ARTICULO MEDICO: MANIFESTACIONES CLINICAS Y DX DE LA FIEBRE MANCHADA DE LAS MONTAÑAS ROCOSAS

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Clinical manifestations and diagnosis of Rocky Mountain spotted fever
Author
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Sheldon L Kaplan, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: mar 16, 2011.
INTRODUCTION — Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne disease. It is the most common rickettsial infection in the United States. The etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate intracellular bacterium with tropism for human endothelial cells. The clinical spectrum of human infection with R. rickettsii ranges from mild to fulminant. The epidemiology, clinical manifestations, and diagnosis of RMSF will be reviewed here.
The basic biology of R. rickettsii infection, the mechanisms of disease, and the treatment of
this disorder are discussed separately. (See "Biology of Rickettsia rickettsii infection" and "Treatment of Rocky Mountain spotted fever".)

EPIDEMIOLOGY
Geography — RMSF occurs throughout the United States, in Canada, Mexico, Central America,
and in parts of South America (Bolivia, Argentina, Brazil, and Colombia). In the United States,
RMSF is most prevalent in the southeastern and south central states. In 2007, there were 2221
cases of RMSF reported to the Centers for Disease Control and Prevention (CDC); this represented
an increase from the 1130 cases reported in 2003 [1]. The estimated national average annual
incidence of RMSF was 2.2 cases per million persons in 2003, but incidence varied by geographic
area from 1 to >15/100,000 persons (figure 1) [1,2]. However, epidemiologic studies that attempt to assess the frequency of RMSF have been hampered by the fact that serologic assays that do not distinguish RMSF from other spotted fever group rickettsiae species and by imprecise case
definitions [3,4].
An outbreak of RMSF in 16 patients from 2002 through 2004 was reported from rural eastern
Arizona, a state that had previously only rarely reported the disease (three cases from 1981 through
2001) [5]. Of these patients, 13 (81 percent) were children ≤12 years of age; all had contact with
tick-infested dogs (see 'Transmission' below).
Although RMSF is more common in rural and suburban locations, it also may occasionally occur in
residents of urban areas. For example, cases of RMSF have been described in New York City in
patients who presumably acquired the infection from tick bites in urban parks [6]. The ease and
frequency of interstate travel means that patients with RMSF acquired in endemic areas may
present to physicians practicing in locations where RMSF is uncommon or unknown. In addition,
family clusters of infection are a well-recognized feature of RMSF because of shared residence and
risks for vector exposure [7,8].
An investigation of clusters of cases in Tennessee and North Carolina concluded that significant
geographic differences in disease severity were present [9]. Similar clusters of severe disease have
been reported in several locations in South America [10].
Seasonal variation — Most cases of RMSF occur in the spring and early summer, when outdoor
activity is most frequent. However, rare cases are seen in the cold weather months in residents of
the southern United States [11]. Whether these "out of season" cases are due to infection with R.
rickettsii or other more benign spotted fever group rickettsiae has recently been questioned [3].
Risk factors — The frequency of reported cases of RMSF is highest among males. Although
previous studies found that the highest incidence of RMSF occurred in children <10 p="" years="">surveillance during 2003 demonstrated the highest age-specific incidence was among persons
aged 40 and 64 years [12]. Individuals with frequent exposure to dogs and who reside near wooded
areas or areas with high grass are probably also at increased risk for infection.
A retrospective study utilizing a national surveillance database found that the incidence of RMSF
among American Indians was 16.8/100,000 during the period from 2000 to 2005. In contrast, the
incidence among whites and blacks was 4.2 and 2.6/100,000, respectively [13].
TRANSMISSION
Route — RMSF is usually transmitted via a tick bite; tick bites are painless and many occur in body
areas obscured by hair or skin folds. Thus it is not surprising that up to one-third of patients with
proven RMSF do not recall a recent tick bite or recent tick contact [14,15]. Transmission rarely
occurs from infective tick tissues or feces by conjunctival contamination, transcutaneous
transmission, or inhalation (eg, after crushing blood-engorged ticks).
Vectors — The principal vector of RMSF in the eastern and south central United States is
Dermacentor variabilis (the American dog tick) (picture 1). In contrast, Dermacentor andersoni (the
Rocky Mountain wood tick) (picture 2) is the primary vector in the mountain states west of the
Mississippi River.
Rhipicephalus sanguineus, the common brown dog tick (picture 3), is also a vector for RMSF in
some areas of the United States [5]. This tick was implicated in the outbreak of RMSF in rural
eastern Arizona, noted above. R. sanguineus ticks in all life-stages of growth were abundantly found in and around many of the patients' homes and R. rickettsii was detected on polymerase chain reaction (PCR) and cultured from engorged and nonengorged ticks. Neither of the primary vectors for RMSF in the United States, D. variabilis nor D. andersonii ticks, was recovered from the homesites. Although the ecology of rural eastern Arizona that allowed the infestation of R.
sanguineous ticks may not be generalizable to other regions of the United States, the R.
sanguineus tick is widely distributed across North America, and should be considered as a potential
vector. The Cayenne tick (Amblyomma cajennense) is a vector for R. rickettsii transmission in
Central and South America. The yellow dog tick (Amblyomma aureolatum) has also been implicated as a vector in Brazil [16].
Incubation period — Infected patients become symptomatic 2 to 14 days after being bitten by an
infected tick, with most cases occurring between five and seven days after exposure.

CLINICAL MANIFESTATIONS
Early nonspecific symptoms — In the early phases of illness, most patients have nonspecific
signs and symptoms such as fever (in virtually all cases), headache (often severe), malaise,
myalgias, arthralgias, and nausea with or without vomiting (each in about 60 percent) [17]. Some
patients, especially children, may also have prominent abdominal pain that may be severe and may
lead to erroneous diagnoses such as acute appendicitis, cholecystitis, and even bowel obstruction
[18,19]. A small number of patients in the early phases of RMSF have been admitted to surgical
services and some have undergone laparotomy.
Rash — Most patients with RMSF develop a rash between the third and fifth days of illness (picture4) [8,17].

PICTURE 4: Rocky mountain spotted fever rash

Child with Rocky Mountain spotted fever has the rash that is characteristic but typically does not appear until several days after fever onset.

From: Fatal Cases of Rocky Mountain Spotted Fever in Family Clusters --- Three States, 2003. MMWR Morb Mortal Wkly Rep 2004; 53(19):407. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5319a1.htm.

 However, only 14 percent of patients have rash on the first day, and less than one-half
develop a rash in the first 72 hours of illness [20]. As a result, rash is often absent when patients
first contact a physician [20,21]. In a small percentage of patients, the rash is delayed in onset past
five days and/or is atypical (eg, confined to one body region).
A potential diagnostic problem is that rash never occurs in up to 10 percent of patients. These cases
of "spotless" RMSF may be severe and end fatally [22]. In addition, the rash can be easily
overlooked in dark-skinned individuals. These observations are important clinically because a delay
in the institution of antimicrobial therapy beyond five days is associated with an increased mortality
rate (22.9 versus 6.5 percent in those treated earlier in one report) [21]. (See "Treatment of Rocky
Mountain spotted fever".)
The typical rash of RMSF begins on the ankles and wrists and spreads both centrally and to the
palms and soles. The evolution of skin rash may vary among patients. Although the rash commonly
begins as a maculopapular eruption and then becomes petechial, some patients may suddenly
develop a petechial rash without a prior maculopapular eruption. Urticaria and pruritus are not
characteristic of RMSF and their presence makes the diagnosis unlikely.
Other symptoms — In addition to early nonspecific symptoms, abdominal pain, and rash, cough,
bleeding, edema (especially in children), confusion, focal neurologic signs, and seizures may also
be present [18]. Conjunctivitis, retinal abnormalities, and electrocardiographic abnormalities may
also rarely occur and lead to diagnostic confusion. The presence or absence of individual clinical
manifestations is in part dependent upon the duration of illness. As an example, physicians in
referral centers often see patients late in the course and are more likely to observe symptoms such
as abnormal mentation, seizures, and focal neurologic deficits such as cranial nerve palsies or
transient deafness. Gangrene of the digits, ears, and scrotum can also occur in severe cases, as
can widespread organ dysfunction [23,24].
Mortality — An estimated 612 deaths were attributable to RMSF in the United States between
1983 and 1998 [25]. The case-fatality rate was highest in the very young (≤4 years, 3 to 4 percent)
and elderly persons (≥60 years, 4 to 9 percent) (figure 2) [26].
DIFFERENTIAL DIAGNOSIS — In view of the protean clinical features of RMSF, it is not surprising
that this disorder is often confused with a wide array of other conditions.
· RMSF is commonly mistaken for an undifferentiated viral illness during the first few days of
illness. If penicillin or a cephalosporin is administered empirically during this phase of
illness, the subsequent rash may then be incorrectly diagnosed as a drug eruption.
· RMSF has been confused with measles, meningococcemia, infectious mononucleosis, viral
hepatitis, leptospirosis, streptococcal infection, parvovirus infection (Fifth disease), roseola,
enteroviral infection, and viral meningitis. In tropical areas typhoid fever, leptospirosis, and
even dengue may be confused with RMSF.
· The clinical features of RMSF overlap with those of both monocytic ehrlichiosis and
granulocytic anaplasmosis. Distinguishing between RMSF and ehrlichiosis on the basis of
clinical features may be impossible, although the presence of leukopenia and the absence
of rash are more typical of ehrlichiosis (table 1). The preferred treatment of
ehrlichiosis, doxycycline, is the same as that of RMSF. (See"Human ehrlichiosis and
anaplasmosis" and "Treatment of Rocky Mountain spotted fever".)
· One study reported that a proposed new rickettsial species (Rickettsia amblyommii) present
in the tick Ambylomma americanum may be in fact responsible for some illnesses in North
Carolina that are identical in their clinical presentation to infection with R. rickettsii [27]. At
present this report remains unconfirmed and of unknown significance.

