BackgroundTyphoid fever, also known as enteric fever, is a
potentially fatal multisystemic illness caused primarily
bySalmonella enterica,subspeciesentericaserovartyphiand, to a
lesser extent, related serovarsparatyphiA, B, and C.The protean
manifestations of typhoid fever make this disease a true diagnostic
challenge. The classic presentation includes fever, malaise,
diffuse abdominal pain, andconstipation. Untreated, typhoid fever
is a grueling illness that may progress todelirium, obtundation,
intestinal hemorrhage, bowel perforation, and death within 1 month
of onset. Survivors may be left with long-term or permanent
neuropsychiatric complications.S typhihas been a major human
pathogen for thousands of years, thriving in conditions of poor
sanitation, crowding, and social chaos. It may have responsible for
the Great Plague of Athens at the end of the Pelopennesian
War.[1]The nameS typhiis derived from the ancient Greektyphos,an
ethereal smoke or cloud that was believed to cause disease and
madness. In the advanced stages of typhoid fever, the patient's
level of consciousness is truly clouded. Although antibiotics have
markedly reduced the frequency of typhoid fever in the developed
world, it remains endemic in developing countries.[2]S
paratyphicauses the same syndrome but appears to be a relative
newcomer. It may be taking over thetyphiniche, in part, because of
immunological naivete among the population and incomplete coverage
by vaccines that targettyphi.Note that some writers refer to the
typhoid and paratyphoid fever as distinct syndromes caused by
thetyphiversusparatyphiserovars, while others use the term typhoid
fever for a disease caused by either one. We use the latter
terminology. We refer to these serovars collectively as typhoidal
salmonella.PathophysiologyAll pathogenicSalmonellaspecies, when
present in the gut are engulfed by phagocytic cells, which then
pass them through the mucosa and present them to the macrophages in
the lamina propria. Nontyphoidal salmonellae are phagocytized
throughout the distal ileum and colon. With toll-like receptor
(TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize
pathogen-associated molecular patterns (PAMPs) such as flagella and
lipopolysaccharides. Macrophages and intestinal epithelial cells
then attract T cells and neutrophils with interleukin 8 (IL-8),
causing inflammation and suppressing the infection.[3, 4]In
contrast to the nontyphoidal salmonellae,S typhiand paratyphi enter
the host's system primarily through the distal ileum.Theyhave
specialized fimbriae that adhere to the epithelium over clusters of
lymphoid tissue in the ileum (Peyer patches), the main relay point
for macrophages traveling from the gut into the lymphatic system.
The bacteria then induce their host macrophages to attract more
macrophages.[3]S typhihas a Vi capsular antigen that masks PAMPs,
avoiding neutrophil-based inflammation, while the most
commonparatyphiserovar,paratyphi A, does not. This may explain the
greater infectivity of typhi compared with most of its
cousins.[5]Typhoidal salmonella co-opt the macrophages' cellular
machinery for their own reproduction[6]as they are carried through
the mesenteric lymph nodes to the thoracic duct and the lymphatics
and then through to the reticuloendothelial tissues of the liver,
spleen, bone marrow, and lymph nodes. Once there, they pause and
continue to multiply until some critical density is reached.
Afterward, the bacteria induce macrophage apoptosis, breaking out
into the bloodstream to invade the rest of the body.[4]The bacteria
then infect the gallbladder via either bacteremia or direct
extension of infected bile. The result is that the organism
re-enters the gastrointestinal tract in the bile and reinfects
Peyer patches. Bacteria that do not reinfect the host are typically
shed in the stool and are then available to infect other hosts.[2,
4]See the image below.
