis is a common and widely distributed food-borne disease that is a global major public health problem affecting millions of individu- als and resulting in 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 sequencing of the Salmonella enterica serovar Typhi (previously called Salmonella typhi) and Salmonella typhimurium genomes indicates an almost 95% genetic homology between the organisms. However, the clinical diseases caused by the 2 organisms differ considerably. Orally ingested salmonellae survive at the low pH of the stomach and evade the multiple defenses of the small intestine so as to gain access to the epithelium. Salmonellae preferentially enter M cells, which transport them to the lymphoid cells (T and B) in the underlying Peyer patches.
Once across the epithelium, Salmonella serotypes that are associated with systemic illness enter intestinal macrophages and disseminate throughout the reticuloendothelial system (RES). By contrast, most nontyphoidal Salmonella (NTS) serovars induce an early local inflam- matory response, which results in the infiltration of polymorphonuclear leukocytes (PMNs) into the intestinal lumen and diarrhea. These NTS serovars cause a gastroenteritis of rapid onset and brief duration, in contrast to typhoid fever, which has a considerably longer incubation period and duration of illness and in which systemic illness predominates and only a small proportion of children have diarrhea.
These differences in the manifestations of infection by the 2 groups of pathogens, one predominantly causing intestinal inflammation and the other leading to systemic disease, may be related to specific genetic pathogenicity islands in the organisms. Most NTS serovars seem unable to overcome defense mechanisms that limit bacterial dissemination from the intestine to systemic circulation in immunocompetent individuals
and produce a self-limiting gastroenteritis. In contrast, S. typhi and S. paratyphi (i.e., typhoidal strains of Salmonella) may possess unique virulence traits that allow them to overcome mucosal barrier func- tions in immunocompetent hosts, and cause severe systemic illness.
Interestingly, the frequencies of typhoid fever in immunocompetent and immunocompromised individuals do not differ. Intriguingly, some invasive NTS strains have been noted in Africa, particularly among HIV- positive adults and among children with HIV, malaria, or malnutrition (see Chapter 225.1). The presentation may resemble typhoid fever more than gastroenteritis.
From a taxonomic, Linnaean, perspective, the genus Salmonella belongs to the family Enterobacteriaceae. Two Salmonella spp. exist: Salmonella enterica and Salmonella bongori. The medically relevant species is Salmonella enterica, which is further divided into serotypes and often named based on presumed syndromes they cause or where they were discovered geographically.
From a medical perspective, among the salmonellae causing human disease, serotypes are also clinically grouped as either being typhoidal or nontyphoidal. There are only a few typhoidal Salmonella serotypes, including Salmonella enterica var. Typhi, also known as S. Typhi, and Salmonella enterica var. Paratyphi A. By contrast, there are 1000s of nontyphoidal Salmonella serotypes, collectively called NTS serotypes.
NTS serotypes have a broad host range, whereas S. Typhi and S. Paratyphi A are restricted to human hosts.
225.1 Nontyphoidal Salmonellosis
Jeffrey S. McKinney 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 54.4°C (130°F) for 1 hr or 60°C (140°F) 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. As with 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 one or a few animal species, such as Salmonella 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 Salmonella Enteritidis (Salmonella enterica var. Enteritidis) and Salmonella Typhimurium (S. enterica var. Typhimurium), the 2 most important serotypes for salmonellosis transmitted from animals to humans. Nontyphoidal salmonellae have emerged as a major cause of bacteremia in Africa, especially among populations with a high incidence of HIV infection.
EPIDEMIOLOGY
Salmonellosis constitutes a major public health burden and represents a significant cost to society in many countries. Typhoid fever caused by this organism is a global problem, with >27 million cases worldwide each year, culminating in an estimated 217,000 deaths. Although there is little information on the epidemiology and the burden of Salmonella gastroenteritis in developing countries, Salmonella infections are rec- ognized as major causes of childhood diarrheal illness. With the burden of HIV infections and malnutrition in Africa, NTS bacteremic infections have emerged as a major cause of morbidity and mortality among children and adults.
NTS 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.
Infections with NTS serovars such as S. Typhimurium and S. Enteritidis
Chapter 225
Salmonella
Jeffrey S. McKinney
Keywords
antibacterial resistance bacteria-host interaction bacteremia
effector enteric fever gastroenteritis intracellular bacteria nontyphoidal Salmonella NTSpathogenicity island S. Enteritidis S. Paratyphi A S. Typhi S. Typhimurium Salmonella carriage Salmonella enterica Salmonella typhimurium Salmonella typhi Salmonella paratyphi salmonellosis serovar typhoid typhoid fever virulence
In addition to the effect of antibiotic use in animal feeds, the relation- ship 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, which predispose them to colonization and infection with antibiotic-resistant Salmonella isolates. These resistant strains of Salmonella can also be more virulent.
The Centers for Disease Control and Prevention (CDC) reports resistance to ceftriaxone in approximately 3% of NTS tested and some level of resistance to ciprofloxacin in 3% of isolates. Approximately 5% of NTS tested by the CDC are resistant to 5 or more types of drugs. Consequently, costs are also expected to be higher for resistant than for susceptible infections because of the severity of the former. These patients are more likely to be hospitalized, and treatment is rendered less effective. The CDC is seeing some level of resistance to ciprofloxacin in two thirds of S. Typhi tested. Resistance to ceftriaxone or azithromycin has been seen in other parts of the world. Variation in resistance among different strains makes Salmonella microbiologic culture and antibacterial susceptibil- ity testing very important.
Given the ubiquitous nature of the organism, nosocomial infections with NTS strains can also occur through contaminated equipment and diagnostic or pharmacologic preparations, particularly those of animal origin (pancreatic extracts, pituitary extracts, bile salts, rattlesnake tail).
