Salmonellosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Salmonellosis is an infection with Salmonella bacteria. The type of salmonella usually associated with infections in humans is called Non-Typhoidal Salmonella. It is usually contracted by ingesting raw or undercooked eggs, or from sources such as; infected poultry and cattle, infected egg, egg products and milk, infected reptiles which carry the bacteria on their skin, and infected pet rodents. Cannabis contaminated with Salmonella muenchen was positively correlated with dozens of cases of salmonellosis in 1981.^[1]Most persons infected with Salmonella develop diarrhea, fever, vomiting, and abdominal cramps 6 to 72 hours after infection. In most cases, the illness lasts 3 to 7 days—most affected persons recover without treatment. However, in some persons the diarrhea may be so severe that the patient becomes dangerously dehydrated and must be taken to a hospital. At the hospital, the patients will receive intravenous fluids to treat their dehydration and medications may be given to provide symptomatic relief, like fever reduction. In severe cases, the Salmonella infection may spread from the intestines to the blood stream, and then to other body sites and can cause death unless the person is treated promptly with antibiotics. The elderly, infants, and those with impaired immune systems are more likely to have a severe illness. Some people afflicted with Salmonellosis later experience reactive arthritis, which can have long-lasting, disabling effects.

A rarer form of salmonella called Typhoidal Salmonella can lead to typhoid fever. It is only carried by humans and is usually contracted through direct contact with the fecal matter of an infected person. It therefore mainly occurs in countries that do not have proper systems for handling human waste.

Salmonella serotype Typhimurium and Salmonella serotype Enteritidis are the most common in the United States. Salmonella has been known to cause illness for over 100 years. They were discovered by a American scientist named Salmon, for whom they are named.

Every year, approximately 40,000 cases of salmonellosis are reported in the United States. Because many milder cases are not diagnosed or reported, the actual number of infections may be thirty or more times greater. There are many different kinds of Salmonella bacteria. Salmonella serotype Typhimurium and Salmonella serotype Enteritidis are the most common in the United States.Salmonellosis is more common in the summer than winter.

Children are the most likely to get salmonellosis. The rate of diagnosed infections in children less than five years old is higher than the rate in all other persons. Young children, the elderly, and the immunocompromised are the most likely to have severe infections. It is estimated that approximately 400 persons die each year with acute salmonellosis.

Every year, approximately 40,000 cases of salmonellosis are reported in the United States. Because many milder cases are not diagnosed or reported, the actual number of infections may be thirty or more times greater. Salmonellosis is more common in the summer than winter. Children are the most likely to get salmonellosis. The rate of diagnosed infections in children less than five years old is about five times higher than the rate in all other persons. Young children, the elderly, and the immunocompromised are the most likely to have severe infections. It is estimated that approximately 400 persons die each year with acute salmonellosis.

National surveillance is conducted through the public health laboratories for culture-confirmed cases and through the National Notifiable Diseases Surveillance System (NNDSS). Active laboratory- and population-based surveillance is conducted in FoodNet sites.

Enterobacteriaceae of the genus Salmonella, a gram-negative rod-shaped bacilli. Approximately 2000 serotypes cause human disease.

There are an estimated 400 fatal cases each year; a few cases are complicated by chronic arthritis. Transmission is through contaminated food, water, or contact with infected animals.

Diarrhea (sometimes bloody), fever, and abdominal cramps. Occasionally can establish localized infection (e.g., in a joint) or enter the blood.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Salmonella was first isolated from the intestines of pigs, by Theobald Smith, an American veterinary pathologist. The bacteria was isolated for the first time, from the spleen of patients with typhoid fever by Gaffkey in 1884. The first vaccine against the disease was made by Pfeiffer and Kalle in 1896. Modern antibiotic therapy against typhoid fever derived from the treatment of the first cured patient in 1948.

Salmonella was initially isolated from the intestines of pigs, by Salmon, an American veterinary pathologist. The bacteria was first associated with hog cholera by Theobald Smith, in 1885. However, this disease was later discovered to be associated with a viral infection, with secondary infection by Salmonella.^[1]

Typhoid fever was confused with typhus prior to the 19th century. It was only in 1829 that P. Luis, in Paris, after the studying the spleen and intestinal lymph nodes was able to distinguish typhoid from other types of fever. Additionally, P. Luis described the hemorrhage, intestinal perforation and rose spots to be related to the disease.^[2]

William Jenner, in 1850, was the first to question the difference between typhoid fever and typhus in the English literature. According to him, typhoid was associated with enlarged mesenteric lymph nodes and Peyer’s patches. He also noted that previous history of typhoid protected the individual from further disease, which did not occur in typhus. The term enteric fever was first introduced by Wilson, who in 1869 suggested it, after the anatomic region where infection occurred. Today both nomenclatures are used, with preference given to enteric fever.^[3]

