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Salmonella Infections
John C. Christenson, MD*
Practice Gaps
1. Because Salmonella disease causes 93.8 million illnesses and 155,000 deaths
Author Disclosure worldwide and 1 million foodborne illnesses and 350 deaths in the United States,
Dr Christenson has clinicians must learn to recognize, treat, and prevent these infections.
disclosed no financial 2. Young infants, persons with hemoglobin disorders, and individuals who are immune
relationships relevant compromised, such as those with human immunodeficiency virus and cancer, are at
to this article. This risk for severe Salmonella disease, including bacteremia, meningitis, and
commentary does not osteomyelitis.
contain discussion of
unapproved/
Objectives After completing this article, readers should be able to:
investigative use of
a commercial product/ 1. Describe the epidemiology of nontyphoidal salmonellosis.
device. 2. Recognize the clinical features of enteric fevers.
3. Appropriately treat the young child with Salmonella infection.
4. Understand ways to prevent Salmonella infections.
5. Use typhoid vaccines when indicated.
Introduction
Salmonella infection is a common cause of gastroenteritis and bacteremia worldwide. The
consumption of contaminated water and food and the close contact with colonized ani-
mals are frequent risk factors for acquisition. Young infants, persons with hemoglobin
disorders, and individuals who have immunocompromising conditions, such as human
immunodeficiency virus (HIV) and cancer, are at risk for severe disease, such as bacter-
emia, meningitis, and osteomyelitis. Salmonella Typhi and Salmonella Paratyphi are re-
sponsible for significant morbidity and mortality in developing countries. Clinicians must
learn to recognize these infections and know how to effectively treat and prevent them.
This review article provides the reader with enhanced knowledge of this diverse group of
pathogens.
Microbiology
The genus Salmonella is composed of motile gram-negative bacteria within the family En-
terobacteriaceae. They are oxidase-negative, indole-negative, and nonlactose fermenters.
The nomenclature of the genus Salmonella can be challenging. The Centers for Disease
Control and Prevention and the World Health Organization have been responsible for
maintaining the format for formula designation. There are 2 Salmonella species, Salmonella
enterica and Salmonella bongori, which are classified further into subspecies according to
their biochemical and genomic relatedness. Most human infections are caused by a serotype
of Salmonella enterica subsp enterica (subspecies I), which infect warm-blooded animals.
Five other subspecies (plus S bongori [subspecies V]) are known to colonize cold-blooded
animals and the environment: enterica subsp salamae (subspecies II), arizonae (subspecies
IIIa), diarizonae (subspecies IIIb), houtenae (subspecies IV), and indica (subspecies VI).
Although more than 2,600 serotypes of Salmonella have been identified, most disease
is caused by subspecies/serotypes Typhimurium and Enteritidis. Historically, serotypes
are frequently reported as species. For simplicity, in this review we use genus and
*Ryan White Center for Pediatric Infectious Disease, Indiana University School of Medicine, Riley Hospital for Children,
Indianapolis, IN.
subspecies/serotype (eg, Salmonella Typhi or Salmonella more likely to be bottle fed, have exposure to reptiles,
Typhimurium). Non–subspecies I are rarely reported as have ridden in a shopping cart next to meat or poultry,
human pathogens. traveled abroad, or attended a day care center with an in-
Certain serotypes frequently correlate with a disease fected infant. (4)
syndrome or food source. As examples, Salmonella chol- Most Salmonella infections are foodborne. In Mexico,
eraesuis and Salmonella dublin are both frequently asso- pork, meat, and poultry were frequently found to be
ciated with bacteremia and extraintestinal infections. contaminated with Salmonella. Consumption of con-
(1)(2) taminated orange juice led to an outbreak in a theme
park. An intentional contamination of restaurant salad
bars was responsible for a large outbreak of Salmonella
Epidemiology gastroenteritis in Oregon in 1984. Contaminated pea-
Nontyphoidal Salmonella Infections nut butter, ice cream, salami products, and mozzarella
Salmonella gastroenteritis is a serious public health prob- cheese has been responsible for multistate outbreaks
lem in the United States. An estimated 1 million food- in the United States. Outbreaks have also been associ-
borne illnesses occur each year, resulting in 350 deaths. ated with exposure to contaminated dry dog food and
(3) The world burden is estimated at 93.8 million ill- pet treats.