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 106-108 Salmonella organisms.
The gastric acidity inhibits multiplication of salmonellae, and most organisms are rapidly killed at gastric pH ≤2.0. Achlorhydria, buffering medications, rapid gastric emptying after gastrectomy or gastroenter- ostomy, 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 required to produce disease is also comparatively smaller because of faster transit through the stomach.
Once they reach the small and large intestines, the ability of Salmonella organisms to multiply and cause infection depends on both the infecting dose and 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 NTS infection is an enterocolitis with diffuse mucosal inflammation and edema, sometimes with erosions and microabscesses. Salmonella organ- isms are capable of penetrating the intestinal mucosa, although destruc- tion of epithelial cells and ulcers are usually not found. Intestinal inflammation with PMNs and macrophages usually involves the lamina propria. Underlying intestinal lymphoid tissue and mesenteric lymph nodes enlarge and may demonstrate small areas of necrosis. Such lymphoid hypertrophy may cause interference with the blood supply to the gut mucosa. Hyperplasia of the RES is also found within the liver and spleen. If bacteremia develops, it may lead to localized infection and suppuration in almost any organ.
Both S. Typhi and NTS possess overlapping and distinct virulence systems (Fig. 225.1). 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. Intestinal infection also induces secretion of interleukin (IL)-8 from the basolateral surface and other chemoattractants from the apical surface, directing recruitment and transmigration of neutrophils into the gut lumen and thus preventing the systemic spread of the bacteria (Fig. 225.2).
Central to S. Typhimurium pathogenesis are 2 type III secretion systems encoded within the pathogenicity islands SPI-1 and SPI-2, which are responsible for the secretion and translocation of a set of bacterial proteins termed effectors into host cells; effectors are able to alter host cell physiology to facilitate bacterial entry and survival. Once delivered by the type III secretion systems, the secreted effectors play cause a significant disease burden, with an estimated 93.8 million cases
worldwide and 155,000 deaths each year. Traditionally, Salmonella gastroenteritis accounts for more than half of all episodes of bacterial diarrhea in the United States, with incidence peaks at the extremes of ages, among young infants and elderly persons. Most human infections have been caused by S. Enteritidis; with S. Typhimurium incidence overtaking it in some countries. Recently, however, a surveillance program testing human stool specimens from 10 U.S. sites showed a relative decline in the incidence of S. Typhimurium vs other salmonellae, perhaps related to the use of a live-attenuated S. Typhimurium vaccine in poultry and more stringent performance standards for Salmonella contamination of poultry carcasses.
Salmonella infections in many parts of the world 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 the use of antimicrobials in food animals. Poultry products were traditionally regarded as a common source of salmonellosis, but consumption of a range of foods is now also associated with outbreaks, including fruits and vegetables, and factory-processed foods such as peanut butter or cookies. It appears that some multidrug-resistant (MDR) strains of Salmonella are also more virulent than susceptible strains, and that poorer outcome does not simply relate to the delay in treatment response because of empirical choice of an ineffective antibiotic.
Strains of MDR Salmonella, such as S. Typhimurium phage type DT104, harbor a genomic island that contains many of the drug-resistance genes. These integrons also contain genes that encode virulence factors.
Several risk factors are associated with outbreaks of Salmonella infections. Animals constitute the principal source of human NTS disease, with cases occurring in individuals who have had contact with infected animals, including domestic animals such as cats, dogs, reptiles, pet rodents, and amphibians; high-risk pets include turtles, iguanas, bearded dragons, lizards, various snakes, salamanders, and geckos. Specific serotypes may be associated with particular animal hosts; children with S. enterica var. Marina typically have exposure to pet lizards. NTS serovars usually cause self-limiting diarrhea, with secondary bacteremia occurring in <10% of patients. The NTS serovars have a broad host range, including poultry and cattle, and NTS infection is usually from food poisoning in developed countries.
Domestic animals probably acquire the infection in the same way that humans do, through oral ingestion. Animal feeds 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 with the use of this group of antimicrobials in animal feeds. Animal- to-animal transmission can occur, with most infected animals being asymptomatic.
Although almost 80% of Salmonella infections are discrete, outbreaks can pose an inordinate burden on public health systems. During 1998–2008, a total of 1,491 outbreaks of Salmonella infections were reported to the Foodborne Disease Outbreak Surveillance System, and 80% of these were caused by a single serotype. Of the single-serotype outbreaks, 50% had an implicated food, and 34% could be assigned to a single food commodity. Of the 47 serotypes reported, the 4 most common, causing more than two thirds of the outbreaks, were Enteritidis, Typhimurium, Newport, and Heidelberg. Overall, eggs were the most frequently implicated food, followed by chicken, pork, beef, fruit, and turkey. Salmonella infections in chickens increase the risk for contamina- tion of eggs, and both poultry and eggs are regarded as a dominant cause of common-source outbreaks. However, a growing proportion of Salmonella outbreaks are also associated with other food sources.
The food sources include many fruits and vegetables, such as tomatoes, sprouts, watermelon, cantaloupe, lettuce, and mangoes. Geographically distributed infections are increasingly possible from foods (e.g., peanut butter) processed at a “point source” and then broadly distributed.
Contemporary surveillance and reporting networks (e.g., ProMED, FoodNet) may help alert physicians and microbiologists to such events.
Fig. 225.1 Overlapping and distinct virulence systems in Salmonella typhi and nontyphoidal Salmonella. (From de Jong HK, Parry CM, van der Poll T, Wiersinga WJ. Host-pathogen interaction in invasive Salmonellosis. PLoSPathog 2012;8(10):e1002933.)