DIAGNOSIS — The diagnosis of RMSF is based upon the probability that individual clinical features represent RMSF in the appropriate epidemiologic setting, as with suggestive symptoms in an endemic area in the spring or early summer [28]. There is no completely reliable diagnostic test in the early phases of illness when therapy should be begun. Later, the diagnosis can be made by skin biopsy and confirmed serologically. Rickettsial blood cultures are highly sensitive and specific but are only available in research centers with specialized laboratories.
Laboratory studies — Most patients with RMSF have a normal white blood cell count at
presentation. However, the white blood cell count may be low, normal, or elevated in individual
patients and is therefore not diagnostically helpful. As the illness progresses, thrombocytopenia
becomes more prevalent and may be severe; it is thought to result from increased destruction at
sites of rickettsia-mediated vascular injury [20]. The low platelet count may be accompanied by a
reduced fibrinogen concentration and elevated fibrin split products; however, true disseminated
intravascular coagulation is rare.
Other findings that are common in advanced cases include hyponatremia, elevations in serum
aminotransferases and bilirubin, azotemia, and prolongation of the partial thromboplastin and
prothrombin times [18]. In a small number of cases, jaundice and renal failure dominate and
confuse the clinical presentation [24,29].
In a review of 114 patients from our hospital, 19 percent developed acute renal failure (defined as
an elevation in the serum creatinine concentration above 2 mg/dL [177 micromol/L]) [29]. A variety of mechanisms may contribute to this complication, including hypotension-induced acute tubular necrosis, intravascular thrombosis, and interstitial vascular inflammation due to direct infection of the endothelial cells by R. rickettsii. (See "Biology of Rickettsia rickettsii infection".)
If a lumbar puncture is performed in a patient with RMSF, cerebrospinal fluid (CSF) analysis usually shows a white blood count (WBC) of <100 a="" cells="" either="" microl="" or="" p="" per="" polymorphonuclear="" with="">lymphocytic predominance [18]. Moderately elevated protein (100 to 200 mg/dL) and a normal glucose level are common [30,31]. These findings may not help distinguish RMSF from meningococcal disease.
Skin biopsy — Biopsy of a skin lesion obtained with a 3 mm punch biopsy can establish the
diagnosis of RMSF. Fresh or formaldehyde-fixed tissue should be examined for rickettsiae using
direct immunofluorescence or immunoenzyme methods [32]. Direct immunofluorescence staining
can provide an answer in a few hours if the necessary conjugates are available locally. If local
facilities are not able to do direct immunofluorescence, reference laboratories can perform
immunoperoxidase stains on fixed tissue specimens. However, the delay in obtaining results makes
this technique of little or no use for initial patient management.
The sensitivity of detecting R. rickettsii in skin biopsies by direct immunofluorescence staining is
approximately 70 percent with a specificity of 100 percent; however, the sensitivity rapidly declines
after antirickettsial therapy is begun [32]. It is therefore not useful to obtain a skin biopsy in patients
who have received a tetracycline (usually doxycycline) or chloramphenicol for more than 48 hours.
Serologic testing — The diagnosis of RMSF is best confirmed serologically using the indirect
fluorescent antibody (IFA) test [33]. IFA testing is available through all state health departments and through several large reference laboratories. Antibodies typically appear 7 to 10 days after the onset of the illness, and the optimal time to obtain a convalescent antibody titer is at 14 to 21 days after the onset of symptoms. The minimum diagnostic titer in most laboratories is 1:64.
The overall sensitivity of the IFA test is approximately 95 percent. However, there are two settings in which false negative results are more likely:
· Serologic testing is usually not helpful during the first five days of symptoms, when therapy
should be initiated, because the antibody response is not yet detectable [21].
· A small percentage of patients who are treated within the first 48 hours after symptoms
have begun may not develop convalescent antibodies [33].
Although the IFA is sensitive, serologic assays are insufficient to identify conclusively the specific
rickettsial agent responsible for the infection. A study of 15 serum specimens with antibodies
reactive with R. rickettsii from the CDC examined the specimens by microimmunofluorescence and
Western blot assays against antigens of R. rickettsii and R. parkeri [34]. Four patients had higher
titers of antibody to R. rickettsii, five had higher titers to R. parkeri, and in six patients titers were
equivalent to both rickettsial pathogens. Thus, spotted fever group rickettsiae, other than R.
rickettsii, may be responsible for cases of tick-borne rickettsiosis in the United States.
Other serologic tests that may be employed include enzyme immunoassay (EIA), complement
fixation (CF) and latex agglutination (LA), indirect hemagglutination (IHA) or microagglutination (MA) assays. A probable diagnosis of RMSF may be established with a titer of 1:128 or greater by LA, IHA, or MA.
The Weil-Felix test, which detects crossreacting antibodies against Proteus vulgaris antigens (OX2
and OX19), lacks sensitivity and specificity and its use is no longer recommended [17,33].

SUMARY AND RECOMMENDATIONS
· Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne
disease. (See 'Introduction' above.)
· RMSF occurs throughout the United States, Canada, Mexico, Central America, and in parts
of South America (Bolivia, Argentina, Brazil, and Colombia). (See 'Geography' above.)
· Most cases of RMSF occur in the spring and early summer, when outdoor activity is most
frequent. (See 'Seasonal variation' above.)
· RMSF is usually transmitted via a tick bite, although up to one-third of patients with proven
RMSF do not recall a recent tick bite or recent tick contact. (See 'Transmission' above.)
· In the early phases of illness, most patients have nonspecific signs and symptoms such as
fever, headache, malaise, myalgias, arthralgias, and nausea with or without vomiting.
Children may also have prominent abdominal pain that may be mistaken for other
intraabdominal processes, like appendicitis. Most patients with RMSF develop a rash
between the third and fifth days of illness. (See 'Clinical manifestations' above.)
· The diagnosis of RMSF is a clinical one based on a constellation of symptoms that is
consistent with the clinical presentation in an appropriate epidemiologic setting (eg, an
endemic area in the spring or early summer). There is no completely reliable diagnostic test
in the early phases of illness when therapy should be initiated. (See 'Diagnosis' above.)
· In later illness, the diagnosis can be made by skin biopsy and confirmed serologically.
(See 'Diagnosis' above.)
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REFERENCES

ARTICULO MEDICO: BIOLOGIA DE LA INFECCION POR RICKETTSIA RICKETTSSI

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Biology of Rickettsia rickettsii infection
Author
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Morven S Edwards, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: mar 28, 2008.
INTRODUCTION — Rickettsia rickettsii is the causative agent of Rocky Mountain spotted fever
(RMSF) and the prototypic member of the genus Rickettsia. The basic biologic features of R.
rickettsii and how it produces disease will be reviewed here. The clinical manifestations of RMSF
and its treatment are discussed separately. (See "Clinical manifestations and diagnosis of Rocky
Mountain spotted fever" and"Treatment of Rocky Mountain spotted fever".)

TAXONOMY — Like other gram-negative bacteria, R. rickettsii is a member of the alpha-group of
purple bacteria. It is a member of the order Rickettsiales and the family Rickettsiaceae. The family
Rickettsiaceae, in turn, contains the genera Rickettsia and Orientia. The genus Rickettsia is divided
into the typhus and spotted fever groups.
R. rickettsii is the prototype of the spotted fever group, which has nine separate pathogenic species.
Phylogenetic studies utilizing the 16S ribosome have shown that R. rickettsii is closely related to
other members of the spotted fever group such as R. conorii and R. sibirica, whereas its
phylogenetic relationship to other spotted fever members such as R. akari, R. australis, and R. belli
is substantially more distant.

MICROBIOLOGY — R. rickettsii is a weakly gram-negative non-motile coccobacillus measuring 0.3 to 0.7 mcm by 0.8 to 2.0 mcm. R. rickettsii are difficult to see in tissue without special stains, but they can be visualized using Giemsa, Machiavello, and Gimenez staining and by the use of direct fluorescent antibody staining techniques.
Ultrastructure — R rickettsii has ribosomes and a single circular chromosome located in an
amorphous cytosol surrounded by a plasma membrane. In addition, an indistinct microcapsular
layer is present on the outer surface of the cell wall. An electron-lucent zone separates this layer
from the host cytosol. This zone is thought to represent a slime layer which may be important in
pathogenicity [1].
Growth and survival characteristics — R. rickettsii is an obligate intracellular parasite that cannot
be propagated on cell-free media. It can be grown in vitro in the yolk sac of developing chicken
embryos, but it is more conveniently cultured on primary or established cell culture monolayers,
such as chicken embryo fibroblasts, mouse L cells, and golden hamster cells. Like all members of
the spotted fever group, R. rickettsii proliferates by binary fission and grows in both the nucleus and cytoplasm of host cells. When inside host cells, R. rickettsii resides directly in the cytosol or nucleus rather than being surrounded by a host cell membrane.
R. rickettsii has the curious ability to spread from cell to cell by traversing cell membranes without
causing obvious damage. Individual rickettsial organisms exit from infected cells via host cell
filopodia and rarely accumulate in large numbers inside individual cells [1]. R. rickettsii moves
between cells at astonishing speeds (up to 4.8 m/minute) by recruiting and polymerizing host cell
actin filaments [2].
Metabolism — R. rickettsii largely depends on the host cell for its nutritional needs. R. rickettsii
lacks enzymes for sugar metabolism lipid and nucleotide synthesis and amino acid metabolism.
Numerous specialized adaptations allow R. rickettsii to exist as an intracellular parasite. These
include the ability to acquire host ATP using a rickettsia-derived ATP translocator protein, and the
ability to utilize host-derived glutamine as an energy source [3]. In addition, R. rickettsii thrives in the presence of high concentrations of potassium and proteins [1].
Antigenic structure — Studies of the antigenic structure of rickettsiae led to the current
classification of the multiple rickettsial species. A still poorly understood cross-reacting surface
antigen is responsible for the Weil-Felix reaction in which sera from patients with a primary
rickettsial infection cross-react with somatic antigens of three strains of Proteus (OX19, OX2, and
OXK) [4]. Other antigens have been developed for complement fixation, agglutination, indirect
hemagglutination, indirect fluorescent antibody, and enzyme-lined immunosorbent assay tests.
(See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever".)
Lipopolysaccharides (LPS) in the rickettsial cell membrane elicit a strong but nonspecific immune
response. Such antibodies are not protective and they cross-react with other members of the
spotted fever group and to a lesser extent with LPS from members of the typhus group [5].