Chronic carriers are responsible for much of the transmission of
the organism. While asymptomatic, they may continue to shed
bacteria in their stool for decades. The organisms sequester
themselves either as a biofilm on gallstones or gallbladder
epithelium or, perhaps, intracellularly, within the epithelium
itself.[7]The bacteria excreted by a single carrier may have
multiple genotypes, making it difficult to trace an outbreak to its
origin.[8]Risk factorsTyphoidal salmonella have no nonhuman
vectors. An inoculum as small as 100,000 organisms oftyphicauses
infection in more than 50% of healthy
volunteers.[9]Paratyphirequires a much higher inoculum to infect,
and it is less endemic in rural areas. Hence, the patterns of
transmission are slightly different.The following are modes of
transmission of typhoidal salmonella: Oral transmission via food or
beverages handled by an often asymptomatic individuala carrierwho
chronically sheds the bacteria through stool or, less commonly,
urine Hand-to-mouth transmission after using a contaminated toilet
and neglecting hand hygiene Oral transmission via
sewage-contaminated water or shellfish (especially in the
developing world).[10, 11, 12]Paratyphiis more commonly transmitted
in food from street vendors. It is believed that some such foods
provide a friendly environment for the microbe.Paratyphiis more
common among newcomers to urban areas, probably because they tend
to be immunologically nave to it. Also, travellers get little or no
protection againstparatyphifrom the current typhoid vaccines, all
of which targettyphi.[13, 14]Typhoidal salmonella are able to
survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor
antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and
achlorhydria decrease stomach acidity and facilitateS
typhiinfection.[4]HIV/AIDSis clearly associated with an increased
risk of nontyphoidalSalmonellainfection; however, the data and
opinions in the literature as to whether this is true forS typhior
paratyphi infection are conflicting. If an association exists, it
is probably minor.[15, 16, 17, 18]Other risk factors for typhoid
fever include various genetic polymorphisms. These risk factors
often also predispose to other intracellular pathogens. For
instance,PARK2andPACGRcode for a protein aggregate that is
essential for breaking down the bacterial signaling molecules that
dampen the macrophage response. Polymorphisms in their shared
regulatory region are found disproportionately in persons infected
withMycobacterium lepraeandS typhi.[11]On the other hand,
protective host mutations also exist. The fimbriae ofS typhibind in
vitro to cystic fibrosis transmembrane conductance receptor (CFTR),
which is expressed on the gut membrane. Two to 5% of white persons
are heterozygous for the CFTR mutation F508del, which is associated
with a decreased susceptibility to typhoid fever, as well as
tocholeraandtuberculosis. The homozygous F508del mutation in CFTR
is associated with cystic fibrosis. Thus, typhoid fever may
contribute to evolutionary pressure that maintains a steady
occurrence of cystic fibrosis, just asmalariamaintainssickle cell
diseasein Africa.[19, 20]As the middle class in south Asia grows,
some hospitals there are seeing a large number of typhoid fever
cases among relatively well-off university students who live in
group households with poor hygiene.[21]American clinicians should
keep this in mind, as members of this cohort often come to the
United States for advanced degrees.EpidemiologyFrequencyUnited
StatesSince 1900, improved sanitation and successful antibiotic
treatment have steadily decreased the incidence of typhoid fever in
the United States. In 1920, 35,994 cases of typhoid fever were
reported. In 2006, there were 314.Between 1999 and 2006, 79% of
typhoid fever cases occurred in patients who had been outside of
the country within the preceding 30 days. Two thirds of these
individuals had just journeyed from the Indian subcontinent. The 3
known outbreaks of typhoid fever within the United States were
traced to imported food or to a food handler from an endemic
region. Remarkably, only 17% of cases acquired domestically were
traced to a carrier.[22]InternationalTyphoid fever occurs
worldwide, primarily in developing nations whose sanitary
