Salmonellosis 

Salmonellae are gram-negative motile bacilli. The genus Salmonella, which belongs to the family Enterobacteriaceae, was named after Daniel E. Salmon, an American veterinarian who first isolated Salmonella choleraesuis from pigs with hog cholera in 1884.^[1]

As with the closely related bacterium Escherichia coli, salmonellae are potential enteric pathogens and a leading cause of bacterial foodborne illness. In addition, Salmonella species have been implicated in a spectrum of other diseases, including enteric or typhoid fever (primarily Salmonella typhi and Salmonella paratyphi), bacteremia, endovascular infections, focal infections (eg, osteomyelitis), and enterocolitis (typically Salmonella typhimurium, Salmonella enteritidis, and Salmonella heidelberg).

Salmonellae can be isolated in the microbiology laboratory using numerous low-selective media (MacConkey agar, deoxycholate agar), intermediate-selective media (Salmonella-Shigella [SS] agar, Hektoen [HE] agar), and highly selective media (selenite agar with brilliant green). Salmonellae are oxidase-negative and predominantly lactose-negative. Fewer than 1% of nontyphoidal Salmonella isolates are lactose-positive (pink on MacConkey agar), but most produce hydrogen sulfide, which is detectable on HE or SS agar. As facultative anaerobes, they grow well both in bottles of standard automated systems for blood cultures and on culture media routinely used for urine, tissue, and respiratory cultures.^[2] Individual isolates can then be distinguished with serogrouping, pulsed-field gel electrophoresis, and bacteriophage serotyping techniques.

Nomenclature and classification

The nomenclature and classification of Salmonella species have been changed and restructured multiple times. Traditionally, Salmonella species were named in accordance with the Kaufmann-White typing system, defined by different combinations of somatic O, surface Vi, and flagellar H antigens. In 2005, Salmonella enterica finally gained official approval as the type species of the genus Salmonella. The genus Salmonella also contains the species Salmonella bongori and Salmonella subterranean, which was recognized in 2005.^[3]

Currently, Salmonella species have the serologically defined names appended as serovars or serotypes. For instance, the current nomenclature of S typhi is S enterica serovar Typhi. S enterica is preferred over confusing name S choleraesuis, which is also the name of a commonly isolated serotype.^[4] To date, more than 2500 serovars of S enterica have been described. Certain serovars are host-restricted, while others have a broad host range.^[5]

The transmission of salmonellae to a susceptible host usually occurs via consumption of contaminated foods. The most common sources of salmonellae include beef, poultry, and eggs. In one recent estimate, consumption of egg shell fragments contaminated with S enteritidis was responsible for approximately 182,060 cases of enteritis in the United States in the year 2000. Improperly prepared fruits, vegetables, dairy products, and shellfish have also been implicated as sources of Salmonella.

In the spring of 2008, 1442 persons across 43 states developed infection with S enterica serotype Saintpaul, with the same genetic fingerprint linking contaminated jalapeno and serrano peppers as a source of infection.^[6] Almost any type food product could serve a source for infection, including peanut butter, as seen during a recent outbreak of more than 600 cases.^[7] Powdered infant formula has been implicated in two consecutive large outbreaks of S enterica serotype Agona among infants in France.^[8]

In addition, human-to-human and animal-to-human transmissions can occur. For example, amphibian and reptile exposures are associated with approximately 74,000 Salmonella infections annually in the United States. Salmonellosis outbreaks have also been associated with handling chicks, ducklings, kittens, and hedgehogs.^{[9, 10, 11, 12, 13, 14]} Recently, a study of 28 cases of Styphimurium identified pet rodents as a previously unrecognized source of human Salmonella infection.^[15]

Although the infectious dose varies among Salmonella strains, a large inoculum is thought to be necessary to overcome stomach acidity and to compete with normal intestinal flora. Large inocula are also associated with higher rates of illness and shorter incubation periods. In general, about 10⁶ bacterial cells are needed to cause infection. Low gastric acidity, which is common in elderly persons and among individuals who use antacids, can decrease the infective dose to 10³ cells, while prior vaccination can increase the number to 10⁹ cells.^[16]

After ingestion, infection with salmonellae is characterized by attachment of the bacteria by fimbriae or pili to cells lining the intestinal lumen. Salmonellae selectively attach to specialized epithelial cells (M cells) of the Peyer patches. The bacteria are then internalized by receptor-mediated endocytosis and transported within phagosomes to the lamina propria, where they are released. Once there, salmonellae induce an influx of macrophages (typhoidal strains) or neutrophils (nontyphoidal strains).

The Vi antigen of S typhi is important in preventing antibody-mediated opsonization and complement-mediated lysis. Through the induction of cytokine release and via mononuclear cell migration, S typhi organisms spread through the reticuloendothelial system, mainly to the liver, spleen, and bone marrow. Within 14 days, the bacteria appear in the bloodstream, facilitating secondary metastatic foci (eg, splenic abscess, endocarditis). In some patients, gallbladder infection leads to long-term carriage of S typhi or S paratyphi in bile and secretion to the stool.^[17] As a rule, infection with nontyphoidal salmonellae generally precipitates a localized response, while S typhi and other especially virulent strains invade deeper tissues via lymphatics and capillaries and elicit a major immune response.

Virulence factors of salmonellae are complex and encoded both on the organism's chromosome and on large (34-120 kd) plasmids. Some areas of active investigation include the means by which salmonellae attach to and invade the intestine, survive within phagosomes, effect a massive efflux of electrolytes and water into the intestinal lumen, and develop drug resistance. Several Salmonella pathogenicity islands have been identified that mediate uptake of the bacteria into epithelial cells (type III secretion system [TTSS]), nonphagocytic cell invasion (Salmonella pathogenicity-island 1 [SPI-1]), and survival and replication within macrophages (Salmonella pathogenicity-island 2 [SPI-2], phoP/phoQ).