Membrane ruffle Tight
junction Salmonella
spp.
Actin
Epithelial cell
SopESopE2 SopB
Rho GTPases
SipASipC
MAPK MAPK
SopB SopA
Cl– Cl– NF-BAP-1
NF-B
IL-8
PMN SipB
Macrophage IL-1IL-18
SspH1 AvrA Rho GTPases SptP
Fig. 225.2 On contact with the epithelial cell, salmonellae assemble the Salmonella pathogenicity island 1–encoded type III secretion system (TTSS-1) and translocate effectors (yellow spheres) into the eukaryotic cytoplasm. Effectors such as SopE, SopE2, and SopB then activate host Rho guanosine triphosphatase (GTPase), resulting in the rearrangement of the actin cytoskeleton into membrane ruffles, induction of mitogen-activated protein kinase (MAPK) pathways, and destabilization of tight junctions. Changes in the actin cytoskeleton, which are further modulated by the actin-binding proteins SipA and SipC, lead to bacterial uptake. MAPK signaling activates the transcription factors activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which turn on production of the proinflammatory polymorphonuclear leukocyte (PMN) chemokine interleukin (IL)-8. SipB induces caspase-1 activation in macrophages, with the release of IL-1β and IL-18, augmenting the inflammatory response. In addition, SopB stimulates Cl− secretion by its inositol phosphatase activity. The destabilization of tight junctions allows the transmigration of PMNs from the basolateral to the apical surface, paracellular fluid leakage, and access of bacteria to the basolateral surface. However, the transmigration of PMNs also occurs in the absence of tight-junction disruption and is further promoted by SopA. The actin cytoskeleton is restored, and MAPK signaling is turned off by the enzymatic activities of SptP. This also results in the downmodulation of inflammatory responses, to which SspH1 and AvrA also contribute by inhibiting activation of NF-κB. (From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells, Nat Rev Microbiol 6:53–66, 2008.)
death in vitro, which depends on the host cell protein caspase-1 and is mediated by the effector protein SipB (Salmonella invasion protein B). Intracellular S. Typhimurium is found within specialized 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 proinflammatory response to S. Typhimurium infection and the subsequent recruit- ment 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 strains recovered from stool. Although 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 225.1); of these factors, HIV infections are assuming greater importance in Africa in all age-groups.
Bacteremia 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 critical roles in manipulating the host cell to allow bacterial invasion,
induction of inflammatory responses, and assembly of an intracellular protective niche conducive to bacterial survival and replication. The type III secretion system encoded on SPI-1 mediates invasion of the intestinal epithelium, whereas the type III secretion system encoded on SPI-2 is required for survival within macrophages. In addition, the expression of strong agonists of innate pattern recognition receptors (lipopolysaccharide and flagellin) is important for triggering a Toll-like receptor (TLR)–mediated inflammatory response.
Salmonella spp. invade epithelial cells in vitro by a process of bacteria- mediated endocytosis involving cytoskeletal rearrangement, disruption of the epithelial cell brush-border, and subsequent formation of membrane ruffles (Fig. 225.3). 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 SPI-1, a 40-kb region that encodes regulator proteins such as HilA and a variety of other products.
Shortly following invasion of the gut epithelium, invasive Salmonella organisms encounter macrophages within the gut-associated lymphoid tissue (GALT). 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, chemokines, IL-1β), receptors or adhesion molecules (tumor necrosis factor [TNF]-α receptor, CD40, intercellular adhesion molecule 1), and antiinflammatory mediators (transforming growth factor-β1, TGF-β2). Other upregulated genes include those involved in cell death or apoptosis (intestinal epithelial cell protease, TNF-R1, Fas) and transcription factors (early growth response 1, interferon [IFN]
regulatory factor 1). S. Typhimurium can induce rapid macrophage
SifA PipB2
SCV
Salmonella spp.
Actin Epithelial cell
Spacious phagosome
Sif SseJ
SseF SseG Nucleus
Golgi
Microtubules
Secretory vesicles SspH2
SpvB Ssel
Microtubule motors
Fig. 225.3 Formation of the Salmonella-containing vacuole (SCV) and induction of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system (TTSS) within the host cell. Shortly after internalization by macropinocytosis, salmonellae are enclosed in a spacious phagosome that is formed by membrane ruffles. Later, the phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium, and is called the SCV. It contains the endocytic marker lysosomal-associated membrane protein 1 (LAMP-1; purple). The Salmonella SPI-2 is induced within the SCV and translocates effector proteins (yellow spheres) across the phagosomal membrane several hours after phagocytosis. The SPI-2 effectors SifA and PipB2 contribute to formation of Salmonella-induced filament along microtubules (green) and regulate microtubule motor (yellow star shape) accumulation on the Sif and the SCV. SseJ is a deacylase that is active on the phagosome membrane. SseF and SseG cause microtubule bundling adjacent to the SCV and direct Golgi-derived vesicle traffic toward the SCV. Actin accumulates around the SCV in an SPI-2–dependent manner, in which SspH2, SpvB, and SseI are thought to have a role. (From Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells, Nat Rev Microbiol 6:53–66, 2008.)
infection focus (perhaps from co-infection or comorbidity). Fever is present in 95% of cases but may have no apparent focus. Fig. 225.4 summarizes other clinical features. Importantly, the lack of specificity of these clinical features severely compromises the ability of current clinical algorithms to identify invasive NTS infections. Accordingly, blood culture and clinical microbiology systems for bacterial growth, isolation, speciation, and antibacterial drug sensitivity testing are required for diagnosis and well-informed treatment decision-making. Among NTS isolates causing invasive systemic disease, the serotypes S.