conditions are poor. Typhoid fever is endemic in Asia, Africa,
Latin America, the Caribbean, and Oceania, but 80% of cases come
from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or
Vietnam.[23]Within those countries, typhoid fever is most common in
underdeveloped areas. Typhoid fever infects roughly 21.6 million
people (incidence of 3.6 per 1,000 population) and kills an
estimated 200,000 people every year.[24]In the United States, most
cases of typhoid fever arise in international travelers. The
average yearly incidence of typhoid fever per million travelers
from 1999-2006 by county or region of departure was as follows:[22]
Canada - 0 Western Hemisphere outside Canada/United States - 1.3
Africa - 7.6 Asia - 10.5 India - 89 (122 in 2006) Total (for all
countries except Canada/United States) - 2.2Mortality/MorbidityWith
prompt and appropriate antibiotic therapy, typhoid fever is
typically a short-term febrile illness requiring a median of 6 days
of hospitalization. Treated, it has few long-term sequelae and a
0.2% risk of mortality.[22]Untreated typhoid fever is a
life-threatening illness of several weeks' duration with long-term
morbidity often involving the central nervous system. The case
fatality rate in the United States in the pre-antibiotic era was
9%-13%.[25]RaceTyphoid fever has no racial
predilection.SexFifty-four percent of typhoid fever cases in the
United States reported between 1999 and 2006 involved
males.[22]AgeMost documented typhoid fever cases involve
school-aged children and young adults. However, the true incidence
among very young children and infants is thought to be higher. The
presentations in these age groups may be atypical, ranging from a
mild febrile illness to severe convulsions, and theS typhiinfection
may go unrecognized. This may account for conflicting reports in
the literature that this group has either a very high or a very low
rate of morbidity and mortality.[21, 26]Proceed toClinical
PresentationHistoryA severe nonspecific febrile illness in a
patient who has been exposed to typhoidal salmonella should always
raise the diagnostic possibility of typhoid fever (enteric
fever).Classic typhoid fever syndromeThe clinical syndromes
associated withS typhiandparatyphiare indistinguishable. Typhoid
fever begins 7-14 days after ingestion of the organism.The fever
pattern is stepwise, characterized by a rising temperature over the
course of each day that drops by the subsequent morning. The peaks
and troughs rise progressively over time.Over the course of the
first week of illness, the notorious gastrointestinal
manifestations of the disease develop. These include diffuse
abdominal pain and tenderness and, in some cases, fierce colicky
right upper quadrant pain. Monocytic infiltration inflames Peyer
patches and narrows the bowel lumen, causing constipation that
lasts the duration of the illness. The individual then develops a
dry cough, dull frontal headache, delirium, and an increasingly
stuporous malaise.[2]At approximately the end of the first week of
illness, the fever plateaus at 103-104F (39-40C). The patient
develops rose spots, which are salmon-colored, blanching, truncal,
maculopapules usually 1-4 cm wide and fewer than 5 in number; these
generally resolve within 2-5 days.[2]These are bacterial emboli to
the dermis and occasionally develop in persons withshigellosisor
nontyphoidalsalmonellosis.[27]During the second week of illness,
the signs and symptoms listed above progress. The abdomen becomes
distended, and soft splenomegaly is common. Relative bradycardia
and dicrotic pulse (double beat, the second beat weaker than the
first) may develop.In the third week, the still febrile individual
grows more toxic and anorexic with significant weight loss. The
conjunctivae are infected, and the patient is tachypneic with a
thready pulse and crackles over the lung bases. Abdominal
distension is severe. Some patients experience foul, green-yellow,
liquid diarrhea (pea soup diarrhea). The individual may descend
into the typhoid state, which is characterized by apathy,
confusion, and even psychosis. Necrotic Peyer patches may cause
bowel perforation and peritonitis. This complication is often
unheralded and may be masked by corticosteroids. At this point,