BASIS FOR VIRULENCE — Individual strains of R. rickettsii can mutate in vitro from highly virulent to relatively avirulent [6]. Virulence can vary strikingly among strains, but is also affected by the feeding status of the tick, inoculum dose, and certain host factors.
Strain variations in virulence — No satisfactory biologic explanation has been made to explain a
number of curious observations about striking variations in the virulence of individual strains of R.
rickettsii. Except for limited information on rickettsial adhesions, other rickettsial virulence factors
have not yet been identified. (See 'Pathophysiology' below.)
· It was noted almost 100 years ago that the mortality rate in RMSF was over 80 percent in
the Bitterroot Valley of Montana, versus only 3 percent in the adjacent Snake River Valley.
However, the etiologic agent appeared to be identical when isolated from patients in both
locations and injected into laboratory animals.
· Individual strains of R. rickettsii isolated from ticks vary in virulence, but isolates made from
humans with fulminant and mild disease appear to be identical when injected into laboratory
animals [6]. Attempts to correlate laboratory growth characteristics (such as plaque
morphology) with pathogenicity in animal models of infection have been unsuccessful or
inconclusive [6].
Tick feeding status — The principal vector of RMSF in the eastern and south central United States
is Dermacentor variabilis (the American dog tick) (picture 1). In contrast, Dermacentor andersonii
(the Rocky Mountain wood tick) (picture 2) is the primary vector in the mountain states west of the
Mississippi River. The common brown dog tick (Rhipicephalus sanguineus) (picture 3) was
implicated as the vector for RMSF in an outbreak during 2002 to 2004 in eastern Arizona [7]. The
disease is usually transmitted via a tick bite.

PICTURE 1:An adult female dermacentor variabilis (American dog tick)




PICTURE 2: An adult female Dermacentor andersoni (rocky mountain wood tick)




PICTURE 3: An adult female rhipicephalus sanguineus (brown dog tick)



The virulence of R. rickettsii strains in ticks is dependent upon the feeding status of the individual
tick. The virulence of R. rickettsii in over-wintered or starved ticks is restored only after the ingestion of a blood meal or after incubation at 37ºC for one to two days. The mechanism for this
"reactivation" phenomenon is uncertain but it may be related in part to the size of extracellular slime
layer [3].
Dose of inoculum — The dose of the inoculum is an additional important virulence factor in
humans. Humans inoculated with ten median guinea pig infectious doses of R. rickettsii had shorter
incubation periods, longer duration of fever after institution of anti-rickettsial treatment, and higher
attack rates than subjects inoculated with one median infectious dose [8].
Pathophysiology — Following inoculation from a feeding tick, the process by which rickettsiae gain
entry into endothelial cells involves a complex interaction between lipopolysaccharides and
rickettsial outer membrane proteins (rOmps), which act as adhesions. Three rOmps on the surface
of R. rickettsii with molecular sizes of 190, 120, and 17 kDa have been cloned in vitro and
sequenced. The 190 kDA and the 120 kDa rOmps are also immunogens capable of eliciting
protective immune responses in experimental animals [1]. OmpB binds to a protein (Ku70) in the
membrane of susceptible host cells. Subsequently, this activated Ku70 protein recruits an enzyme
(ubiquitin ligase) that causes ubiquitination of Ku70. This process, in turn, sets off a signaling
cascade that causes the rearrangement of cellular actin and allows the cell to engulf the rickettsia
via endocytosis [9,10]. Once inside cells, rickettsiae utilize two enzymes (phospholipase D and tlyC) to lyse the phagosomal membrane and escape into the cytosol [11,12]. R. rickettsii then express a series of other proteins that lead to polymerization of host cell monomeric actin filaments in the cytoplasm, which allows for invagination of host cell membranes and passage into neighboring cells via filopodia derived from host cell membranes [1,3,12,13]. R. rickettsii subsequently spread throughout the body via the bloodstream or lymphatics.
The mechanism by which R. rickettsii produces its characteristic damage to small blood vessels is
not known. Rickettsia do not secrete exotoxins and they can kill infected cells independent of any
host immune response. Cell injury and death has been associated with phospholipase A activity,
protease activity, and free radical-induced lipid peroxidation [1]. The primary mode of rickettsiainduced cell death is cell necrosis [11]. Infected cells can also be eliminated by immune effector mechanisms, such as CD8+ cytotoxic T-lymphocyte induced apoptosis [13,14]. The net effect of these processes is endothelial cell injury, which is followed by immune and phagocytic cellular responses via the local accumulation of lymphocytes and macrophages, resulting in a
lymphohistiocytic vasculitis.
Widespread rickettsii-induced vasculitis leads to minute foci of hemorrhage, increased vascular
permeability, edema, and the activation of humoral inflammatory and coagulation mechanisms.
Leakage of fluid from the bloodstream to tissue can have devastating results when the lung or brain
are involved, since both sites lack lymphatic vessels to remove interstitial fluid [11]. Although R.
rickettsii and other spotted fever group rickettsial infections induce a procoagulant state,
disseminated intravascular coagulation is rare in patients with RMSF. Thus, vascular thrombosis
and hemorrhage that results in widespread organ dysfunction is probably a physiological result of
widespread endothelial denudation [11].
Host factors — A number of host factors have been associated with an increase in severity of or
fatal RMSF [15,16]:
· Increasing age
· Male gender
· Presence of glucose-6-phosphate dehydrogenase deficiency
Black race and alcohol have also been associated with more severe disease and higher fatality, but
it is difficult to exclude the role of a delay in seeking or receiving antimicrobial therapy in these
patients [17].
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REFERENCES
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Clin Microbiol Rev 1989; 2:227.
2. Heinzen RA. Rickettsial actin-based motility: behavior and involvement of cytoskeleta l
regulators. Ann N Y Acad Sci 2003; 990:535.
3. Winkler HH. Rickettsia species (as organisms). Annu Rev Microbiol 1990; 44:131.
4. Kaplan JE, Schonberger LB. The sensitivity of various serologic tests in the diagnosis of
Rocky Mountain spotted fever. Am J Trop Med Hyg 1986; 35:840.
5. Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin
Microbiol Rev 1997; 10:694.
6. McDade JE. Evidence supporting the hypothesis that rickettsial virulence factors determine
the severity of spotted fever and typhus group infections. Ann N Y Acad Sci 1990; 590:20.
7. Demma LJ, Traeger MS, Nicholson WL, et al. Rocky Mountain spotted fever from an
unexpected tick vector in Arizona. N Engl J Med 2005; 353:587.
8. DuPont HL, Hornick RB, Dawkins AT, et al. Rocky Mountain spotted fever: a comparative
study of the active immunity induced by inactivated and viable pathogenic Rickettsia rickettsii. J
Infect Dis 1973; 128:340.
9. Walker DH. Targeting rickettsia. N Engl J Med 2006; 354:1418.
10. Martinez JJ, Seveau S, Veiga E, et al. Ku70, a component of DNA-dependent protein
kinase, is a mammalian receptor for Rickettsia conorii. Cell 2005; 123:1013.
11. Walker DH, Valbuena GA, Olano JP. Pathogenic mechanisms of diseases caused by
Rickettsia. Ann N Y Acad Sci 2003; 990:1.
12. Walker DH. Rickettsiae and rickettsial infections: the current state of knowledge. Clin Infec t
Dis 2007; 45 Suppl 1:S39.
13. Olano JP. Rickettsial infections. Ann N Y Acad Sci 2005; 1063:187.
14. Walker DH, Olano JP, Feng HM. Critical role of cytotoxic T lymphocytes in immune
clearance of rickettsial infection. Infect Immun 2001; 69:1841.
15. Hattwick MA, O'Brien RJ, Hanson BF. Rocky Mountain spotted fever: epidemiology of an
increasing problem. Ann Intern Med 1976; 84:732.
16. Walker DH. The role of host factors in the severity of spotted fever and typhus rickettsioses.
Ann N Y Acad Sci 1990; 590:10.
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Mountain spotted fever. Clin Infect Dis 1995; 20:1118.
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Treatment and prevention of typhoid fever

Author

Elizabeth L Hohmann, MD

Section Editor

Stephen B Calderwood, MD

Deputy Editor

Elinor L Baron, MD, DTMH

Disclosures

All topics are updated as new evidence becomes available and our peer review process is

complete.

Literature review current through: Jan 2013. | This topic last updated: jul 13, 2012.

INTRODUCTION — Typhoid fever and paratyphoid fever (also known as enteric fever, but

collectively referred to here as typhoid fever) are severe systemic illnesses characterized by

sustained fever and abdominal symptoms. The treatment and prevention of typhoid fever will be

reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of typhoid

fever are discussed separately. (See"Pathogenesis of typhoid fever" and "Epidemiology,

microbiology, clinical manifestations, and diagnosis of typhoid fever".)

ANTIBIOTIC THERAPY — Treatment of typhoid fever has been complicated by the development and rapid dissemination of typhoidal organisms resistant to ampicillin, trimethoprimsulfamethoxazole, and chloramphenicol. In recent years, development of creeping resistance to fluoroquinolones has resulted in more challenges.