Typhimurium and S. Enteritidis have been frequently reported, but several other serotypes can cause invasive disease as well.
It remains unclear exactly why invasive infections by NTS seem so much more frequent in Africa, compared with the dominance of typhoidal Salmonellae in Asia. HIV infection is one identified host risk factor for NTS infection. Indeed, recurrent NTS infection was part of early CDC case definitions for the AIDS. However, only 20% of African children with NTS disease are HIV positive. Other risks for pediatric NTS may include recent or severe malaria infections, sickle cell anemia, active schistosomiasis, and malnutrition.
The epidemiologic patterns thus far appreciated for invasive infections by NTS in Africa suggest epidemics may occur over several years, peaking in the rainy season. However, it remains unclear as to the extent that invasive NTS infections are related to human diarrheal disease or GI carriage. Likewise, obvious food or animal sources of invasive NTS in humans have not been conclusively identified, and the relative role(s) of zoonotic and/or anthroponotic transmission is uncertain. Thus, optimal strategies for interrupting transmission of invasive NTS infections remain unclear. This is particularly problematic, given the emergence of antibacterial drug resistance that has also been noted among NTS organisms, including the multidrug-resistant strain referred to as (DNA multilocus “sequence type”) ST313.
For invasive NTS infections in Africa, resistance to ampicillin, chloramphenicol, and co-trimoxazole may force increasing reliance on more expensive treatment options. Depending on local resistance patterns, drug availability, and patient state, empirical treatments may require third-generation cephalosporins (e.g., ceftriaxone), fluoroquinolones (e.g., ciprofloxacin), or macrolide/azalides (e.g., azithromycin). Of note, while Salmonella strains may be killed in culture in vitro by aminogly- cosides, this drug class is not appropriate for treatment of invasive salmonellae, because aminoglycosides are not able to penetrate the intracellular niches in hosts that salmonellae so effectively exploit as part of their life cycle.
Nontyphoidal Salmonella Bacteremia in Other Geographic Regions
The emergence of invasive, high-mortality NTS infections in sub-Saharan Africa suggests that historical clinical divisions of Salmonella infections 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 are HIV-negative.
Children with Schistosoma mansoni infection and hepatosplenic involve- ment, as well as chronic malarial anemia, are also at a greater risk for development of chronic salmonellosis. Children with sickle cell disease are at increased risk for Salmonella septicemia and osteomyelitis. This risk may be related to the presence of numerous infarcted areas in the gastrointestinal (GI) tract, bones, and RES, as well as reduced phagocytic and opsonizing capacity of patients.
CLINICAL MANIFESTATIONS Acute Enteritis
The most common clinical presentation of salmonellosis is acute enteritis.
After an incubation period of 6-72 hr (mean: 24 hr), there is an abrupt onset of nausea, vomiting, and crampy abdominal pain, located 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 with acute enteritis are febrile, although younger infants may exhibit a normal or subnormal temperature.
Symptoms usually subside within 2-7 days in healthy children, and fatalities are rare. However, some children experience severe disease with a septicemia-like picture (high fever, headache, drowsiness, confu- sion, meningismus, seizures, abdominal distention). The stool typically contains a moderate number of PMNs 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 1–5% of children with Salmonella diarrhea. Bacteremia can occur with minimal associated symptoms in newborns and very young infants, but 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 result for Salmonella and sometimes with no identifiable focus of infec- tion. NTS GI infections typically cause bacteremia in developing countries.
Nontyphoidal Salmonella Bacteremia as Emerging Disease in Africa
In Africa, particularly sub-Saharan, NTS has been increasingly appreci- ated as among the most common causes of all bacteremia cases in febrile adults and children. Bacteremia from NTS in Africa has had an accompanying case fatality rate of 20–25%. Notably, children age 6-36 mo and adults age 30-50 yr are at greatest risk.
Clinical features among children with invasive NTS infections can be confusing, in that diarrhea is often not a prominent feature. Fur- thermore, 60% of children have an apparent lower respiratory tract
Neonates and young infants (≤3 mo old) HIV/AIDS
Other immunodeficiencies and chronic granulomatous disease Defects in interferon γ production or action
Immunosuppressive and corticosteroid therapies Malignancies, especially leukemia and lymphoma
Hemolytic anemia, including sickle cell disease, malaria, and bartonellosis
Collagen vascular disease Inflammatory bowel disease
Achlorhydria or use of antacid medications Impaired intestinal motility
Schistosomiasis, malaria Malnutrition
Table 225.1 Host Factors and Conditions Predisposing to Development of Systemic Disease with Nontyphoidal Salmonella (NTS) Strains
Fever: 95% of cases, no
apparent focus in 35% Blood tests: Severe anemia in 40–50%
of adults and 25–40% of children, 95% of adults and 20% of children are HIV positive, CD4 count <200 cells per µL in 80% of adults
Splenomegaly: 30–45% of cases
Hepatomegaly: 15–35% of cases Diarrhea: 20–50% of cases, but
often not a prominent feature Pneumonia: 60% of children and 30% of adults have an apparent lower respiratory tract infection focus, commonly due to co-infection
Fig. 225.4 Clinical features of invasive nontyphoidal Salmonella (NTS) disease in adults and children in Africa. (From Feasey NA, Dougan G, Kingsley RA, et al: Invasive non-typhoidal Salmonella disease: an emerging and neglected tropical disease in Africa, Lancet 379: 2489–2499, 2012.)
presentation and culture of and subsequent identification of Salmonella organisms from feces or other body fluids. In children with gastroenteritis, stool cultures have higher yields than rectal swabs. In children with NTS gastroenteritis, prolonged fever lasting ≥5 days and young age should be recognized as 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, and nutrient broth, but stool specimens containing mixed bacterial flora require a selective medium, such as MacConkey, xylose-lysine- deoxycholate, bismuth sulfite, or Salmonella-Shigella (SS) agar for isolation of Salmonella.