overwhelming toxemia,myocarditis, or intestinal hemorrhage may
cause death.If the individual survives to the fourth week, the
fever, mental state, and abdominal distension slowly improve over a
few days. Intestinal and neurologic complications may still occur
in surviving untreated individuals. Weight loss and debilitating
weakness last months. Some survivors become asymptomaticS
typhicarriers and have the potential to transmit the bacteria
indefinitely.[21, 28, 29, 2, 4]Various presentations of typhoid
feverThe clinical course of a given individual with typhoid fever
may deviate from the above description of classic disease. The
timing of the symptoms and host response may vary based on
geographic region, race factors, and the infecting bacterial
strain. The stepladder fever pattern that was once the hallmark of
typhoid fever now occurs in as few as 12% of cases. In most
contemporary presentations of typhoid fever, the fever has a steady
insidious onset.Young children, individuals with AIDS, and one
third of immunocompetent adults who develop typhoid fever develop
diarrhea rather than constipation. In addition, in some localities,
typhoid fever is generally more apt to cause diarrhea than
constipation.Atypical manifestations of typhoid fever include
isolated severe headaches that may mimicmeningitis, acute lobar
pneumonia, isolated arthralgias, urinary symptoms, severe jaundice,
or fever alone. Some patients, especially in India and Africa,
present primarily with neurologic manifestations such asdeliriumor,
in extremely rare cases, parkinsonian symptoms or Guillain-Barr
syndrome. Other unusual complications include
pancreatitis,[30]meningitis,orchitis, osteomyelitis, and abscesses
anywhere on the body.[2]Table 1. Incidence and Timing of Various
Manifestations of Untreated Typhoid Fever[2, 31, 32, 33, 34,
35](Open Table in a new window)ever[2, 31, 32, 33, 34, 35](Open
Table in a new window)IncubationWeek 1Week 2Week 3Week 4Post
SystemicRecovery phase or death (15% of untreated cases)10%-20%
relapse; 3%-4% chronic carriers;
long-term neurologic sequelae (extremely rare);
gallbladder cancer (RR=167; carriers)
Stepladder fever pattern or insidious onset feverVery
commonaVery common
Acute high feverVery rareb
ChillsAlmost allc
RigorsUncommon
AnorexiaAlmost all
DiaphoresisVery common
Neurologic
MalaiseAlmost allAlmost allTyphoid state (common)
InsomniaVery common
Confusion/deliriumCommondVery common
PsychosisVery rareCommon
CatatoniaVery rare
Frontal headache
(usually mild)
Very common
Meningeal signsRareeRare
ParkinsonismVery rare
Ear, nose, and throat
Coated tongueVery common
Sore throatf
Pulmonary
Mild coughCommon
Bronchitic coughCommon
RalesCommon
PneumoniaRare (lobar)RareCommon
(basal)
Cardiovascular
Dicrotic pulseRareCommon
MyocarditisRare
PericarditisExtremely rareg
ThrombophlebitisVery rare
Gastrointestinal
ConstipationVery commonCommon
DiarrheaRareCommon (pea soup)
Bloating with tympanyVery common (84%)[35]
Diffuse mild abdominal painVery common
Sharp right lower quadrant painRare
Gastrointestinal hemorrhageVery rare; usually traceVery
common
intestinal perforationRare
HepatosplenomegalyCommon
JaundiceCommon
Gallbladder painVery rare
Urogenital
Urinary retentionCommon
HematuriaRare
Renal painRare
Musculoskeletal
MyalgiasVery rare
ArthralgiasVery rare
Rheumatologic
Arthritis (large joint)Extremely rare
Dermatologic
Rose spotsRare
Miscellaneous
Abscess (anywhere)Extremely rareExtremely rareExtremely rare
aVery common: Symptoms occur in well over half of cases
(approximately 65%-95%).
bVery rare: Symptoms occur in less than 5% of cases.
cAlmost all: Symptoms occur in almost all cases.
dCommon: Symptoms occur in 35%-65% of cases.
eRare: Symptoms occur in 5%-35% of cases.
fBlank cells: No mention of the symptom at that phase was found
in the literature.
gExtremely rare: Symptoms have been described in occasional case
reports.
Treated typhoid feverIf appropriate treatment is initiated
within the first few days of full-blown illness, the disease begins
to remit after about 2 days, and the patient's condition markedly
improves within 4-5 days. Any delay in treatment increases the
likelihood of complications and recovery time.PhysicalSee
History.CausesS typhiandSalmonella paratyphicause typhoid
fever.