Multidrug-resistant strains — Multidrug-resistant (MDR) strains have caused numerous outbreaks

in the Indian subcontinent, Southeast Asia, Mexico, the Arabian Gulf, and Africa [1,2]. These

patterns of resistance are reflected in travelers returning to the United Kingdom and the United

States. In 1999, 26 percent of S. typhi strains characterized at a United Kingdom reference lab were MDR strains [3], and 17 percent of 293 strains evaluated by the Centers for Disease Control and Prevention (CDC) from 1996 to 1997 were resistant to five drugs [4]. In contrast, a study from India has reported the "reemergence" of sensitivity to older drugs: 67 percent of 60 S. typhi blood isolates and 80 percent of 20 S. paratyphi blood isolates from 2001 through 2004 were sensitive

to chloramphenicol [5,6].

Resistance patterns have led to a shift toward the third generation cephalosporins, azithromycin,

and fluoroquinolones as empiric therapy for typhoid fever while awaiting the results of antimicrobial

susceptibilities.

A report of 113 S. typhi strains collected in India from 1987-2006 demonstrated possible “MIC

creep” for ceftriaxone, though no frank resistance. A gradual increase in ceftriaxone MIC has been

observed in five-year increments: 0.047 mcg/mL, 0.098 mcg/mL, 0.211 mcg/mL, and 0.365 mcg/mL for ceftriaxone MIC [7].

Two isolates of S. paratyphi B expressing extended-spectrum beta-lactamases have been reported

from Turkey [8].

Fluoroquinolone-resistant organisms — Nalidixic acid-resistant organisms with decreased

susceptibility to the clinically important fluoroquinolones have become a major problem worldwide.

Isolated cases of high-level resistance to ciprofloxacin have been reported from India in S. paratyphi

and S. typhi (MICs of 8 mcg/mL to 16 mcg/mL) [9-11].

Nalidixic acid-resistant S. typhi (NARST, NaR, or NALR) have decreased ciprofloxacin sensitivity

and are less effectively treated with fluoroquinolones, especially with the use of a "short course" of

three to five days, which is very effective against susceptible organisms. The clinical impact of NaR

organisms is illustrated by the following studies:

· A retrospective review of 150 patients from Vietnam showed that patients infected with NaR

S. typhi defervesced more slowly (256 versus 84 hours) and more frequently required

retreatment (33 versus 0.8 percent) than those infected with nalidixic acid-sensitive

organisms [12].

· Pooled data from several studies of almost 500 bacteremic patients treated with two, three,

or five days of ofloxacin, found that those patients with NaR strains who got ofloxacin had

greater rates of clinical treatment failure than those treated with comparator drugs

(eg, ceftriaxone, azithromycin, or cefixime) [13].

· Additional reports from other parts of the world identified treatment failures with

fluoroquinolones for enteric fever caused by nalidixic acid-resistant S. typhi and S.

paratyphi that tested susceptible to the quinolones [14-16].

· An open label, randomized study in 88 Vietnamese patients with bacteremia due to NaR or

MDR S. typhi strains compared oral treatment with azithromycin (1 g daily for five days)

to ofloxacin (200 mg twice daily for five days) [17]. There was no difference in clinical cure

rate between the regimens, but patients with NaR S. typhi treated with ofloxacin took longer

to defervesce and had a higher rate of positive stool cultures following therapy compared

with those receiving azithromycin (41 versus 0 percent). Early convalescent fecal shedding

may spread the organism in a community even if few of these individuals become chronic

carriers.

This situation has been further complicated by the emergence of newer mechanisms of resistance

to fluoroquinolones [18]. Some isolates may have decreased sensitivity to clinically important

fluoroquinolones, but appear to be sensitive to nalidixic acid, calling into question the reliability of

using NaR as a marker of FQ resistance. As a result, both the Clinical and Laboratory Standards

Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) have

revised the fluoroquinolone breakpoints for extra-intestinal Salmonella isolates. CLSI standards now

designate Salmonella isolates with aciprofloxacin MIC ≥1 mcg/mL as resistant (formerly MIC 2 to 4

mcg/mL), MIC 0.125 to 0.5 mcg/mL as intermediate, and MIC ≤0.064 mcg/mL as susceptible.

Laboratories in the United States are in the process of implementing such changes [18].

S. typhi isolates should be screened for resistance to nalidixic acid and, when possible, directly

tested for ciprofloxacin or ofloxacin sensitivity utilizing the new breakpoints as described above [18-

20]. However, the latter may be technically challenging especially in resource-limited settings.

Infectious disease consultation should be considered for such cases if clinicians are not familiar with

typhoid fever and its treatment.

When possible, patients with enteric fever caused by NaR organisms or organisms with

decreased ciprofloxacin or ofloxacin sensitivity should ideally be treated with a nonquinolone drug.

However, it is important to note that alternatives are expensive, sometimes not available, and may

require parenteral administration. Alternative treatments that are likely to be investigated more in the future include azithromycin, imipenem, the newer fluoroquinolones, higher doses of

fluoroquinolones, and combination therapies.

Antimicrobial regimens — Typhoid fever is usually treated with a single antibacterial drug. The

optimal choice of drug and duration of therapy are uncertain [12,21,22]. Antibiotic selection depends upon local resistance patterns, patient age, whether oral medications are feasible, the clinical setting, and available resources. In some circumstances, older agents such as chloramphenicol, ampicillin, or trimethoprim-sulfamethoxazole may be appropriate, but these

drugs are generally not used widely because of high levels of resistance. Oral chloramphenicol is

no longer available in the United States but is still used in other parts of the world. Successful

treatment in uncomplicated cases usually results in clinical improvement within three to five days. It

is reasonable to begin with a parenteral agent and then complete therapy with an oral drug once

symptoms improve.

Adults — Drugs of choice for the treatment of typhoid fever in adults include [23]:

· A fluoroquinolone such as ciprofloxacin (500 mg twice daily) or ofloxacin (400 mg twice

daily), either orally or parenterally for 7 to 10 days. The fluoroquinolones should not be used

as a first-line treatment for typhoid fever in patients from South Asia or other regions with

high rates of fluoroquinolone resistance unless antibiotic susceptibility data demonstrate

fluoroquinolone or nalidixic acid sensitivity [14,15]. (See 'Fluoroquinolone-resistant

organisms' above.)

· A beta-lactam such as ceftriaxone (2 to 3 g once daily) parenterally or cefixime (20 to 30

mg/kg per day orally in two divided doses) for 7 to 14 days.

Alternative agents for adult patients who cannot be treated with the above antimicrobials, and for

fluoroquinolone resistant isolates include:

· Azithromycin (1 g orally once followed by 500 mg once daily for five to seven days, or 1 g

orally once daily for five days) [24-27].

· Chloramphenico l 2 to 3 g per day orally in four divided doses for 14 days.

Fluoroquinolones appear to have therapeutic advantages over beta-lactams for the treatment of

uncomplicated typhoid fever and are now considered by many experts to be the drug of choice for

fully susceptible organisms in patients who can take these drugs. Quinolones are bactericidal and

concentrated intracellularly and in the bile. Ciprofloxacin, ofloxacin, and pefloxacin are widely

available and efficacious:norfloxacin is very poorly absorbed and should not be used. When treating

fully susceptible organisms, the quinolones may result in more rapid defervescence than betalactam

agents or chloramphenicol because of more rapid elimination of intracellular bacteria [28,29].

An open label randomized trial of 82 children randomized to receive cefixime (20 mg/kg per day

divided twice daily for five days) or ofloxacin (10 mg/kg per day divided daily for five days)

demonstrated more rapid resolution of fever in the ofloxacin group (4.4 versus 8.5 days) [30]. There was one treatment failure in the ofloxacin group compared with 10 treatment failures and one

relapse in the cefixime group. Another open label randomized trial among patients older than 15

years demonstrated that ofloxacin (200 mg orally twice daily for three days) was superior

to ceftriaxone (3 g intravenously once daily for three days) [29].

Azithromycin is capable of achieving excellent intracellular concentrations, and its use for treatment

of typhoid fever has been increasing as a result of rising fluoroquinolone resistance. There are no

standard microbiological breakpoints for determining Salmonellae MICs in routine clinical practice;

in research studies MICs are typically 4 to 32 mcg/mL. These values typically exceed serum drug

levels; azithromycin is concentrated intracellularly at levels 50 to 100 greater than serum levels [31].

The first report of azithromycin resistance (MIC by E-test 64 mcg/mL) in S. paratyphi A resulting in treatment failure was reported in a traveler returning from Pakistan to Great Britain. The patient was successfully treated with a two week course of IV ceftriaxone, 2 g daily [32].

In a study of 358 Vietnamese patients with infection due to resistant isolates (96 percent of isolates

were resistant to nalidixic acid and 58 percent were multidrug resistant), outcomes among those

treated with seven days of gatifloxacin or azithromycin were essentially equivalent [33]. A large

open label randomized controlled trial of gatifloxacin (10 mg/kg once daily for seven days)

versus chloramphenicol (75 mg/kg/day in four divided doses for 10 days) for uncomplicated, cultureproven

typhoid fever showed equivalent cure and relapse rates in children and adults in Nepal. The

authors concluded that gatifloxacin should be the preferred treatment for enteric fever in developing

countries because of its shorter treatment duration and fewer adverse events (14 versus 24 percent

of patients) [34].

Children — In patients with severe systemic illness, therapy should be initiated with a parenteral

agent. Current drugs of choice and dosing regimens for the treatment of typhoid fever in children

differ depending on local practice preferences. For these reasons, we present treatment regimens

used in the United States [35,36] and those used in endemic countries (eg, Southeast Asia) [23].

The practice preference in the United States for typhoid fever in children include one of the following treatment regimens [35,36]:

· A beta-lactam such as:

· Ceftriaxone 100 mg/kg per day intravenously once daily, maximum 4 g per day for

10 to 14 days.

· Cefotaxime 150 to 200 mg/kg per day intravenously in three to four equally divided

doses, maximum 12 g per day for 10 to 14 days.

· Cefixime orally 20 mg/kg per day orally in two divided doses, maximum 400 mg per

day for 10 to 14 days.