nesses, with 155,000 deaths each year. Salmonella Enter- Animals such as chickens, pigs, turtles, lizards, iguanas,
itidis is the most common isolated subspecies because it is hedgehogs, and amphibians have been identified as res-
responsible for 65% of these infections, followed by S Ty- ervoirs of Salmonella. Many of these colonizations have
phimurium at 12%. In the United States, exposures to resulted in human outbreaks. An outbreak of S Typhi-
chicken and eggs are most likely sources for infection. murium was associated with exposures to pet rodents.
Many risk factors are associated with infection and dis- Feeder rodents used for the feeding of reptiles and am-
semination. Achlorhydria, the use of antacids or proton phibians were found to be colonized with Salmonella,
pump inhibitors, and rapid gastric emptying favor bacterial resulting in human infections. Patients with Salmonella
survival. Conditions that impair cell-mediated lymphocyte arizonae acquired from iguanas and snakes have a predis-
function, such as HIV/AIDS, malnutrition, corticosteroid position for musculoskeletal infections. In a rare event, 2
therapy, and posttransplantation immunosuppressive ther- patients developed S Enteritidis sepsis (in one case fatal)
apy, are major risk factors. An overloaded reticuloendothe- after a platelet transfusion. The donor most likely had
lial system with iron or hemoglobin, such as in patients asymptomatic bacteremia from handling his pet boa
with sickle cell anemia, hemolytic anemia, thalassemia, constrictor.
and malaria, may increase the likelihood of severe disease. Nosocomial outbreaks are uncommon. However, in-
Infarcts in the gastrointestinal tract and bone and defective adequate infection control practices, understaffing, and
phagocytic and opsonic function also appear to contribute overcrowding may lead to environmental contamination.
to the severity of disease observed in patients who have In some developing countries, asymptomatic carriage of
sickle cell anemia. Diseases such as leukemia and lym- Salmonella can be high among children attending day
phoma also impair the reticuloendothelial system function. care centers. Outbreaks of salmonellosis in day care cen-
The morbidity and mortality associated with Salmonella ters have been reported, but these are considered rare
infections are also influenced by the serotype that causes events.
the infection. Salmonella choleraesuis is more likely to Although the incidence of salmonellosis related to
cause invasive disease. In one study, 85% of isolates were international travel appears to be decreasing in the
recovered from extraintestinal sites, especially blood. United States, many travel-acquired cases are still re-
(1) Seventy-two percent of patients were younger than ported. Salmonella stanley, a common serotype in
3 years. Pediatric patients were more likely to have diar- Southeast Asia (second most common in Thailand),
rhea than adults. Most of the children with diarrhea were has been frequently isolated in Europe. (5) In South-
also bacteremic. Mycotic aneurysms, a complication ob- east Asia, the serotype is frequently associated with
served in adults, was not detected in any of the pediatric the pork industry.