Differential Diagnoses Abdominal Abscess Amebic Hepatic
Abscesses Appendicitis Brucellosis Dengue Fever Influenza
Leishmaniasis Malaria Rickettsial diseases Toxoplasmosis
Tuberculosis Tularemia Typhus
Laboratory StudiesThe diagnosis of typhoid fever (enteric fever)
is primarily clinical.Importantly, the reported sensitivities of
tests forS typhivary greatly in the literature, even among the most
recent articles and respected journals.CultureThe criterion
standard for diagnosis of typhoid fever has long been culture
isolation of the organism. Cultures are widely considered 100%
specific.Culture of bone marrow aspirate is 90% sensitive until at
least 5 days after commencement of antibiotics. However, this
technique is extremely painful, which may outweigh its
benefit.[36]Blood, intestinal secretions (vomitus or duodenal
aspirate), and stool culture results are positive forS typhiin
approximately 85%-90% of patients with typhoid fever who present
within the first week of onset. They decline to 20%-30% later in
the disease course. In particular, stool culture may be positive
forS typhiseveral days after ingestion of the bacteria secondary to
inflammation of the intraluminal dendritic cells. Later in the
illness, stool culture results are positive because of bacteria
shed through the gallbladder.Multiple blood cultures (>3) yield
a sensitivity of 73%-97%. Large-volume (10-30 mL) blood culture and
clot culture may increase the likelihood of detection.[37]Stool
culture alone yields a sensitivity of less than 50%, and urine
culture alone is even less sensitive. Cultures of punch-biopsy
samples of rose spots reportedly yield a sensitivity of 63% and may
show positive results even after administration of antibiotics. A
single rectal swab culture upon hospital admission can be expected
to detectS typhiin 30%-40% of patients.S typhihas also been
isolated from the cerebrospinal fluid, peritoneal fluid, mesenteric
lymph nodes, resected intestine, pharynx, tonsils, abscess, and
bone, among others.Bone marrow aspiration and blood are cultured in
a selective medium (eg, 10% aqueous oxgall) or a nutritious medium
(eg, tryptic soy broth) and are incubated at 37C for at least 7
days. Subcultures are made daily to one selective medium (eg,
MacConkey agar) and one inhibitory medium
(eg,Salmonella-Shigellaagar). Identification of the organism with
these conventional culture techniques usually takes 48-72 hours
from acquisition.Table 2. Sensitivities of Cultures[2, 37, 38,
39](Open Table in a new window)IncubationWeek 1Week 2Week 3Week
4
Bone marrow aspirate (0.5-1 mL)90% (may decrease after 5 d of
antibiotics)
Blood (10-30 mL), stool, or duodenal aspirate
culture40%-80%~20%Variable (20%-60%)
Urine25%-30%, timing unpredictable
Polymerase chain reactionPolymerase chain reaction (PCR) has
been used for the diagnosis of typhoid fever with varying success.
Nested PCR, which involves two rounds of PCR using two primers with
different sequences within the H1-d flagellin gene ofS typhi,
offers the best sensitivity and specificity. Combining assays of
blood and urine, this technique has achieved a sensitivity of 82.7%
and reported specificity of 100%. However, no type of PCR is widely
available for the clinical diagnosis of typhoid fever.[40,
41]Specific serologic testsAssays that identifySalmonellaantibodies
or antigens support the diagnosis of typhoid fever, but these
results should be confirmed with cultures or DNA evidence.The Widal
test was the mainstay of typhoid fever diagnosis for decades. It is
used to measure agglutinating antibodies against H and O antigens
ofS typhi. Neither sensitive nor specific, the Widal test is no
longer an acceptable clinical method.Indirect hemagglutination,
indirect fluorescent Vi antibody, and indirect enzyme-linked
immunosorbent assay (ELISA) for immunoglobulin M (IgM) and IgG
antibodies toS typhipolysaccharide, as well as monoclonal
antibodies againstS typhiflagellin,[42]are promising, but the
success rates of these assays vary greatly in the literature.Other
nonspecific laboratory studiesMost patients with typhoid fever are
moderately anemic, have an elevated erythrocyte sedimentation rate
(ESR), thrombocytopenia, and relative lymphopenia.Most also have a
slightly elevated prothrombin time (PT) and activated partial
thromboplastin time (aPTT) and decreased fibrinogen
levels.Circulating fibrin degradation products commonly rise to
levels seen in subclinicaldisseminated intravascular
coagulation(DIC).Liver transaminase and serum bilirubin values
usually rise to twice the reference range.Mild hyponatremia and