The transmission of typhoid fever was only described in 1873 by Budd, who demonstrated that the disease could be transmitted by fomites, food and water.^[4]

In 1884, Gaffkey isolated the bacterium in Germany, from the spleen of patients with the disease.^[5]

The first typhoid vaccine was only made in 1896 by Pfeiffer and Kalle, using organisms killed by heat. Widal et all. also demonstrated, on the same year, that sera from convalescent typhoid patients made the live organisms lose motility and group in clusters.^[6]

After several years of antibody studies, and their interactions with the bacterial surface, Salmonella was classified into serotypes, according to its antigens, by Kauffman and White.^[7]

Modern antibiotic therapy of typhoid fever derives from the successful treatment of a Malaysian patient in 1948.^[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [2]

The pathogenesis of salmonellosis varies among the different Salmonella serovars. Typhoidal and nontyphoidal Salmonella (NTS) interact with host defense mechanisms, eliciting variable immune responses in humans. NTS colonizes the intestine, induces neutrophil migration into the intestinal lumen, and causes a self limiting inflammatory diarrhea. Bacteremia due to NTS is rare but can occur, especially in persons infected with HIV. Individuals with type I cytokine pathway deficiencies are at increased risk of developing NTS infection.

The pathogenesis of salmonellosis varies between different Salmonella serovars and depends on the interaction of multiple virulence programs with host defense mechanisms. These interactions occur in different tissues and at various stages of infection leading to variable host morbidity and mortality.^[1] Salmonella enterica serovar Typhi (S. Typhi) and Salmonella Paratyphi A both cause bacteremia. Non-typhoidal Salmonella (NTS) usually cause self-limiting diarrhea although NTS may lead to secondary bacteremia. Immunocompromised individuals and infants in sub-Saharan Africa may develop primary NTS bacteremia.^[2]

Typhoidal and nontyphoidal Salmonella (NTS) serovars elicit different immune responses in humans.^[3] NTS serovars induce a greater inflammatory interaction with human gut mucosa compared to typhoidal serovars. In animal models, S. enterica colonizes the intestine and localizes to the apical epithelium, inducing inflammatory changes. These changes include PMN infiltration, necrosis of the epithelium, crypt abscesses, and edema. The recruitment of neutrophils to the intestinal epithelium is the histopathological hallmark of intestinal disease. The various S. enterica serovars that are able to cause intestinal disease do so by attracting PMNs, specifically by inducing interleukin-8. With serovar Typhimurium, this recruitment occurs within the first few hours of infection. Massive migration of neutrophils and exudate secretion into the intestinal lumen occurs approximately 8-10 hours after infection. The onset of diarrhea begins between 8-72 hours after colonization. Salmonella serovar Typhimurium enterocolitis is the most severe in the caudal ileum, cecum, and proximal colon. Disease among humans usually occurs after ingesting more than 50 000 bacteria.^[1]

Typhoidal serovars do not usually cause acute diarrhea or induce a large neutrophil recruitment into the intestinal lumen. In typhoid infection, S. Typhi bacteria is first ingested, usually through contaminated water or animal products. The bacteria is able to withstand the highly acidic environment of the stomach and proceeds to colonize the ileum and cecum. Upon colonization, the bacteria can gain entry into host circulation by either invading phagocytic M-cells or through dendritic cell uptake. Dissemination via the reticuloendothelial system (RES)occurs once extraintestinal infection is achieved. The bacteria can then take up residence in splenocytes, mostly within macrophages, dendritic cells, and polymorphonuclear leukocytes. Hepatocytes and other hepatic non-professional phagocytes may also serve as targets for infection and replication. Once Salmonella is internalized in the host cells, it resides in the Salmonella containing vacuole(SCV). In phagocytes, this specific vacuole formation evades fusion with the phagocyte oxidase complex. The ability of Salmonella to survive phagocytic killing is a central component of the bacteria’s virulence. ^[1]

Salmonella bacteria are widely distributed in domestic and wild animals. They are prevalent in food animals such as poultry, pigs, cattle; and in pets, including cats and dogs, birds and reptiles such as turtles. Salmonella can pass through the entire food chain from animal feed, primary production, and all the way to households or food-service establishments and institutions. Salmonellosis in humans is generally contracted through the consumption of contaminated food of animal origin (mainly eggs, meat, poultry and milk), although other foods, including green vegetables contaminated by manure, have been implicated in its transmission. Person-to-person transmission through the faecal-oral route can also occur. Human cases also occur where individuals have contact with infected animals, including pets. ^[4]