cases. Of importance, only 21% of children had leukocy- Nontyphoidal Salmonella infections remain a frequent
tosis. Occult bacteremia, where the child presents only cause of invasive disease in many regions of the world, es-
with fever, was a common presentation. pecially in sub-Saharan Africa. Children younger than
In a population-based, case-control study of salmonel- 3 years and those infected with HIV have the greatest
losis in infants younger than 1 year, infected infants were burden. Mortality remains high, especially in children with
bacteremia and meningitis. Seasonal peaks of disease Nontyphoidal isolates are rarely invasive because most
coincide with the rainy season, which leads to fecal con- do not extend past the lamina propria or the intestinal
tamination of drinking water. In many countries, an as- lymphatic system. However, interactions with host cells
sociation between malaria and Salmonella is well known. in the intestines may lead to a release of proinflammatory
This situation often delays treatment, causing greater cytokines that result in the recruitment of neutrophils to
morbidity and mortality. Frequently, febrile persons are the area, resulting in gastroenteritis. Some genes appear
treated only for malaria without considering the likeli- to play a role in the survival of bacteria within the liver
hood of a coinfection. Clinical features, such as fevers, and spleen and promote the replication within macro-
anemia, and splenomegaly, are frequent findings in both phages. (8)
conditions. Salmonella Typhi is known to adhere to epithelial cells
over the lymphatic Peyer patches, allowing for penetra-
Enteric Fever (Typhoid and Paratyphoid Fever) tion through the intestinal mucosa. Engulfment by
Enteric fever, an infection caused by S Typhi (typhoid macrophages and translocation into draining lymph
fever) or S Paratyphi A, B, or C (paratyphoid fever), is nodes results in bacteremia and subsequent dissemina-
a common cause of death and disease in many parts of tion. The organism survives within the host cells in a Salmo-
the world. Approximately 22 million cases are thought to nella-containing vacuole, assuring its ability to replicate,
occur worldwide each year, with 200,000 deaths as a result. survive, and invade and resulting in the multiplication
(6) Most infections occur in Southern and Southeast Asia. and survival of bacteria within the liver, spleen, and
Parts of Africa and Latin America are also affected but at bone marrow. After an incubation period of 7 to 14 days,
a lower frequency. In Asia, it is estimated that the inci- bacteremia occurs and symptoms emerge. Salmonella
dence approximates 100 cases per 100,000 population. Typhi can be found in the gallstones of individuals
Travelers to endemic regions are at risk. Most cases in who live in endemic regions. Its presence correlates with
the United States have been associated with international fecal shedding, and these people are known to infect
travel. Travelers visiting friends and relatives are at the others.
highest risk of infection.
In countries such as India, children and adolescents in
the 5- to 19-year age group are affected most. On rare Clinical Aspects
occasions, neonatal infections have been reported. These Nontyphoidal Salmonella Infections
infections are frequently acquired from the mother. In Gastroenteritis is the most frequent presentation. Most
South and Southeast Asia, S Typhi is the most common affected children are younger than 1 year. The usual in-
cause of community-acquired bacteremia. cubation period for Salmonella gastroenteritis is 6 to 12
Between 1960 and 1999, 60 outbreaks of typhoid hours. Nausea, vomiting, and diarrhea are common
fever had been reported in the United States. (7) symptoms. Diarrhea is usually nonbloody. Myalgias, ar-
Ninety percent were domestically acquired. Recently, thralgias, and headaches are also reported. Although ob-
cases were found to be related to the consumption of served in children with Salmonella gastroenteritis, fever,
a fruit shake made from frozen mamey fruit from chills, and abdominal pain are more commonly observed
Guatemala. (7) In recent years, an outbreak of S Para- with shigellosis. The presence of rectal tenesmus accom-
typhi B was found to be related to exposure to pet panied by stools with mucus and/or blood is more dis-
turtles. tinctive of Shigella infections. Symptoms are generally
The major factor responsible for the magnitude of this self-limited. Hepatomegaly and splenomegaly are infre-
problem is poor sanitary infrastructure, resulting in substan- quently noted.
dard drinking water and contaminated food. Person-to- Bacteremia is commonly observed in infants with gas-
person transmission from chronic asymptomatic carriage troenteritis. Most children require hospitalization. Persis-
also contributes to the infection of susceptible individuals tent bacteremia can be detected in approximately 40% of
(eg, typhoid Mary). patients. Salmonella Enteritidis was a frequently isolated
pathogen in bacteremic patients. In children, bacteremia
is rarely fatal. In contrast, one-third of adults presenting
Pathogenesis with primary bacteremia have extraintestinal organ in-
The pathogenesis of salmonellosis is complex. Several vir- volvement and will die.
ulence genes are responsible for the severity of disease ob- Clinical features or laboratory parameters were unable
served with certain species. to detect children more likely to have persistent bacteremia.