· A fluoroquinolone (See 'Fluoroquinolone-resistant organisms' above.)

· Ciprofloxacin 30 mg/kg daily, maximum 1000 mg either orally or parenterally for 7 to

10 days.

· Ofloxacin 30 mg/kg daily, maximum 800 mg per day, either orally or parenterally for

7 to 10 days.

· Azithromycin 10 to 20 mg/kg to 1 g maximum once daily for five to seven days.

· In children with infection due to a fully susceptible S. typhi strain, one of the following

alternative regimens may be used:

· Chloramphenico l 75 mg/kg per day divided every six hours, maximum 3 g per day

for 14 to 21 days.

· Amoxicillin 100 mg/kg per day divided every eight hours, maximum 4 g per day for

14 days.

· Trimethoprim-sulfamethoxazole 8 to 12 mg/kg trimethoprim/40 to 60 mg/kg

sulfamethoxazole per day divided every six hours, maximum 320 mg trimethoprim/1600

mg sulfamethoxazole per day for 14 days.

The practice preferences for children treated outside the United States, particularly in endemic

countries in Southeast Asia, more closely mirror treatment regimens used for adults and include one

of the following [23]:

· For fluoroquinolone-sensitive strains (see 'Fluoroquinolone-resistant organisms' above):

· Ciprofloxacin 15 mg/kg daily, maximum 1000 mg and 800 mg per day either orally

or parenterally for 10 to 14 days.

· Ofloxacin 15 mg/kg daily, maximum 800 mg per day either orally or parenterally for

10 to 14 days.

· In children with infection due to a fully susceptible S. typhi strains, one of the following

alternative regimens may be used:

· Chloramphenico l 100 mg/kg per day divided every six hours, maximum 3 g per day

for 14 to 21 days.

· Ampicillin 100 mg/kg per day divided every eight hours, maximum 4 g per day for

10 to 14 days.

· Trimethoprim-sulfamethoxazole 8 mg/kg trimethoprim/40 mg/kg sulfamethoxazole

per day divided every six hours, maximum 320 mg trimethoprim/1600 mg

sulfamethoxazole per day for 10 to 14 days.

· Alternative agents in children with infection due to multiple drug-resistant isolates, including

nalidixic acid-resistant S. typhi, include:

· Ceftriaxone 60 mg/kg per day intravenously once daily, maximum 2 g per day.

· Cefotaxime 80 mg/kg per day intravenously in three to four equally divided doses,

maximum 12 g per day for 10 to 14 days.

· A fluoroquinolone using a higher dose such as, ciprofloxacin or ofloxacin (20 mg/kg

daily, maximum 1000 mg and 800 mg per day, respectively), either orally or parenterally

for 10 to 14 days.

· Azithromycin 10 to 20 mg/kg to 1 g maximum for five to seven days.

Differences in practice preferences in children are in part due to concern in the United States about

the use of fluoroquinolones because of cartilage toxicity of these drugs in immature animals [37,38].

Large series have found no evidence of acute adverse bone or joint events [39] or of adverse

effects on growth [40] in humans. These findings are reassuring and suggest that, for a serious

illness such as infection with MDR S. typhi, a fluoroquinolone may be reasonably used in children

when other less toxic agents are not available or appropriate [41].

The optimal duration of third generation cephalosporin therapy in children has not been firmly

established, but the following observations have been made:

· A seven day course does not appear to be sufficient. In two randomized trials, seven days

of ceftriaxone (50 to 75 mg/kg per day) resulted in relapse within four weeks in 14 percent

of children [42,43]. In one of these studies, children ages 4 to 17 years were assigned to

seven days of therapy with either azithromycin (10 mg/kg per day; maximum 500 mg) or

ceftriaxone (75 mg/kg per day, maximum 2.5 g per day) [42]. There were four relapses with

ceftriaxone compared with none with azithromycin (14 versus 0 percent).

· Among the third generation cephalosporins, ceftriaxone may be superior to cefotaxime [44].

Oral cefixime is probably comparable to ceftriaxone for uncomplicated typhoid, although the

two drugs have not been extensively studied head-to-head [45,46].

Based upon these observations, ceftriaxone or cefixime is probably best given for 10 to 14 days to

minimize risk of relapse [42,43,45,46].

OTHER TREATMENT CONSIDERATIONS

Corticosteroids — Early studies with chloramphenicol suggested that concomitant corticosteroid

therapy might be beneficial in patients with typhoid fever. In a randomized, prospective, double blind study performed in Indonesia in the early 1980s, the administration of 3 mg/kg of dexamethasone as an initial dose with chloramphenicol was associated with a substantially lower

mortality in critically ill patients (shock, obtundation) with typhoid fever compared with those who

received chloramphenicol alone (10 versus 55 percent) [47]. Whether these findings will be

confirmed in the "post-chloramphenicol era" and in different clinical settings is uncertain, but severe

typhoid fever remains one of the few indications among acute bacterial infections for corticosteroid

therapy infections [48]. Dose in adults and children with severe disease (delirium, obtundation,

stupor, coma, or shock) consists of an initial dose of 3 mg/kg followed by 1 mg/kg every six hours

for a total of 48 hours.

Ileal perforation — Typhoid ileal perforation usually occurs in the third week of febrile illness and is

due to necrosis of the Peyer's patches in the antimesenteric bowel wall [49]. Affected patients

present with increasing abdominal pain, distension, peritonitis, and sometimes secondary

bacteremia with enteric aerobic and anaerobic microorganisms.

Prompt surgical intervention is usually indicated, as is wider antimicrobial coverage to cover fecal

peritonitis. The extent of surgical intervention remains controversial; the best surgical procedure

appears to be segmental resection of the involved intestine, when possible [50,51].

In a retrospective review from West Africa including 112 patients undergoing laparotomy for typhoid perforation, most of the perforations were single (80 percent) and in the terminal ileum [52]. Primary repair was successful in 84 percent of cases, although reoperative management was required in some patients who did not respond immediately. Even with surgery, mortality rates of 14, 16, and 34 percent have been reported in series from Nigeria, Togo, and the Ivory Coast.

Relapse — Relapse of typhoid fever after clinical cure can occur in immunocompetent individuals;

in such cases, it typically occurs two to three weeks after resolution of fever. Earlier studies in which the bacteriostatic agent chloramphenicol was the standard drug used noted relapse rates of 10 to 25 percent [55,56]. Most recent studies, which include multidrug resistant S. typhi infections and

newer antibiotics, have noted lower relapse rates of 1 to 6 percent. Thus, the fluoroquinolones may reduce relapse rates when the organisms are fully sensitive. An additional course of therapy with a drug to which the organism is clearly sensitive is indicated for relapsing illness. Longer treatment courses with third generation cephalosporins are also reasonable.

Chronic carriage — Chronic carriage of Salmonellae is defined as excretion of the organism in

stool for more than 12 months after the acute infection. Chronic carriage rates after S. typhi

infection range from 1 to 6 percent; rates are higher in patients with cholelithiasis or other biliary

tract abnormalities [58]. Chronic carriage occurs much more frequently with typhoidal strains than

nontyphoidal strains. (See "Approach to the patient with nontyphoidal Salmonella in a stool

culture".)

Chronic carriers do not develop recurrent symptomatic disease. They appear to have reached an

immunologic equilibrium in which they are chronically colonized, and may excrete large numbers of

organisms, but have high levels of systemic immunity and do not develop clinical disease. However,

chronic carriers represent an infectious risk to others, particularly if involved in food preparation. For this reason, eradication of carriage is usually attempted once such individuals are identified.

In the past, high dose ampicillin (4 to 6 g/day), sometimes in combination with cholecystectomy,

was frequently employed but not always successful for eradication of chronic carriage [59,60]. The

fluoroquinolones appear to be much more effective and better tolerated than ampicillin for

eradication of chronic carriage. In one study of 23 carriers, for example, the cure rate

with norfloxacin (400 mg orally twice daily for 28 days) was 86 percent in those with normal

gallbladders and 75 percent in those with gallstones [61]. Several smaller studies, evaluating 10 to

12 patients each, have found that ciprofloxacin (500 or 750 mg orally twice daily) for 14 to 28 days

eliminated carriage in 90 to 93 percent of cases [62].

Thus, attempted eradication with four weeks of fluoroquinolone therapy (eg, ciprofloxacin 500 to

750 mg orally twice daily or ofloxacin 400 mg orally twice daily) is a reasonable approach, with

subsequent consideration of additional therapy and cholecystectomy, if needed and appropriate.

Chronic urinary carriage of S. typhi is rare. It is usually associated with abnormalities of the urinary

tract such as urolithiasis or prostatic hypertrophy [63], or concurrent infection with Schistosoma

haematobium [64,65].

PREVENTION — Typhoid fever results from the ingestion of contaminated food or water. For

travelers, the main mechanism of transmission is ingestion of the local cuisine in areas where

sanitation and personal hygiene may be poor. The inoculum in food is likely higher than that in

contaminated water. (See "Travel advice", section on 'Food and water'.)

Typhoid vaccines — There are two vaccines available for protection against S. typhi: live oral S.

Typhi vaccine strain TY21a and parenteral Vi polysaccharide vaccine. Neither is completely

effective against S. typhi and neither provides protection against paratyphoid fever.

For travelers to high-risk areas such as the Indian subcontinent, typhoid vaccination may provide

protection at very little risk. In a review of laboratory-confirmed cases reported to the Centers for

Disease Control and Prevention (CDC) between 1994 and 1999, 75 percent of cases were

associated with travel; only 4 percent of these travelers had been vaccinated [66].

(See "Immunizations for travel", section on 'Typhoid vaccine'.)