Susceptibility to salmonella infection is associated with multiple cytokine abnormalities. Studies have demonstrated that individuals with genetic deficiencies in the type I cytokine pathway (IL-12/IL-23 system) are greatly susceptible to infection with NTS, particularly to severe extraintestinal disease. These individuals, however, are not more susceptible to S. Typhi or S. Paratyphi infections. ^[3]

Invasive infections caused by NTS are frequently associated with immunocompromised adults, particularly those with HIV infection. ^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Salmonella is a rod-shaped, facultative intracellular, gram-negative enterobacteria.^[1] Salmonella species shows motility, produces hydrogen sulfide, and only 1% is able to ferment lactose.^[2] It may be isolated from the stool of infected patients, and grown in culture media, such as MacConkey agar and deoxycholate agar. Salmonella enters the body through contaminated food or water, and invades the intestinal epithelial cells, causing inflammation.

This bacterium may be classified into 2 different species: Salmonella enterica and Salmonella bongori. Salmonella enterica is divided in 6 different subspecies, of which I, contains most pathogenic serotypes for humans. Salmonella may be serogrouped into more than 2500 serovars with polyvalent antisera, according to the capsular antigen, polysaccharide O antigens, and flagellar antigens. The bacteria show tropism for the epithelial cells of the gastrointestinal tract, macrophages, dendritic cells, and neutrophils. Different serotypes of Salmonella may have different natural reservoirs, some have humans as their only natural reservoir (serotypes Sendai and Typhi), while others (serotype Dublin) may infect humans and cattle.

Cellular organism; Bacteria; Proteobacteria; Gammaproteobacteria; Enterobacteriales; Enterobacteriaceae^[3]

Salmonella is a gram-negative, facultative intracellular, anaerobic, non-spore-forming bacillus. It measures 2 to 3 by 0.4 to 0.6 μm. Salmonella is a non-lactose fermenting bacterium. It reduces nitrates, produces acid on glucose fermentation and does not produce cytochrome oxidase.^[5] Due to the presence of flagella, almost all salmonella species are motile. 1% of the bacteria is able to ferment lactose, which may be responsible for its non-detection in some culture media.

For the isolation of salmonella in culture, freshly passed stool are preferred. Common media for the growth of salmonella include: MacConkey agar, deoxycholate agar, and xylose-lysine-deoxycholate agar.^[6]

When the sample has a low number of bacteria, special enrichment broths, such as the selenite-based enrichment broth, may be used to raise the number of bacteria.^[6]

Salmonella enterica enters the body through the mouth, by ingestion of contaminated food and water. For the bacteria to cause disease, an inoculum of about 50 000 pathogens is often required. Once in the intestine, the bacteria will first infect the apical epithelium. Salmonella will then initiate bacterial mechanisms that allow invasion of the host cells, inducing inflammatory changes, such as:^{[7][8][9][10]}

• Diffuse and focal infiltration of PMN
• Crypt abscesses
• Necrosis of the epithelium
• Fluid secretion
• Edema

Different serovars will have different preferable intestinal locations. An example is the enterocolitis at the terminal ileum, cecum, and proximal colon caused by serovar Typhimurium. Intestinal disease is marked by neutrophil migration to the intestinal epithelium. This recruitment is done by the secretion of interleukin-8, induced by Salmonella.^[11]

Before 1983 Salmonella was classified in several species. However, its genome study has shown high levels of DNA similarities among different types of salmonella, which leads to the actual classification of salmonella in 2 different species:

• Contains six subspecies – I, II, IIIa, IIIb, IV, and VI:^[12][13]
  • I – enterica
  • II – salamae
  • III – arizonae
  • IIIb – diarizonae
  • IV – houtenae
  • VI – indica
• Subspecies I contains most pathogenic serotypes for humans
• Subspecies IIIa and IIIb, formerly belonging to the genus Arizonae, are responsible for rare human infections

• Formerly subspecies V^[14]

Salmonella subspecies may be serogrouped into more than 2500 serovars with polyvalent antisera. For this division the following bacterial structures are considered:^[15]

• Capsular antigen
• Polysaccharide O antigens
• Flagellar antigens

Different salmonella serotypes may also be distinguished in culture, according to their different metabolism of sugars.^[16] Different serovars may also have different disease manifestations. For example, Salmonella enterica, serovar Typhimurium is the causative agent of typhoid fever, and is not associated with classical salmonellosis.