Although focal infections were observed in 2.5% of pre- observed in approximately 15% of patients. Severe dis-
viously healthy children, one-third of children with un- ease resulted in more hospitalizations. Intestinal perfo-
derlying medical conditions had focal disease, consisting ration was a rare complication observed in less than 1%
of meningitis, osteomyelitis, septic arthritis, pneumonia, of children.
or cholangitis. In parts of Africa, the fatality rate for bac- Thrombocytopenia and disseminated intravascular co-
teremia is close to 25%. Lower respiratory tract coinfec- agulation are markers of severe disease. Splenic abscess,
tions with tuberculosis and Streptococcus pneumoniae were brain abscess, and subdural empyema are rare complica-
common. tions of typhoid fever.
Meningitis and musculoskeletal infections are com- An analysis of travel-related cases in the United King-
mon complications in infants younger than 3 months. dom found that S Typhi and S Paratyphi infections were
It is estimated that 50% to 75% of Salmonella meningitis indistinguishable clinically. (10) Infections caused by S
occurs in the first year of life. Asymptomatic disease is also Paratyphi can be just as severe as those caused by S Typhi.
common in young infants. A well-appearing infant with Most patients had normal white blood cell counts (91%),
Salmonella gastroenteritis may be bacteremic. and 82% of patients had an elevated alanine aminotrans-
Malaria has been found to be a risk factor for invasive ferase level. Among travelers, more cases of enteric fever
nontyphoidal Salmonella infections in children. A reduc- were caused by S Paratyphi A than by S Typhi. Guillain-
tion in cases of salmonellosis was associated with a de- Barré syndrome has been described in association with S
crease in the number of malaria cases. Paratyphi A infection.
Compared with children with gastroenteritis Mixed infections with multiple pathogens occur in
alone, bacteremic children appear to have a longer du- endemic tropical countries. Treatment against enteric
ration of symptoms, a less severe clinical appearance, fever should be considered for children with unremit-
and fewer signs of dehydration. This gradual presen- ting fevers after completing adequate antimalarial
tation with less dehydration and fewer toxic effects therapy.
may lead to premature discharges from emergency
departments. Diagnosis
There are no features of Salmonella gastroenteritis that
Typhoid and Paratyphoid Fever would allow its diagnosis based on clinical findings alone.
Fever, gastrointestinal symptoms (eg, vomiting, severe The routine microscopic stool examination for polymor-
diarrhea, abdominal distension, and pain), cough, rel- phonuclear cells is of limited clinical utility because a large
ative bradycardia, rose spots (pink macules frequently number of children with gastroenteritis will have a nega-
observed on the abdomen and chest), and splenomeg- tive test result (<5 polymorphonuclear cells per high-
aly are frequently regarded as features of typhoid and power field). All young infants with diarrhea, especially
paratyphoid fever. However, many patients lack these those younger than 3 months with a positive stool culture
findings, making diagnosis difficult if solely based on result, should have a blood culture performed, even if the
clinical features. In a reported foodborne epidemic, infant is well-appearing. Infants younger than 3 months
most patients had nonspecific symptoms, consisting with a positive blood culture result should undergo a lum-
of fever, headache, diarrhea, and anorexia. Hepato- bar puncture and careful examination assessing for the
megaly was seen in 7% of patients, splenomegaly in presence of musculoskeletal involvement (Table 1).