In endemic areas, prevention of enteric fever would require implementing immunization for young

children. In a study including more than 37,000 children two to five years of age, the parenteral Vi

polysaccharide vaccine was useful for inducing both direct and indirect protection (overall protection was 57 percent). These data should inform further efforts in prevention of typhoid in endemic areas. Natural infection does not provide complete protection against recurrent illness (which is not the same as relapsed infection). One study suggests early treatment of natural infection may blunt humoral responses to capsular antigens [68]. Vaccination may be considered even after clinical illness, particularly in those not living in endemic areas, if re-exposure is expected. The optimal timing for vaccination following clinical illness is not known.

Experimental vaccines — Research is ongoing for alternative vaccines for the prevention of

typhoid due to the inconvenience of the oral vaccine and the frequent need for reimmunization with

both the oral and injectable formulations [69].

One vaccine far along in development follows the model of other polysaccharide-protein conjugate

vaccines (eg, Haemophilus influenzae and Streptococcus pneumoniae vaccines) by conjugating the

Vi capsular polysaccharide of S. typhi to a nontoxic recombinant Pseudomonas aeruginosa

exotoxin A. The vaccine was tested for safety, immunogenicity, and efficacy in a randomized

controlled trial in Vietnamese children ages two to five years [70]. S. typhi was isolated from 4 of

5525 children receiving two doses of vaccine compared with 47 of 5566 injected with placebo for a

91.5 percent efficacy over the subsequent 27 months. This efficacy persisted at 89 percent over 19

additional months of passive surveillance [71]. Although not yet available, this vaccine holds

promise for the immunization of individuals ≥2 years of age.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or

e-mail these topics to your patients. (You can also locate patient education articles on a variety of

subjects by searching on “patient info” and the keyword(s) of interest.)

· Basics topics (see "Patient information: Typhoid fever (The Basics)")

SUMMARY AND RECOMMENDATIONS

· Treatment of typhoid fever has been complicated by the development and rapid

dissemination of typhoidal organisms resistant to ampicillin, trimethoprim-sulfamethoxazole,

and chloramphenicol. In recent years, development of creeping resistance to

fluoroquinolones has resulted in more challenges. (See 'Multidrug-resistant strains' above.)

· Fluoroquinolone-resistant organisms have become a major problem worldwide. Laboratory

breakpoints for fluoroquinolone sensitivity have been decreased such that previously

nonresistant organisms may now be designated as resistant. Nalidixic acid resistance is still

a reasonable marker for decreased sensitivity to fluoroquinolones, but laboratories are

moving to direct testing for ciprofloxacin andofloxacin sensitivity. Nalidixic acid-resistant

organisms are less effectively treated with fluoroquinolones, especially "short courses" of

three to five days (such courses are very effective when used against organisms

susceptible to nalidixic acid and fluoroquinolones). (See 'Fluoroquinolone-resistant

organisms' above.)

· For treatment of severe systemic illness, we recommend antibiotic therapy

with ceftriaxone (Grade 1B). For treatment of uncomplicated illness in the absence of

known or suspected antimicrobial resistance, we suggest antibiotic therapy

with ciprofloxacin (Grade 2B). In general, fluoroquinolones should NOT be used as a firstline

treatment for typhoid fever in patients from South Asia or other regions with high rates

of fluoroquinolone resistance unless antibiotic susceptibility data demonstrate

fluoroquinolone or nalidixic acid sensitivity. For treatment of uncomplicated typhoid due to a

known or suspected quinolone-resistant isolate, we suggest antibiotic therapy

with azithromycin (Grade 2B); ceftriaxone may also be used. Antibiotics can be adjusted if

and when formal sensitivities are available. (See'Antimicrobial regimens' above.)

· For treatment of severe systemic illness with shock or coma, dexamethasone (3 mg/kg

followed by 1 mg/kg every six hours for a total of 48 hours) should be considered in addition

to antibiotic therapy. (See'Corticosteroids' above.)

· Treatment of ileal perforation requires surgical therapy in addition to antibiotic therapy.

(See 'Ileal perforation' above.)

· Relapse of typhoid fever after clinical cure can occur two to three weeks after resolution of

illness. Relapse should be treated with an additional course of antimicrobial therapy with a

drug to which the organism is known to be susceptible (See 'Relapse' above.)

· Chronic Salmonella carriage is defined as excretion of the organism in stool >12 months

after acute infection. Chronic carriers represent an infectious risk to others, particularly in

the setting of food preparation. We suggest treatment of chronic carriers with four weeks of

fluoroquinolone therapy for eradication of carriage (Grade 2C). (See 'Chronic

carriage' above.)

· Typhoid fever results from the ingestion of contaminated food or water; attention to

behavioral precautions is important for travelers to regions where sanitation and personal

hygiene may be poor. There are two vaccines available for protection against S. typhi: live

oral S. Typhi vaccine strain TY21a and parenteral Vi polysaccharide vaccine.

(See 'Prevention' above and "Immunizations for travel", section on 'Typhoid vaccine'.)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

ARTICULO MEDICO: PATOGENESIS DE GASTROENTERITIS POR SALMONELA

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Pathogenesis of Salmonella gastroenteritis
Authors
Camille N Kotton, MD
Elizabeth L Hohmann, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: may 1, 2012.
INTRODUCTION — Salmonellae cause a broad range of infections, including gastroenteritis,
enteric fever, bacteremia, endovascular infections, and focal infections such as osteomyelitis and
abscesses. Salmonellae are facultative anaerobic gram-negative bacilli and usually enter the body
via the gastrointestinal (GI) tract, where they can persist for long periods of time. Salmonellae can
act as both commensals and pathogens and are found in the GI tracts of domestic and wild
animals, including insects, reptiles, birds, and mammals.
Although there are many types of Salmonella, they can be divided into two broad categories: those
that cause typhoid and enteric fever and those that primarily induce gastroenteritis:
· The typhoidal Salmonella, such as S. typhi or S. paratyphi primarily colonize humans, are
transmitted via the consumption of fecally contaminated food or water, and cause a
systemic illness usually with little or no diarrhea. (See "Epidemiology, microbiology, clinical
manifestations, and diagnosis of typhoid fever".)
· The much broader group of nontyphoidal Salmonella usually results from improperly
handled food that has been contaminated by animal or human fecal material. It can also be
acquired via the fecal-oral route, either from other humans or farm or pet animals [1].
(See "Microbiology and epidemiology of salmonellosis".)
The bacterial and host factors that contribute to Salmonella gastroenteritis will be reviewed here
(figure 1).




FIG. 1.Pathogenic bacterial properties and host factors conferring increased susceptibility to Salmonella infection

The approach to patients with Salmonella in a stool culture is discussed separately.
(See "Approach to the patient with nontyphoidal Salmonella in a stool culture".)
GENERAL ISSUES — A number of different serovars of Salmonella cause human infection. The
source of infection typically is from food.
Serotypes — The 2000-plus serovars of Salmonella can be characterized by three major antigens:
the somatic O antigen, which is derived from the LPS cell wall component; the flagellar H antigen,
and the surface Vi antigen. The O-antigen is widely used by clinical laboratories to divide
Salmonella into serogroups A, B, C1, C2, D, and E (table 1).

Salmonella serogroups: Examples of important specific serotypes and their characteristic clinical infections

Serogroup	Example (serotype)*	Characteristic syndrome
A	S. paratyphi A	Enteric fever
B	S. paratyphi B	Enteric fever or gastroenteritis
B	S. typhimurium	Gastroenteritis
B	S. heidelberg	Gastroenteritis, bacteremia
C	S. paratyphi C	Enteric fever
C	S. choleraesuis	Bacteremia
C	S. newport	Gastroenteritis
D	S. typhi	Enteric fever
D	S. enteritidis	Gastroenteritis
D	S. dublin	Bacteremia

* All listed serotypes are formally members of the species Salmonella enterica, subspecies enterica. There are many additional serotypes of Salmonellae that are named after geographical locales: S. javiana, S. tennessee, S. cubana, etc. Chronic biliary carriage occurs almost exclusively with S. typhi or S. paratyphi.