In vitro, Salmonella is able to interact with different types of cells. However, in vivo, the bacteria was found to enter only certain human cells, namely:^[17]

• Epithelial cells of the gastrointestinal tract – first cells to be infected by Salmonella
• Macrophages – where Salmonella survives and replicates
• Dendritic cells – relevant for dissemination of bacteria in the initial stages of infection, yet, they are not considered adequate reservoirs for Salmonella at latter stages
• Neutrophils – interaction is based on the immune response against the bacteria, hence this might not be considered true tropism

Salmonella gastroenteritis must be differentiated from other causes of viral, bacterial, and parasitic gastroentritis.

8Small bowel diarrhea: watery, voluminous with less than 5 WBC/high power field

Large bowel diarrhea: Mucousy and/or bloody with less volume and more than 10 WBC/high power field
† It could be as high as 1000 based on patient’s immunity system.

The table below summarizes the findings that differentiate inflammatory causes of chronic diarrhea^{[18][19][20][21][21]}

Different salmonella serovars may have different natural reservoirs. Common types of serovars of salmonella enterica that infect the human gastrointestinal tract include serovars Sendai, Typhi, and Paratyphi. Humans are their only natural reservoir. Other serotypes, such as serotype Dublin, have cattle as their natural reservoir, but has also the capacity to cause infection in humans.^[22][23]

• Vedolizumab

• 1984 Rajneeshee bioterror attack
• List of foodborne illness outbreaks
• Food Testing Strips

• 
  Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL). ^[4]
• 
  Salmonella bacteria in tetrathionate enrichment broth stained using direct FA staining technique. From Public Health Image Library (PHIL). ^[4]
• 
  Triple sugar iron agar (TSI) tested for Salmonella (H2S+) and (H2S-); Citrobacter sp. and S. arizonae. From Public Health Image Library (PHIL). ^[4]
• 
  Gram-negative bacilli, or rod-shaped Salmonella sp. bacteria. From Public Health Image Library (PHIL). ^[4]
• 
  SEM depicts a number of red-colored Salmonella sp. bacteria invading a mustard-colored ruffled immune cell. From Public Health Image Library (PHIL). ^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jolanta Marszalek, M.D. [2]

Salmonellosis must be differentiated from other types of infectious diseases that can cause acute inflammatory diarrhea. It is important to consider other underlying pathogens including Shigella, Campylobacter, E.coli, C. difficile, and E. histolytica.^[1]

Salmonellosis should be differentiated from other pathogens that lead to acute inflammatory diarrhea. The table below lists the underlying pathogens known to cause acute inflammatory diarrhea:^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]

Salmonellosis is a global health issue and is estimated to cause approximately 93.8 million cases of gastroenteritis each year. There are major limitations preventing assessment of the global burden of salmonellosis. Many regions of the world, especially those with a large proportion of the global population such as South/Southeast Asia and South America, do not have publicly available data regarding salmonellosis surveillance. In the U.S., the incidence rate was approximately 2.8 cases per 100,000 persons in 2008. In Europe, the overall reported incidence rate was 39.01 per 100,000 persons in 2005.^[1] Children and the elderly have a higher rate of incidence.^[2]

Worlwide, salmonellosis is estimated to cause approximately 93.8 million cases of gastroenteritis each year. In 2005, the estimated overall incidence rate for Europe was 39.01 per 100,000 persons. The countries with highest reported incidence were the Czech Republic and Slovakia. In 2007, the notification rate of salmonellosis by EU and EEA/EFTA countries was 34.26 per 100,000 persons. In the U.S., Salmonella causes approximately 1 million foodborne infections annually. The incidence of salmonellosis in the U.S., was approximately 2.8 cases per 100,000 persons in 2008. Incidence was highest in the youngest age groups(≤ 4 years) at approximately 4.7 – 6.9 cases per 100,000 population. ^[2][1]

The highest incidence of salmonellosis occurs in the age group 0-4. Older age groups also have a greater incidence.

The incidence of salmonellosis does not vary by gender.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Risk factors for salmonellosis are all those that expose the person to the bacteria, and that create an adequate environment for infection, such as: low gastric pH; changes in intestinal flora; malignancy; diabetes; and immunosuppressive therapies. Risk factors for the persistence of infection with Salmonella, include locals of anatomic disruptions, such as: gallstones; kidney stones; and atherosclerotic plaque.^[1][2]

Affects all age groups. Groups at greatest risk for severe or complicated disease include infants, the elderly, and persons with compromised immune systems.