hypokalemia are common.A serum alanine amino transferase
(ALT)tolactate dehydrogenase (LDH) ratio of more than 9:1 appears
to be helpful in distinguishing typhoid from viral hepatitis. A
ratio of greater than 9:1 supports a diagnosis of acute viral
hepatitis, while ratio of less than 9:1 supports typhoid
hepatitis.[43]Imaging StudiesRadiography: Radiography of the
kidneys, ureters, and bladder (KUB) is useful if bowel perforation
(symptomatic or asymptomatic) is suspected.CT scanning and MRI:
These studies may be warranted to investigate for abscesses in the
liver or bones, among other sites.ProceduresBone marrow aspiration:
The most sensitive method of isolatingS typhiis BMA culture (see
Lab Studies).Histologic FindingsThe hallmark histologic finding in
typhoid fever is infiltration of tissues by macrophages (typhoid
cells) that contain bacteria, erythrocytes, and degenerated
lymphocytes. Aggregates of these macrophages are called typhoid
nodules, which are found most commonly in the intestine, mesenteric
lymph nodes, spleen, liver, and bone marrow but may be found in the
kidneys, testes, and parotid glands. In the intestines, 4 classic
pathologic stages occur in the course of infection: (1)
hyperplastic changes, (2) necrosis of the intestinal mucosa, (3)
sloughing of the mucosa, and (4) the development of ulcers. The
ulcers may perforate into the peritoneal cavity.In the mesenteric
lymph nodes, the sinusoids are enlarged and distended by large
collections of macrophages and reticuloendothelial cells. The
spleen is enlarged, red, soft, and congested; its serosal surface
may have a fibrinous exudate. Microscopically, the red pulp is
congested and contains typhoid nodules. The gallbladder is
hyperemic and may show evidence ofcholecystitis. Liver biopsy
specimens from patients with typhoid fever often show cloudy
swelling, balloon degeneration with vacuolation of hepatocytes,
moderate fatty change, and focal typhoid nodules. Intact typhoid
bacilli can be observed at these sites.[2, 4]StagingThe proper
treatment approach to typhoid fever depends on whether the illness
is complicated or uncomplicated. Complicated typhoid fever is
characterized by melena (3% of all hospitalized patients with
typhoid fever), serious abdominal discomfort, intestinal
perforation, marked neuropsychiatric symptoms, or other severe
manifestations. Depending on the adequacy of diagnosis and
treatment, complicated disease may develop in up to 10% of treated
patients. Delirium, obtundation, stupor, coma, or shock demands a
particularly aggressive approach (see Treatment).[34]
Medical CareIf a patient presents with unexplained symptoms
described in Table 1 within 60 days of returning from an typhoid
fever (enteric fever) endemic area or following consumption of food
prepared by an individual who is known to carry typhoid,
broad-spectrum empiric antibiotics should be started immediately.
Treatment should not be delayed for confirmatory tests since prompt
treatment drastically reduces the risk of complications and
fatalities. Antibiotic therapy should be narrowed once more
information is available.Compliant patients with uncomplicated
disease may be treated on an outpatient basis. They must be advised
to use strict handwashing techniques and to avoid preparing food
for others during the illness course. Hospitalized patients should
be placed in contact isolation during the acute phase of the
infection. Feces and urine must be disposed of safely.Surgical
CareSurgery is usually indicated in cases of intestinal
perforation. Most surgeons prefer simple closure of the perforation
with drainage of the peritoneum. Small-bowel resection is indicated
for patients with multiple perforations.If antibiotic treatment
fails to eradicate the hepatobiliary carriage, the gallbladder
should be resected. Cholecystectomy is not always successful in
eradicating the carrier state because of persisting hepatic
infection.ConsultationsAn infectious disease specialist should be
consulted. Consultation with a surgeon is indicated upon suspected
gastrointestinal perforation, serious gastrointestinal hemorrhage,
cholecystitis, or extraintestinal complications (arteritis,
endocarditis, organ abscesses).DietFluids and electrolytes should
be monitored and replaced diligently. Oral nutrition with a soft
digestible diet is preferable in the absence of abdominal
distension or ileus.ActivityNo specific limitations on activity are
indicated for patients with typhoid fever. As with most systemic
diseases, rest is helpful, but mobility should be maintained if
tolerable. The patient should be encouraged to stay home from work
until recovery.