Culture-independent diagnostic tests have some utility for screening or epidemiologic studies, but without susceptibility results, these tests do not show which drugs will be effective for any given patient.
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. Antibiotics are not generally recommended for the treatment of isolated uncomplicated Salmonella gastroenteritis, because they may disrupt normal intestinal flora and prolong the excretion of Salmonella and increase the risk for creating a chronic carrier state. However, given the risk for bacteremia in young infants (<3 mo old) and the risk of disseminated infection in high-risk groups with immune compromise (HIV, malignancies, immunosuppressive therapy, sickle cell anemia, immunodeficiency states), these children must receive an appropriate empirically chosen antibiotic until culture results are available (Table 225.2). The S. Typhimurium phage type DT104 strain is usually resistant to the following 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.
PROGNOSIS
Most healthy children with Salmonella gastroenteritis recover fully.
However, malnourished children and children who do not receive optimal supportive treatment are at risk for development of 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.
into typhoidal and nontyphoidal may become problematic oversimplifica- tion. Currently, however, in settings outside sub-Saharan Africa, NTS infections still tend to be self-limiting and noninvasive and are low- mortality events for most children who are immunocompetent. Risk factors for systemic spread of NTS include HIV infection, diabetes, sickle cell disease, systemic corticosteroid use, malignancy, chronic liver or kidney disease, chronic granulomatous disease, B-cell deficiencies, and dysfunction of proinflammatory cytokine pathways. Neonates and infants are also at particular risk for disseminated infection and thus warrant more aggressive evaluation and treatment.
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, intravascular sites, and sites of preexisting abnormalities. The peak incidence of Salmonella meningitis is in infancy, and the infection may be associated with a florid clinical course, high mortality, and neurologic sequelae in survivors.
Chronic Salmonella Carriage
While traditionally viewed primarily as a complication of Salmonella infection among adults, Salmonella chronic carriage has important medical and epidemiologic implications, and may occur in children.
Colonization of the gallbladder by Salmonella typhi has long been appreciated, but reports suggest that some nontyphoidal Salmonella (e.g., invasive NTS currently in Africa) can also establish long-term asymptomatic carriage states.
Antibacterial treatments of Salmonella infections are paradoxical, in that the prospect of becoming a chronic carrier is believed to be increased by exposure to antibacterial agents. Yet, clearance of established chronic carrier status requires prolonged medical treatment using antibacterial agents to which the relevant Salmonella strain is susceptible and sometimes requires gallstone or gallbladder removal. Chronic carriers of Salmonella may only have intermittently positive stool cultures and are often asymptomatic, which makes approaches to diagnosis and treatment especially complex.
COMPLICATIONS
Salmonella gastroenteritis can be associated with acute dehydration and complications that result 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, including causing osteomyelitis in children, particularly among children with sickle cell disease. Reactive arthritis may follow Salmonella gastroenteritis, especially in adolescents with the 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 old, and children with primary or secondary immunodeficiency may have symptoms that persist for several weeks.
The course of illness and complications may also be affected by coexisting pathologies. In children with AIDS, Salmonella infection frequently becomes widespread and overwhelming, causing multisystem involve- ment, septic shock, and death. In patients with inflammatory bowel disease, especially active ulcerative colitis, Salmonella gastroenteritis may lead to 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 RES dysfunc- tion, which can be associated with underlying problems such as hemolytic anemia or malaria.
DIAGNOSIS
Few clinical features are specific to Salmonella gastroenteritis to allow differentiation from other bacterial causes of diarrhea. Definitive diagnosis of Salmonella infection is based on clinical correlation of the
ORGANISM AND INDICATION
Salmonella infections in infants <3 mo old or in
immunocompromised persons (in addition to appropriate treatment for underlying disorder)
DOSE AND DURATION OF TREATMENT
Cefotaxime,† 100-200 mg/kg/day every 6-8 hr for 5-14 days*
orCeftriaxone, 75 mg/kg/day once daily for 7 days*
orAmpicillin, 100 mg/kg/day every 6-8 hr for 7 days*
orCefixime, 15 mg/kg/day for 7-10 days*
*A blood culture should be obtained prior to antibiotic therapy. In a well appearing immunocompetent child without evidence of disseminated disease, a single dose of ceftriaxone may be given followed by oral azithromycin;
ampicillin, trimethoprim-sulfamethoxazole, or a fluoroquinolone may be substituted once sensitivities are known.
†If available.
Table 225.2 Treatment of Salmonella Gastroenteritis
225.2 Enteric Fever (Typhoid Fever)
Jeffrey S. McKinney
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 S. enterica serovar Typhi (S. Typhi), a gram- negative bacterium. A very similar but often less severe disease is caused by Salmonella 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 approximately 10 : 1, although the proportion of S. Paratyphi A infections is increasing in some parts of the world, for reasons that are unclear. Although S. Typhi shares many genes with Escherichia coli and at least 95% of genes with S.
Typhimurium, several unique gene clusters known as pathogenicity islands and other genes 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.
EPIDEMIOLOGY
It is estimated that >26.9 million typhoid fever cases occur annually, of which 1% result in death. The vast majority of this disease burden is witnessed in Asia. Additionally, an estimated 5.4 million cases caused by paratyphoid occur each year. In 2010, 13.5 million cases of typhoid fever were recorded, and both typhoid and paratyphoid fevers together accounted for >12 million disability-adjusted life-years. The mortality caused by typhoid fever in the same year was found to be 7.2 per 100,000 population for sub-Saharan Africa. Given the paucity of microbiologic facilities in developing countries, these figures may be more representative of the clinical syndrome rather than of culture-proven disease. In most developed countries, the incidence of typhoid fever is <15 cases per 100,000 population, with most cases occurring in travelers. In contrast, the incidence may vary considerably in the developing world, with estimated rates ranging from 100-1,000 cases per 100,000 population.