 Significant cross-reactivity can occur between serogroups. The serogroups cannot be used to divide enteric fever-causing strains from
gastroenteritis-causing strains: group D contains both S. enteritidis and S. typhi, while group B
contains S. typhimurium as well as some strains of S. paratyphi. To investigate a possible outbreak,
further identification must be done with bacteriophage typing, restriction fragment length
polymorphism analysis, pulsed-field gel electrophoresis, and plasmid profile determination.
The host specificity of different Salmonella serotypes often determines the nature of the clinical
illness. Classic typhoid or enteric fever is caused by Salmonella typhi and Salmonella paratyphi.
These strains are highly adapted for humans and do not colonize or cause disease in animals,
though S. paratyphi has very rarely been associated with domestic animals. (See "Pathogenesis of
typhoid fever".) Those serotypes which cause enteric fever are frequently not associated with
significant diarrheal symptoms, although enteric fever may be heralded by transient diarrhea prior to
the onset of fever.
Salmonella enteritidis and Salmonella typhimurium have broad host ranges and may produce
colonization or gastroenteritis in humans, mice, and fowl. (See "Microbiology and epidemiology of
salmonellosis".) These serotypes are most frequently associated with gastroenteritis in humans
because of the large reservoirs of bacteria in domestic animals. Salmonella choleraesuis (adapted
for swine) and Salmonella dublin (adapted for cattle) are associated with human septicemia and
metastatic foci of infection but are uncommon causes of gastroenteritis [2]. Salmonella gallinarumpullorum
(adapted for fowl) causes relatively transient illness in humans only after very large inocula
are ingested. The molecular bases of these species specificities is complex and currently under
investigation.
The epidemiology of Salmonella has evolved over time. During the 2000s, the incidence of
Salmonella typhimurium decreased, while serotypes Newport, Mississippi, and Javiana increased in
incidence. Specific control programs focusing on contaminated eggs might have led to the reduction
of S. enteritidis infections. Rates of antibiotic resistance among several serotypes have been
increasing and are an area of significant concern; a substantial proportion of S. typhimurium and S.
newport isolates are multi-drug resistant [3].
Sources of infection — There are an estimated two to four million cases of Salmonellosis per year
in the United States, with gastroenteritis as the most common clinical presentation. Nontyphoidal
Salmonella account for 9.7 percent of all bacterial foodborne illnesses and 30.6 percent of deaths
as of 1999 [4]; between the time periods 1996 to 1998 and 2005, the number of Salmonella cases
decreased by 9 percent [5]. Salmonella gastroenteritis usually results from improperly handled food.
It can also be acquired via the fecal-oral route, either from other humans or farm or pet animals.
(See "Differential diagnosis of microbial foodborne disease".) In the United States, serotypes
Typhimurium, Enteritidis, and Newport are the most common serotypes. During 2006, large
multistate outbreaks of Salmonellosis were linked to consumption of tomatoes, fruit salad, pet
turtles, and peanut butter [3].
It is estimated that 1 in 10,000 egg yolks is infected with Salmonella enteritidis. In 1976, there were
0.6 cases of Salmonella enteritidis per 100,000; by 1996 there were 3.6 cases per 100,000, with the
majority of the increase due to eggs. A recent risk assessment model for Salmonella enteritidis
infection in eggs estimates that of the approximately 69 billion eggs produced annually, 2.3 million
would be contaminated with Salmonella enteritidis and that an average of 661,633 human illnesses
would develop from their consumption [6]. An estimated 94 percent of these cases recover without
medical care, 5 percent visit a physician, an additional 0.5 percent are hospitalized, and 0.05
percent result in death.
A multistate outbreak of S. newport from imported mangos was felt to be related to hot water
treatment of the fruit to prevent importation of the Mediterranean fruit fly [7]. While fruit skin usually
acts as a physical barrier to pathogens, the heating and cooling of the fruit may have created an
inward hydrostatic force that allowed for the entry of S. newport. There have been numerous other
outbreaks, some of which are discussed separately. (See "Microbiology and epidemiology of
salmonellosis".) The incidence of salmonellosis is highest during the summer in temperate climates
(eg, from May to October in the Northern hemisphere) and during the rainy season in tropical
climates, which coincides with the peak in foodborne outbreaks.
Exotic pets may be a source of salmonellosis. Approximately 90 percent of reptiles carry
Salmonella. Cases of salmonellosis in infants have been reported in households in which iguanas,
bearded dragons, or snakes were handled by adults with probable subsequent spread to the
children [8]. An estimated 3 to 5 percent of all cases of salmonellosis in humans is due to exposure
to pets, including turtles, birds, rodents, dogs, and cats. (See "Zoonoses from dogs" and "Zoonoses
from cats" and "Zoonoses from pets other than dogs and cats".)
Infectious dose — Data on the number of Salmonella organisms required for clinical illness have
been obtained from studies on human volunteers and outbreaks in which the vehicle of inoculation
was quantitatively cultured [9]. Several general statements about infectious doses can be made:
· Large inocula (>10(4)) produce higher rates of illness after shorter incubation periods than
small inocula (≤10(3)).
· Asymptomatic excretion may occur after ingestion of small inocula, although even very
small inocula (5 to 100 organisms) may cause disease in susceptible hosts.
· Antibiotic use can reduce the infectious dose necessary to cause disease by diminishing
the normally protective indigenous flora (see below).
· The infectious dose is lower in patients with clinical conditions associated with a reduction
in gastric acidity such as neonates [10], achlorhydric states [11], gastric surgery [12,13] and
the use of antacids or H2 blockers [13,14].
· Water supplies are contaminated at lower levels than food, resulting in lower attack rates
and longer incubation periods in waterborne outbreaks.
· Salmonella may persist for months in cheese, frozen meat, or ice cream.
PATHOGENESIS — A number of factors related both to the pathogen and the host influence the
pathogenesis of Salmonella gastroenteritis.
Interaction of Salmonellae with enteric host defenses — Ingested microorganisms must
traverse the acidic barrier of the stomach in order to establish enteric infection (table 2).

 TABLE 2. Host factors that predispose to severe Salmonella infection

Impaired cell-mediated immunity

AIDS

Use of corticosteroids or other immunomodulatory agents

Malignancy

Impaired phagocytic function

Hemoglobinopathies

Chronic granulomatous disease

Malaria

Histoplasmosis

Schistosomiasis

Extremes of age

Neonates

Elderly

Decreased gastric acidity

Antacids or suppression of acid secretion

Achlorhydria

Altered intestinal function

Inflammatory bowel disease

Prior antibiotic therapy

Although Salmonella and other enteric pathogens survive poorly at the very low pH encountered in the stomach, Salmonella exhibit increased tolerance to "acid shock" if first exposed to a moderately
acidic environment (pH 4 to 5). The organism's ability to adapt to low pH has been called the acid
tolerance response [15].
Salmonellae that survive passage through the stomach must then compete with the normal
intestinal microbial flora. The indigenous flora is an important but often overlooked barrier to
infection with enteric pathogens. Elegant mouse studies performed in the 1960s showed that a
single injection of streptomycin reduced the oral infectious dose of Salmonella typhimurium by over
100,000-fold [16]. Studies in animals have shown that the protective effect of indigenous microbes
is due to a variety of factors including competition for nutrients, maintenance of a low luminal pH,
and production of inhibitory compounds such as volatile fatty acids [17,18].
These findings appear to be applicable to humans, as can be illustrated by the following
observations:
· Prophylactic antimicrobial therapy increases the frequency of salmonellosis among
travelers [19].
· Patients found to be infected during an outbreak of multidrug resistant Salmonella
typhimurium enteritis used antimicrobials in the month before the onset of illness much
more frequently than controls (30 versus 6 percent) [20]. A similar association with prior
antimicrobial use was noted in a multistate outbreak of illness caused by Salmonella
havana which was pansensitive to antimicrobial agents (30 versus 13 percent) [21]. The
association persisted even when controlled for the presence of underlying illness or
immunosuppression.
S. Typhimurium has a marked and unique growth advantage over other bacteria when using a
specific nutrient, ethanolamine, which is released from host tissue in the lumen of the inflamed
intestine and is not utilizable by competing bacteria [22]. Thus, by inducing intestinal inflammation,
S. Typhimurium sidesteps nutritional competition and creates a significant survival advantage for
itself.
In addition to competition from the indigenous bacterial flora, Salmonella must withstand a gamut of
enteric defenses including bile salts, pancreatic enzymes, Paneth cell antimicrobial peptides [23],
and secretory IgA [24].
Mechanisms of adherence and invasion — There are two main components to Salmonella
infection of the GI tract: adherence and subsequent invasion. Adherence is complex and is
mediated by multiple genes. Fimbriae are very important in adhering to and adapting to a eukaryotic
cell surface [25]; several fimbrial operons may facilitate adherence [26]. Biofilms may play a role as
well [25]. The invasion operon (inv) can also induce adherence [27].
Invasion may be achieved by several different mechanisms:
· Salmonella can selectively attach to specialized epithelial cells overlying Peyer's patches in
the colon known as M (microfold) cells. These cells are an important portal of entry of
Salmonellae and other pathogens into the submucosal lymphoid system [28]. M cells are
highly endocytic and can rapidly transfer material from their luminal side to their basal side,
where the T cells and antigen-presenting cells reside, ready to elicit an immune response.
· It has been suggested that the cells of the columnar epithelium may also be an important
common portal of entry for Salmonella, particularly since they greatly outnumber the M cells
[29].
· Salmonellae can also induce nonphagocytic cells such as enterocytes to internalize them.
This process of bacterial-mediated endocytosis has been extensively studied in vitro and
appears to be important in the pathogenesis of Salmonella gastroenteritis [30,31].
· Invasion can also occur via the dendritic cells that intercalate between epithelial cells by
extending protrusions into the gut lumen.
· Numerous small foci of solitary intestinal lymphoid tissues (SILTs) with a strong
inflammatory response can be found in the murine small intestine; Salmonella can be
observed within these SILTs at early stages of infection, and the SILTs may act as portals of
entry [32].
Following invasion into the cell, the bacteria remain within a modified phagosome known as the
Salmonella-containing vacuole (SCV), within which they will survive and replicate. Type III secretion
systems are used to translocate bacterial effector proteins into the host cell, mediating both invasion
and vacuole biogenesis. Vacuole biogenesis is a complex and dynamic process involving extensive
membrane remodeling, interactions with the endolysosomal pathway, actin rearrangements, and
microtubule-based movement and tubule extension [33].
The mechanisms of persistent Salmonella fecal shedding of Salmonella are under investigation.
The shdA gene, which encodes an outer membrane autotransporter protein that binds fibronectin, is
required for persistent shedding of Salmonella typhimurium in mice [34]. This raises the question of
whether this locus might mediate adherence of Salmonella at other clinically important structures
known to be foci of metastatic infection, such as arteries and bone.
Pathogenicity islands — Two Salmonella "pathogenicity islands" (SPI) have been found, termed
SPI-1 and 2, each about 40 kilobases of DNA and located at centrosomes 63 and 30 of the
chromosome, respectively [35-40]. Both SPIs encode multiple virulence factors, including Type III
secretions systems (TTSS). The TTSS creates a hypodermic needle-like apparatus (figure 2) and
injects proteins into the cells, facilitating uptake of the bacteria into those cells. SPI-1 encodes
genes needed for nonphagocytic cell invasion via a ruffling mechanism and initiation of intestinal
secretory and inflammatory responses. SPI-2 is induced within the cell and contains genes needed
for survival and replication within macrophages [41].