The severity of illness in individuals with salmonellosis is determined not only by the virulence factors of the infecting strain but also by host properties. In a recent study of 129 nonfecal Salmonella isolates at the Massachusetts General Hospital, the most common risk factors were found to be corticosteroid use, malignancy, diabetes, HIV infection, prior antimicrobial therapy, and immunosuppressive therapy.^[2]

Sickle cell disease, malaria, schistosomiasis, bartonellosis, and pernicious anemia have been mentioned in the literature as other comorbidities that predispose to salmonellosis. Infants are at a high risk of developing CNS infection as a result of Salmonella bacteremia. Specific anatomical sites, such as an altered urinary or biliary tract, atherosclerotic aorta, or endovascular devices may facilitate persistent focal Salmonella infection.

Frequency

United States

• The incidence of Salmonella infections in the United States has been stable since 2004 but has decreased approximately 8% from 1996-1998 levels.^[18] In 2007, the reported annual incidence of salmonellosis was 14.9 cases per 100,000 population.^[18] The true annual burden of nontyphoidal Salmonella infection in the United States is calculated to be 520 cases per 100,000 population, compared with 13.4 laboratory-confirmed cases per 100,000 population per year. This reflects an estimate of approximately 38.6 cases of nontyphoidal Salmonella infection for each culture-confirmed case.^[19]
• In 2007, 364 Salmonella infections (5.4% of the overall reported cases) were associated with salmonellosis outbreaks, similar to the proportion in previous years. Four large multistate outbreaks of Salmonella infections that included FoodNet sites were investigated in 2007: an outbreak of S enterica serotype Tennessee infections caused by contaminated peanut butter, an outbreak of S enterica serotype I 4,5,12:i:- caused by contaminated frozen pot pies, an outbreak of S enterica serotype Wandsworth and Styphimurium infections attributed to a puffed vegetable snack, and an outbreak of S paratyphi B variant Java associated with exposure to turtles.^[18]
• In 2008-2009, a nationwide outbreak of S typhimurium was traced to peanut products and frozen chicken products. Because the contaminated peanuts were used to make a variety of products that were distributed across the country, this outbreak highlighted how difficult it can be to trace the source of an outbreak.^[20]
• Although the prevalence of Salmonella infections is highest in children, salmonellosis outbreaks are common among individuals who are institutionalized and residents of nursing homes. Approximately one case of paratyphoid fever is reported per every four of typhoid fever. Typhoid fever is increasingly associated with travel to developing countries (currently 72% of approximately 400 cases per year). Common sources of infection include India (30%), Pakistan (13%), Mexico (12%), Bangladesh (8%), Philippines (8%), and Haiti (5%).^[21]

International

The incidence of salmonellosis has markedly increased in many countries; however, a paucity of good surveillance data exists. In 2000, approximately 21.6 million worldwide cases of typhoid fever caused 216,500 deaths.^[22] The incidence of typhoid fever in south-central Asia, Southeast Asia, and, possibly, southern Africa was high (>100 cases per 100,000 population per year). The rest of Asia, Africa, Latin America, and Oceania (except for Australia and New Zealand) typically see intermediate rates of typhoid fever (10-100 cases per 100,000 population), while the incidence is low in the other parts of the world (< 10 cases per 100,000 population). In countries where typhoid fever is endemic, most cases of the disease occur in children aged 5-19 years and young adults.^[23]

Mortality/Morbidity

• Infection with nontyphoidal salmonellae typically produces a self-limiting gastroenteritis, and dehydrated patients occasionally require hospitalization. Death is rare. The mortality rate associated with S enteritidis infection outbreaks in the United States from 1985-1991 was 0.4%. Case-fatality rates were 70 times higher in nursing homes and hospitals. Mortality rates associated with typhoid fever are similarly low in the United States (< 1%), but mortality rates of 10-30% have been reported in some Asian and African countries. Between 1996 and 1999, an estimated 1.4 million nontyphoidal Salmonella infections occurred in the United States, with an estimated 15,000 hospitalizations and 400 deaths annually. A related study during the same period found that 22% of people infected with nontyphoidal Salmonella required hospitalization, with an annual incidence of 0.08 deaths per 100,000 population.
• Development of bacteremia worsens the prognosis. In the 1990s, at Massachusetts General Hospital, 18% of 45 patients with Salmonella bacteremia died.^[2]
• Although uncommon, extraintestinal complications of salmonellosis caused by seeding of other organs are associated with increased mortality rates. Such complications include endocarditis, vascular infections, cholecystitis, hepatic and splenic abscesses, urinary tract infections, pneumonia or empyema, meningitis, septic arthritis, and osteomyelitis. Half of all Salmonella CNS infections are fatal.^[2]
• Multidrug-resistant typhoid fever in childhood is associated with increased risk of mortality, especially in infancy,^[23] possibly because of the increased virulence of multidrug-resistant S typhi, as well as a higher number of circulating bacteria.^[24]

Race

Salmonellosis has no racial predilection.

Sex

Salmonellosis has no sexual predilection.

Age

The incidence of salmonellosis in the United States is greatest among children younger than 5 years (61.8 per 100,000 people), with a peak among those younger than 1 year. Infants and people older than 60 years are most susceptible and tend to have more severe infections. In one 4-year surveillance study, 47% of people hospitalized with nontyphoidal Salmonella infections were older than 60 years.