There are significant differences in the age distribution and population at risk. Population-based studies from South Asia also indicate that the age-specific incidence of typhoid fever may be highest in children <5 yr old, in association with comparatively higher rates of complications and hospitalization.
Typhoid fever is notable for the emergence of drug resistance. Following sporadic outbreaks of chloramphenicol-resistant S. Typhi infections, many strains of S. Typhi have developed plasmid-mediated multidrug resistance to all 3 of the primary antimicrobials: ampicillin, chloram- phenicol, and trimethoprim-sulfamethoxazole. There is also a consider- able increase in nalidixic acid–resistant and even ceftriaxone-resistant isolates of S. Typhi, as well as the emergence of fluoroquinolone-resistant isolates. Nalidixic acid–resistant isolates first emerged in Southeast Asia and India and now account for the majority of travel-associated cases of typhoid fever in the United States. Given the ongoing global movement of resistant S. Typhi, an international awareness of resistance patterns is needed for effective patient care.
S. Typhi is highly adapted to infection of humans 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 sug- gests that the genome of this pathogen has undergone degeneration to facilitate a specialized association with the human host. 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 as a consequence of poor sanitation or contamination have been described in developing countries. In other parts of the world, oysters and other shellfish cultivated in water contaminated by sewage and the use of night soil as fertilizer may also cause infection.
After infection, NTS are excreted in feces for a median of 5 wk. A prolonged carrier state after nontyphoidal salmonellosis is rare but may be seen in children, particularly those with biliary tract disease and cholelithiasis after chronic hemolysis. 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 anti- biotics 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. Because large outbreaks are often related to mass food production, it should be rec- ognized that contamination of just one 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 are critical to reducing person-to-person transmission. Salmonella may remain viable when cooking practices prevent food from reaching a temperature >65.5°C (150°F) for >12 min.
Parents should be advised of the risk of various pets(classically including reptiles and amphibians but also rodents) and be given recommenda- tions for preventing transmission from these frequently infected hosts (Table 225.3).
In contrast to the situation in developed countries, relatively little is known about the transmission of NTS infections in developing countries, and person-to-person transmission may be relatively more important in some settings. Although some vaccines have been used in animals, no human vaccine against NTS 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.
Bibliography is available at Expert Consult.
Pet store owners, healthcare 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 <5 yr old, 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 <5 yr old 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 childcare centers.
Persons should always 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, 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 Centers for Disease Control and Prevention: Reptile-associated salmonellosis—selected states, 1998–2002, MMWR 52:1206–1210, 2003.
Table 225.3 Recommendations for Preventing Transmission of Salmonella from Reptiles and Amphibians to Humans
Bibliography
Bottichio L, Webb LM, Leos G, et al: Salmonella oranienburg infection linked to consumption of rattlesnake pills—Kansas and Texas, 2017, MMWR Morb Mortal Wkly Rep 67(17):502–503, 2018.
Centers for Disease Control and Prevention: Reptile-associated salmonellosis—selected states, 1998–2002, MMWR Morb Mortal Wkly Rep 52:1206–1210, 2003.
Centers for Disease Control and Prevention: Notes from the field: update on human Salmonella typhimurium infections associated with aquatic frogs—United States, 2009–2011, MMWR Morb Mortal Wkly Rep 60:628, 2011.
Coburn B, Grassl GA, Finlay BB: Salmonella, the host and disease: a brief review, Immunol Cell Biol 85:112–118, 2007.
Crump JA, Mintz ED: Global trends in typhoid and paratyphoid fever, Clin Infect Dis 50:241–246, 2010.
Feasey NA, Dougan G, Kingsley RA, et al: Invasive non-typhoidal salmonella disease:
an emerging and neglected tropical disease in Africa, Lancet 379:2489–2499, 2012.
Gunn JS, Marshall JM, Baker S, et al: Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence, Trends Microbiol 22(11):648–655, 2014.
Hanning IB, Nutt JD, Ricke SC: Salmonellosis outbreaks in the United States due to fresh produce: sources and potential intervention measures, Foodborne Pathog Dis 6:635–648, 2009.
Haraga A, Ohlson MB, Miller SI: Salmonellae interplay with host cells, Nat Rev Microbiol 6:53–66, 2008.
Jackson BR, Griffin PM, Cole D, et al: Outbreak associated Salmonella enterica serotypes and food commodities 1998–2008, United States, Emerg Infect Dis 19:1239–1244, 2013.
Onwuezobe IA, Oshun PO, Odigwe CC: Antimicrobials for treating symptomatic non- typhoidal Salmonella infection, Cochrane Database Syst Rev (11):CD001167, 2012.
Su CP, de Perio MA, Fagan K, et al: Occupational distribution of campylobacteriosis and salmonellosis cases—Maryland, Ohio, and Virginia, 2014, MMWR Morb Mortal Wkly Rep 66(32):850–853, 2017.
containing vacuole. A 2nd type III secretion system encoded on SPI-2 is induced within the Salmonella-containing vacuole and translocates effector proteins SifA and PipB2, which contribute to Salmonella-induced filament formation along microtubules.
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 asymptomatic, and blood culture results are frequently negative at this stage of the disease. The bloodborne bacteria are disseminated throughout the body and are thought to colonize the organs of the RES, 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 that coincides with the onset of clinical symptoms and marks the end of the incubation period (Fig. 225.5).