Risk factors for salmonellosis are all those that expose the person to the bacteria, and that create an adequate environment for infection.^[1] All these factors affect somehow, one or more of the defense mechanisms of the body, and may include:^[1][2]

• Low gastric pH in children
• Low gastric pH from antacids and H2 antagonists
• Pernicious anemia
• Changes in the normal endogenous intestinal flora (often caused by antibiotic treatments or surgery)
• Malignancy
• Diabetes
• Blockage of reticuloendothelial system, such as malaria or drepanocytosis
• HIV infection
• Immunosuppressive therapies

Salmonella may persist, in foci, in certain organs of the body, particularly locals with anatomical disruptions. These may include:^[1]

• Gallstones
• Kidney stones
• Atherosclerotic plaque
• Schistosomiasis
• Prosthetic devices

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2] Jolanta Marszalek, M.D. [3]

Symptoms of salmonellosis begin between 6 to 72 hours after ingestion of contaminated food. These may include nausea, vomiting, crampy abdominal pain, diarrhea, and fever. Uncomplicated infection often affects only the gastrointestinal tract, and resolves within 5 to 7 days. Infants, elderly and immunocompromised patients may experience severe forms of the disease, and are more prone for the development of complications, such as: bacteremia, and endovascular or focal infections. Focal infections may be located in the abdomen, CNS, lungs, urinary and genital tracts, or in the bones and joints. The prognosis of salmonellosis is good in most cases, however, severe forms of the disease, and presence of complications are associated with poor prognosis.

Salmonellosis may occur at any age, and start with symptoms that are indistinguishable from those caused by other gastrointestinal pathogens. Symptoms typically develop 6 to 72 hours after ingestion of contaminated food, and include acute onset of nausea, vomiting, crampy abdominal pain, fever (38-39ºC) and diarrhea. Diarrhea may be mild nonbloody, loose stools, in moderate volume, or may consist of a large volume of watery, bloody stool. Children with enterocolitic infection often present with severe inflammatory disease, with bloody diarrhea, increased symptom duration and risk of complications.^[1]

Salmonellosis affects most commonly the ileum, however, the large bowel may also be affect in certain cases. The stomach, duodenum and jejunum are usually spared of inflammation.^[1][2][3]

For the infections that are limited to the gastrointestinal tract, in the absence of treatment, symptoms commonly have a spontaneous resolution within 5 to 7 days.^[1]

Persons with diarrhea usually recover completely, although it may take several months before their bowel habits become entirely normal. In some cases complications may occur, including:^[4]

About 8% of patients develop bacteremia. This complication is more common in children, elderly and immunocompromised patients. Of the different serotypes of salmonella enterica non-typhi, bacteremia is most common among patients infected with the serotypes Choleraesuis and Dublin.^[5]

In the presence of persistent bacteremia, endovascular infection should be suspected. Previous conditions that are prone to the development of endovascular infection include:^[6]

• Atherosclerotic vascular disease
• Preexisting valvular heart disease
• Prosthetic vascular graft
• Aortic aneurysm

In elder patients presenting with prolonged chest, back or abdominal pain, and prolonged fever, that are subsequent to an episode of gastroenteritis, arteritis should be suspected.^[7]

In rare cases (<1%) arteritis and endocarditis may complicate and lead to severe, often fatal, complications, such as:^[8]

• Valve perforation
• Endomyocardial abscess
• Mycotic aneurysms
• Infected mural thrombus
• Aorto-enteric fistula
• Aneurysm rupture
• Pericarditis

Of the 8% of patients who develop bacteremia, 5-10% evolve into localized infections. These may include:^[9]

Intra-abdominal complications may include cholecystitis, splenic or hepatic abscesses. They may be identified and monitored with abdominal CT, or ultrasound.

These complications are prone to occur in patients with:

• Splenic abscesses from sickle cell disease
• Hepatobiliary anatomic abnormalities
• Abdominal malignancy

Non-typhoid salmonella may lead to different CNS infections, such as:^[10]

• Subdural empyema
• Brain abscess
• Ventriculitis
• Meningitis

Pulmonary infections caused by non-typhoid salmonella commonly lead to lobar pneumonia. Complications may include:^[11]

• Bronchopleural fistula
• Lung abscess
• Empyema

Non-typhoid salmonella may complicate into urinary and genital tract infections, such as:^[12]

• Cystitis
• Pyelonephritis
• Ovarian abscess
• Testicular abscess
• Prostatitis
• Epididymitis

Non-typhoid salmonella may lead to Reiter’s syndrome^[13]

The prognosis of salmonellosis is good for most patients. Persons with diarrhea usually recover completely, although in some cases, it may take several months until their bowel habits become entirely normal. The development of a severe form of the disease, or complications, are associated with poor prognosis.^[14]

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