13% of patients, and rose spots in 5% of patients. Rel- (11) Any ill-appearing infant with a positive stool culture
ative bradycardia and rose spots are seldom observed in result should undergo a blood culture and lumbar punc-
children. Jaundice is frequently observed among chil- ture, be hospitalized, and be treated with parenteral
dren. Febrile convulsions have been reported in chil- antibiotics.
dren with enteric fever and may be the presenting The Widal test, a classic test that measures antibodies
symptom in some children. The incubation period against O and H antigens of S Typhi, was used for the
for enteric fevers is generally 7 to 14 days, with a range diagnosis of typhoid fever. However, its lack of sensitivity
of 3 to 60 days. and specificity has limited its utility. A false-positive test
In Pakistan, children younger than 5 years were result may lead to overtreatment and a delay in consider-
found to have more severe disease. More than 95% of ing other conditions. This outcome is especially likely in
children had fever, 20% to 41% had hepatomegaly, 5% parts of the world where typhoid fever is rare among chil-
to 20% had splenomegaly, 19% to 28% had abdominal dren and significantly less frequent than other bacterial
pain, and 8% to 35% had diarrhea. (9) Cough was pathogens.
Vaccination against typhoid fever is recommended against paratyphoid fever B has been demonstrated.
for all travelers to developing countries in Asia, (19)(20)
Latin America, and Africa, especially for those plan- Parents and their children need to be counseled about
ning to visit friends and relatives with 2 vaccines the potential risk of acquiring Salmonella if they own
available (Table 3). Travel to India, Pakistan, a high-risk pet, such as an iguana, lizard, snake, or turtle
Mexico, and Bangladesh account for most travel- (Table 2). Owners need to wash their hands after han-
related cases in the United States. Generally, typhoid dling the animals. The Centers for Disease Control and
vaccines are 50% to 80% effective in preventing Prevention has advised that reptiles and amphibians
disease. should be kept out of households with children younger
In many highly endemic countries, S Paratyphi than 5 years. Individuals at high risk of severe disease
causes close to 50% of all cases of enteric fever. In should have no contact with these animals. Reptiles
the United States, most cases of paratyphoid fever and amphibians should be kept out of child care centers
are related to international travel. No effective licensed and households with children younger than 1 year.
vaccine against S Paratyphi is available. However, cross- All documented cases of Salmonella infection must be
protective efficacy of Ty21a oral typhoid vaccine reported to county and state health departments.
PIR Quiz
This quiz is available online at http://www.pedsinreview.aappublications.org. NOTE: Learners can take Pediatrics in Review quizzes and claim credit
online only. No paper answer form will be printed in the journal.
1. A 6–year–old girl who presents with fever and diarrhea after a trip to India is suspected of having typhoid
fever. Which of the following findings is most frequently noted with this diagnosis?
A. Normal hemoglobin level.
B. Normal liver enzyme level.
C. Normal white blood cell count.
D. Positive blood culture result.
E. Positive stool culture result.
2. A previously healthy 9–month–old with vomiting and nonbloody diarrhea has a stool culture result positive for
Salmonella. Which of the following is appropriate treatment of this infant?
A. Azithromycin.
B. Ceftriaxone.
C. Chloramphenicol.
D. No antibiotics.
E. Trimethoprim-sulfamethoxazole.
3. A 7–month–old girl is traveling with her parents to Pakistan. Which of the following preventive measures is
most appropriate for this child?
A. Avoid fresh fruits and vegetables.
B. Bathe only in fresh water ponds.
C. Injectable Vi typhoid vaccine.
D. Oral typhoid vaccine Ty21a.
E. Prophylaxis with azithromycin.
4. A 6–month–old female has a stool culture result positive for Salmonella. Her parents inquire as to what they
could do to prevent this from happening again. Which of the following features is an established risk factor for
this infection?
A. Breastfeeding.
B. Nanny at home.
C. Oatmeal cereal.
D. Pet turtle at home.
E. Travel to New Mexico.
5. Mixed infections with multiple pathogens occur in endemic tropical countries. Which of the following
disorders in children treated for enteric fever who present with unremitting fevers is therapy most appropriate?
A. Dengue.
B. Malaria.
C. Rickettsia.
D. Shigella.
E. Tuberculosis.
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