FIG. 2.Salmonella type III secretion system


Some of these genes induce secretory and inflammatory responses [42,43].Some of these genes on SPI-1 encode proteins homologous to Shigella proteins which direct the export and translocation of signaling molecules capable ofinteracting with eukaryotic cells [35,36]. The secreted proteins of both Salmonella and Shigella induce ruffled projections in eukaryotic cell membranes which subsequently invaginate and internalize the invading bacterium within a membrane bound vacuole, called macropinocytosis [44].
Mutants lacking these genes display reduced virulence. In one study avirulent environmental
isolates of S. senftenberg and S. litchfield contained deletions in SPI-1, while clinical isolates of the
same serotypes retained the gene cluster [45].
Inflammatory response mechanisms — In addition to facilitating their own uptake, virulent strains
of Salmonella are able to induce migration of subepithelial neutrophils across polarized epithelial
cells in vitro [46]. A substantial neutrophil infiltration into the intestine occurs in Salmonella
typhimurium-induced colitis in humans; whether this is due to effectors from Salmonella or innate
pathways of inflammation triggered by pathogen recognition receptors on cells in the lamina propria
is a matter of debate [47]. The paracellular traffic of neutrophils has been hypothesized to induce
diarrhea by causing paracellular fluid and electrolyte fluxes. This theory is supported by the
observation that strains which do not usually cause enteritis, such as S. typhi and S. gallinarum,
also do not induce neutrophil transmigration [48].
In addition to IL-8, Salmonella induce other proinflammatory cytokines such as GM-CSF, monocyte
chemotactic protein-1, and tumor necrosis factor-alpha in colonic epithelial cells, which in turn
mediate further immune responses [49]. Macrophages respond to S. typhimurium infection via
flagellin-mediated activation of Ipaf, a NACHT-leucine-rich repeat family member that activates
caspase-1 [50]. Activated caspase-1 is required for the secretion of proinflammatory cytokines, such
as interleukin (IL)-1beta and IL-18, and is important in host defense against a variety of pathogens;
caspase-1-deficient mice are more susceptible to several pathogens including, Shigella, Listeria
and Francisella tularensis [51-53], as well as Salmonella [54].
Lipid A is the biologically active component of lipopolysaccharide (LPS) found in the cell wall of
Salmonella and other gram-negative bacteria. Lipid A is toxic to mammalian cells and is a potent
immunomodulator. Certain features of the lipid A in Salmonella may correlate with virulence or with
activation of host inflammation [55,56]. Lipid A induces toll-like receptor 4 (TLR4)-mediated
responses, which are important for host defense against Salmonella infection, and modifications in
lipid A as part of Salmonella's adaptation to host environments reduce this signaling [57]. Death in
mice from Salmonella may be related to the toxic effect of lipid A, which triggers further production
of TNF-alpha and IL-1 beta. S. typhimurium mutants with a defective lipid A molecule have greatly
attenuated virulence in mice [58]. Structural modifications of lipid A are influenced by the Salmonella
virulence regulatory locus (phoP/phoQ) which responds to a variety of host intracellular
environmental signals [59]. For example, antimicrobial peptides have been shown to be part of the
first step in signal transduction across the bacterial membrane, resulting in activation of phoQ and
promotion of bacterial virulence [60]. PhoP has also been found to bind a promoter region of a drug
efflux system, thus connecting virulence with possible drug resistance [61].
Enterotoxins may also play a role in Salmonella gastroenteritis. An enterotoxin, encoded by the stn
gene and antigenically similar to cholera toxin has been identified [62-64]. While many Salmonellae
carry the stn gene, only a fraction express the gene, as assessed by CHO cell assay [65]. Additional
characterization of the enterotoxin is needed to assess its role in human pathogenesis.
Survival within phagocytes — Salmonellae have long been known to persist within the
reticuloendothelial system. Macrophages may be the main cell type to support bacterial growth in
vivo, and this growth is regulated by both the host and the Salmonella [66]. The ability of Salmonella
to survive within macrophages contributes to the dissemination of the microorganism from the
submucosa to the circulation and the reticuloendothelial system. Intracellular bacterial growth within
phagocytes is limited by mechanisms requiring reactive oxygen intermediates, reactive nitrogen
intermediates, lysosomal enzymes, and defensins. Both the phoP/phoQ virulence regulatory locus
[67-69] and the SPI-2 contain genes that are important for survival within macrophages. The
importance of this process is illustrated by studies that showed that phoP/phoQ-deleted S.
typhimurium, when used as a vaccine vector, caused no bacteremia or late sequelae in a limited
number of subjects who received a large oral inoculum [70]. Isolates of Salmonella typhimurium that
are unable to survive within macrophages in vitro are avirulent in mice [71].
Role of virulence plasmids — Nontyphoidal Salmonellae also carry a variety of virulence plasmids
[72]. A highly conserved 8 kilobase region of DNA contained within these plasmids has been
associated with the ability of strains to induce bacteremia and persist within the reticuloendothelial
system [72,73]. S. typhimurium has a self-transmissible [74] 90 kilobase virulence plasmid that
contains the genes spvRABCD and while it increases the growth rate of Salmonellae in
macrophages, it may have a limited contribution to virulence [75]. The virulence plasmid stimulates
IL-12 production in a mouse model, which may lead to attenuated T cell proliferation [76].
Immune response to Salmonella infection — Because of the frequency and nonspecific nature of
the symptoms of Salmonella gastroenteritis, little is known about the rates of reinfection and
correlates of immunity. The innate immune system, cell-mediated immunity, and humoral immunity
all play important roles in limiting Salmonella infection.
Innate immune system — The innate immune system plays a critical role in the initial response to
Salmonella infection. It may be the determining factor in whether the infection is subclinical or more
aggressive. The importance of macrophages and polymorphonuclear (PMN) leukocyte response to
Salmonella has been well described. Neutropenic mice have a high mortality in experimental
Salmonella infection [77], and depressed PMN function increases the incidence of Salmonella
infection in humans. These conditions most commonly include sickle cell anemia [78], malaria
[79,80], schistosomiasis [81], and histoplasmosis [82]. In addition, Toll receptor agonists such as
LPS, lipoprotein, and flagellin stimulate proinflammatory cytokine production, resulting in TNF-alpha
and interleukin responses [29]. Activation of Toll-like receptor 5 and Ipaf by Salmonella flagellin has
been a significant finding [83].
Cell-mediated immunity — Cell-mediated immunity plays an important role in clearing infection
and protecting against subsequent Salmonella infection. Clinical vigilance in the diagnosis and
management of Salmonella infections should be increased in settings associated with cellular
immunosuppression. As an example, infection is more severe and prolonged in patients with
depressed cellular immunity due to glucocorticoids [84], AIDS [85-87], and malignancy [88]. In one
study, nontyphoidal Salmonella (14 percent) were the second most frequent bacterial isolate after
Staphylococcus aureus (29 percent) in a study of 249 bacteremias in HIV-infected individuals [89].
Nude mice and mice deficient in alpha-beta T cells are more susceptible to Salmonella infections.
Murine models suggest that CD4+ T cells are more contributory than CD8+ T cells [29].
Humoral immune responses — The humoral response to Salmonella infection is complex and
may be protective or maladaptive. Its importance in containing Salmonella infection is illustrated by
the protective immunity induced in vaccination studies with S. typhi. Mice deficient in B cells due to
a targeted deletion of the Ig-mu gene show increased susceptibility to Salmonella infection and are
unable to mount a significant convalescent immune response [90]. In addition, mucosal humoral
immune responses may play a contributory role. Murine studies have shown that secretion of large
amounts of a single monoclonal IgA directed against Salmonella typhimurium lipopolysaccharide
(LPS) into the intestinal lumen provides significant protection against systemic disease [36].
Furthermore, mucosal antibodies to nontyphoidal Salmonellae appear to inhibit the "take" of the oral
live attenuated typhoid fever vaccine Ty21a [91].
However, in a study that evaluated the effect of serum from HIV-infected patients on the killing of S.
typhimurium in vitro, a high serum concentration of antibodies against the LPS of non-typhoidal
Salmonellae paradoxically prevented the destruction of Salmonella [92]. The authors postulated that
inhibitory antibodies in the serum of HIV-infected individuals could be responsible for this effect by
blocking the action of bactericidal antibodies. These results suggest that the preferred vaccine
target should be the bacterial outer-membrane proteins of non-typhoidal Salmonellae as opposed to
LPS, since LPS could potentially elicit inhibitory rather than the desired bactericidal antibodies.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The
Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language,
at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might
have about a given condition. These articles are best for patients who want a general overview and
who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer,
more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or
e-mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on “patient info” and the keyword(s) of interest.)
· Basics topics (see "Patient information: Salmonellosis (Salmonella) (The Basics)")
SUMMARY
· The 2000-plus serovars of Salmonella can be characterized by three major antigens: the
somatic O antigen, which is derived from the lipopolysaccharide cell wall component, the
flagellar H antigen, and the surface Vi antigen. (See 'Serotypes' above.)
· The size of the inoculum is proportional to the frequency and rapidity of disease onset, but
even small inocula can cause disease. Enteric host factors that defend against Salmonella
infection include the acidic environment of the stomach and the normal intestinal microbial
flora. The infectious dose necessary to cause disease can be lower in settings of antibiotic
use and reduction of gastric acid. (See'Infectious dose' above and 'Interaction of
Salmonellae with enteric host defenses' above.)
· Salmonellae adhere to and invade the gastrointestinal tract and submucosal lymphoid
system through several different mechanisms. Bacterial entry into and survival within host
cells are facilitated by multiple virulence factors. (See 'Mechanisms of adherence and
invasion' above and 'Pathogenicity islands' above.)
· The ability of Salmonella to survive within macrophages contributes to the dissemination of
the microorganism from the submucosa to the circulation and the reticuloendothelial
system. (See 'Survival within phagocytes' above.)
· Virulent strains of Salmonella induce multiple host inflammatory responses and cytokines.
This is in part mediated by lipid A, a component of lipopolysaccharide in the cell wall.
(See 'Inflammatory response mechanisms' above.)
· The host innate immune response may determine whether Salmonella infection is
subclinical or more aggressive. Adaptive cell-mediated immunity plays an important role in
clearing and protecting against subsequent infection. The humoral response is complex and
may be protective or maladaptive. (See 'Immune response to Salmonella infection' above.)
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