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, perhaps by avoiding the triggering of an early inflammatory response in the gut, S. Typhi can 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. The resulting 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 perfora- tion. The mesenteric lymph nodes, liver, and spleen are hyperemic and generally have 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 than in older children and adults.
Several virulence factors, including the type III secretion system encoded on SPI-2, may be necessary for the virulence properties and ability to cause systemic infection. The surface Vi (virulence) polysac- charide 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 and may PATHOGENESIS
Enteric fever occurs through 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 105-109 organisms, with an incubation period ranging from 4-14 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 GALT, 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. In contrast to NTS, S. Typhi expresses virulence factors that allow it to downregulate the pathogen recognition receptor–
mediated host inflammatory response. Within the Peyer patches in the terminal ileum, S. Typhi can traverse the intestinal barrier through several mechanisms, including the M cells in the follicle-associated epithelium, epithelial cells, and dendritic cells. At the villi, Salmonella can enter through the M cells or by passage through or between compromised epithelial cells.
On contact with the epithelial cell, S. Typhi assembles type III secretion system encoded on SPI-1 and translocates effectors into the cytoplasm.
These effectors activate host Rho guanosine triphosphatases, resulting in the rearrangement of the actin cytoskeleton into membrane ruffles, induction of mitogen-activated protein kinase (MAPK) pathways, and destabilization of tight junctions. Changes in the actin cytoskeleton are further modulated by the actin-binding proteins SipA and SipC and lead to bacterial uptake. MAPK signaling activates the transcription factors activator protein (AP)-1 and nuclear factor (NF)-κB, which turn on production of IL-8. The destabilization of tight junctions allows the transmigration of PMNs from the basolateral surface to the apical surface, paracellular fluid leakage, and access of bacteria to the basolateral surface.
Shortly after internalization of S. Typhi by macropinocytosis, salmonellae are enclosed in a spacious phagosome formed by membrane ruffles.
Later, the phagosome fuses with lysosomes, acidifies, and shrinks to become adherent around the bacterium, forming the Salmonella-
Salmonella typhi M cell Enterocytes lining
terminal ileum
Peyer patch and resident macrophage
Mesenteric lymph nodes
Primary bacteremia
Seeding of RES:
liver, spleen, gall bladder, bone marrow
Secondary bacteremia Peyer patches
re-exposed to S. typhi via bile
Widespread dissemination Pathogenesis of typhoid fever
Fig. 225.5 Pathogenesis of typhoid fever. RES, Reticuloendothelial system. (Adapted from Richens J: Typhoid fever. In Cohen J, Powderly WG, Opal SM, editors: Infectious diseases, ed 2, London, 2004, Mosby, pp 1561–1566.)
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 and dengue fever. In approximately 25% of cases, a macular or maculopapular rash (“rose spots”) may be visible around the 7th-10th day of the illness, and lesions may appear in crops of 10-15 on the lower chest and abdomen and last 2-3 days (Fig. 225.6). These lesions may be difficult to see in dark-skinned children. Patients managed as outpatients present with fever (99%) but have less emesis, diarrhea, hepatomegaly, splenomegaly, and myalgias than patients who require hospital admission.
The presentation of typhoid fever may be modified by coexisting morbidities and early diagnosis and 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 (MDR) 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 greater virulence as well as higher numbers of circulating bacteria. The emergence of typhoid infections resistant to nalidixic acid and fluoroquinolones is associated with higher rates of morbidity and treatment failure. These findings may have implications for treatment algorithms, especially in endemic areas with high rates of MDR and nalidixic acid– or fluoroquinolone- resistant typhoid.
If no complications occur, the symptoms and physical findings gradually resolve within 2-4 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, there have been several outbreaks of infection with drug-resistant S. Paratyphi A, suggesting 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 (0.5–1%) are infrequent among children. Intestinal perforation may be preceded by a marked increase in abdominal pain (usually in the right lower quadrant), 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 proinflammatory cytokines (IL-6, IL-1β, and TNF-α) from the infected cells.
Characterization of a toxin, referred to as the typhoid toxin, represents a major advance in understanding Salmonella biology; with implications for longstanding observations about typhoidal vs nontyphoidal disease features, and the human host restriction of typhoidal infections. Although the exact role of typhoid toxin in disease pathophysiology is still being elucidated, the enzymatically active subunits of typhoid toxin are CdtB and PltA, which are, respectively, a cytothelial distending toxin (a DNase that causes double-stranded breaks in host cell DNA) and a pertussis-like toxin (with ADP-ribosyltransferase activity). These 2 active “A” subunits form a unique A2B5 architecture with a heptomeric set of PltB “B”
subunits. The trafficking of the A2B5 typhoid toxin uses an elegant autocrine/paracrine delivery mechanism, which passes through the Salmonella-containing vesicle environment, where it is dependent on effectors released by the Salmonella pathogenicity island 2–encoded type III secretion system. After assembly in this host intracellular niche so characteristic of Salmonella biology, the typhoid exotoxin is exported into the extracellular space. Typhoid toxin binds a range of different glycans but has a preference for those with terminal sialic acids, notably sialoglycans terminated in Neu5Ac. Intriguingly, humans have a domi- nance of these glycans compared with other species. Accordingly, typhoid toxin binding preferences may help explain the human restriction of typhoidal infections and pathophysiology at a molecular level.
Importantly, S. Typhi and S. Paratyphi both express typhoid toxin, whereas “nontyphoidal” Salmonella spp. do not. Not only does this offer the prospect that typhoid toxin may help explain important clinical distinctions between typhoidal and nontyphoidal Salmonella infections, it raises hopes for new approaches to disease treatment and diagnostics.
For example, antitoxin-based vaccines, therapeutics, or diagnostic tests might finally address the full microbiologic range of typhoid fever(s), because the typhoid toxin is conserved among not only S. Typhi but also S. Paratyphi isolates.
In addition to the virulence of the infecting organisms, host factors and immunity may also play an important role in predisposition to infection. Patients who are infected with HIV are at significantly higher risk for clinical infection with S. Typhi and S. Paratyphi. Similarly, patients with Helicobacter pylori infection have an increased risk of acquiring typhoid fever.
CLINICAL MANIFESTATIONS
The incubation period of typhoid fever is usually 7-14 days but depends on the infecting dose and ranges between 3 and 30 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 dis- comfort 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 parts of Africa suggest that typhoid may manifest as a mild illness in young children, presentation 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 old, with comparatively higher rates of complications and hospitalization. Diarrhea, toxicity, and complications such as dis- seminated intravascular coagulation (DIC) are also more common in infancy, resulting in higher case fatality rates. However, some of the other features and complications of typhoid fever seen in adults, such as neurologic manifestations and GI bleeding, are rare in children.
Typhoid fever usually manifests as high-grade fever with a wide variety of associated features, such as generalized myalgia, abdominal pain, hepatosplenomegaly, and anorexia (Table 225.4). In children, diarrhea may occur in the earlier stages of the illness and may be followed by
FEATURE RATE (%)
High-grade fever 95
Coated tongue 76
Anorexia 70
Vomiting 39
Hepatomegaly 37
Diarrhea 36
Toxicity 29
Abdominal pain 21
Pallor 20
Splenomegaly 17
Constipation 7
Headache 4
Jaundice 2
Obtundation 2
Ileus 1
Intestinal perforation 0.5
*Data collected in Karachi, Pakistan, from 2,000 children.
Table 225.4 Common Clinical Features of Typhoid Fever in Children*
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 as arrhythmias, sinoatrial block, or cardiogenic shock (Table 225.5).
Neurologic complications are also relatively uncommon among children;
they include delirium, psychosis, increased intracranial pressure, acute cerebellar ataxia, chorea, deafness, and Guillain-Barré 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, DIC, hemolytic-uremic syndrome, pyelonephritis, nephrotic syndrome, meningitis, endocarditis, parotitis, orchitis, and suppurative lymphadenitis.
The propensity to become a carrier follows the epidemiology of gallbladder disease, increasing with patient age and the antibiotic resistance of the prevalent strains. Although limited data are available, rates of chronic carriage are generally lower in children than adults.
DIAGNOSIS
The mainstay of the diagnosis of typhoid fever is a positive result of culture from the blood or another anatomic site. Results of blood cultures are positive in 40–60% of the patients seen early in the course of the disease, and serial blood cultures may be required to identify Salmonella bacteremia. Stool and urine culture results may become positive after the 1st wk. The stool culture result is also occasionally positive during the incubation period. The sensitivity of blood cultures in diagnosing typhoid fever in many parts of the developing world is limited. Wide- spread liberal antibiotic use may render bacteriologic confirmation even more difficult. Bone marrow cultures may increase the likelihood of bacteriologic confirmation of typhoid and may provide a diagnosis for patients with classic fever of unknown origin caused by Salmonella.
Still, collection of bone marrow specimens is difficult and relatively invasive.
A
B
Fig. 225.6 A, “Rose spot” in volunteer with experimental typhoid fever. B, 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 5:341–348, 2005.)
ORGAN SYSTEM PREVALENCE (%) RISK FACTORS COMPLICATIONS
Central nervous system 3-35 Residence in endemic region, malignancy, endocarditis, congenital heart disease, paranasal sinus infections, pulmonary infections, meningitis, trauma, surgery, osteomyelitis of skull
Encephalopathy, cerebral edema, subdural empyema, cerebral abscess, meningitis, ventriculitis, transient Parkinsonism, motor neuron disorders, ataxia, seizures, Guillain-Barré syndrome, psychosis Cardiovascular system 1-5 Cardiac abnormalities—e.g., existing
valvular abnormalities, rheumatic heart disease, congenital heart defects
Endocarditis, myocarditis, pericarditis, arteritis, congestive heart failure
Pulmonary system 1-6 Residence in endemic region, past
pulmonary infection, sickle cell anemia, alcohol abuse, diabetes, HIV infection
Pneumonia, empyema, bronchopleural fistula
Bone and joint <1 Sickle cell anemia, diabetes, systemic
lupus erythematosus, lymphoma, liver disease, previous surgery or trauma, extremes of age, corticosteroid use
Osteomyelitis, septic arthritis
Hepatobiliary system 1-26 Residence in endemic region, pyogenic infections, intravenous drug use, splenic trauma, HIV, hemoglobinopathy
Cholecystitis, hepatitis, hepatic abscesses, splenic abscess, peritonitis, paralytic ileus Genitourinary system <1 Urinary tract abnormalities, pelvic
pathology, systemic abnormalities Urinary tract infection, renal abscess, pelvic infections, testicular abscess, prostatitis, epididymitis
Soft tissue infections At least 17 cases reported in
English-language literature Diabetes Psoas abscess, gluteal abscess, cutaneous vasculitis
Hematologic At least 5 cases reported in
English-language literature Hemophagocytosis syndrome
From Huang DB, DuPont HL: Problem pathogens: extra-intestinal complications of Salmonella enterica serotype Typhi infection, Lancet Infect Dis 5:341–348, 2005.
Table 225.5 Extraintestinal Infectious Complications of Typhoid Fever Caused by Salmonella enterica Serotype Typhi