AntibioticsClass SummaryDefinitive treatment of typhoid fever
(enteric fever) is based on susceptibility. As a general principle
of antimicrobial treatment, intermediate susceptibility should be
regarded as equivalent to resistance. Between 1999 and 2006, 13%
ofS typhiisolates collected in the United States were multidrug
resistant.Until susceptibilities are determined, antibiotics should
be empiric, for which there are various recommendations. The
authors of this article recommend combination treatment with
ceftriaxone and ciprofloxacin when neither the sensitivities nor
the geographical origin of the bacteria is known.The particular
sensitivity pattern of the organism in its area of acquisition
should be the major basis of empiric antibiotic choice. It may soon
become necessary to treat all cases presumptively for multidrug
resistance until sensitivities are obtained.History of antibiotic
resistanceChloramphenicol was used universally to treat typhoid
fever from 1948 until the 1970s, when widespread resistance
occurred. Ampicillin and trimethoprim-sulfamethoxazole (TMP-SMZ)
then became treatments of choice. However, in the late 1980s, someS
typhiandS paratyphistrains (multidrug resistant [MDR]S typhiorS
paratyphi) developed simultaneous plasmid-mediated resistance to
all three of these agents.Fluoroquinolones are highly effective
against susceptible organisms, yielding a better cure rate than
cephalosporins. Unfortunately, resistance to first-generation
fluoroquinolones is widespread in many parts of Asia.In recent
years, third-generation cephalosporins have been used in regions
with high fluoroquinolone resistance rates, particularly in south
Asia and Vietnam. Unfortunately, sporadic resistance has been
reported, so it is expected that these will become less useful over
time.[44]Mechanisms of antibiotic resistanceThe genes for
antibiotic resistance inS typhiandS paratyphiare acquired
fromEscherichia coliand other gram-negative bacteria via plasmids.
The plasmids contain cassettes of resistance genes that are
incorporated into a region of theSalmonellagenome called an
integron. Some plasmids carry multiple cassettes and immediately
confer resistance to multiple classes of antibiotics. This explains
the sudden appearance of MDR strains ofS typhiandS paratyphi,often
without intermediate strains that have less-extensive
resistance.The initial strains of antibiotic-resistantS typhiandS
paratyphicarried chloramphenicol acetyltransferase type I, which
encodes an enzyme that inactivates chloramphenicol via acetylation.
MDR strains may carry dihydrofolate reductase type VII, which
confers resistance to trimethoprim. Interestingly, in areas where
these drugs have fallen out of use,S typhihas reverted to wild
type, and they are often more effective than newer agents.[45, 46,
47, 35]Resistance to fluoroquinolones is evolving in an ominous
direction. Fluoroquinolones target DNA gyrase and topoisomerase IV,
bacterial enzymes that are part of a complex that uncoils and
recoils bacterial DNA for transcription.[48]S typhimost commonly
develops fluoroquinolone resistance through specific mutations
ingyrAandparC,which code for the binding region of DNA gyrase and
topoisomerase IV, respectively.A single point mutationgyrAconfers
partial resistance. If a secondgyrApoint mutation is added, the
resistance increases somewhat. However, a mutation inparCadded to a
singlegyrAmutation confers full in vitro resistance to
first-generation fluoroquinolones. Clinically, these resistant
strains show a 36% failure rate when treated with a
first-generation fluoroquinolone such as ciprofloxacin.[49]The risk
of relapse after bacterial clearance is higher in both partially
and fully resistant strains than in fully susceptible
strains.[23]The third-generation fluoroquinolone gatifloxacin
appears to be highly effective against all known clinical strains
ofS typhiboth in vitro and in vivo. due to its unique interface
withgyrA. It achieves better results than cephalosporins even among
strains that are considered fluoroquinolone resistant. However,
gatifloxacin is no longer on the market in the United States, and
its use cannot be generalized to any other member of the class.[50,
51]In any case, as gatifloxacin replaces older fluoroquinolones in
high-prevalence resistance is bound to emerge. Any two of a number
ofgyrAmutations, when added to theparCmutation, confer full in
vitro resistance. Although such a combination has yet to be
discovered in vivo, all of these mutations exist in various clinic
strains, and it seems highly likely that a gatifloxacin-resistant
one will be encountered clinically if selective pressure with
fluoroquinolones continues to be exerted.[49]Geography of
resistanceAmongS typhiisolates obtained in the United States
between 1999 and 2006, 43% were resistant to at least one
antibiotic.Nearly half ofS typhiisolates found in the United States
now come from travelers to the Indian subcontinent, where
fluoroquinolone resistance is endemic (see Table 3). The rate of
fluoroquinolone resistance in south and Southeast Asia and, to some
extent, in East Asia is generally high and rising (see Table 3).
Susceptibility to chloramphenicol, TMP-SMZ, and ampicillin in South
Asia is rebounding. In Southeast Asia, MDR strains remain
predominant, and some acquired resistance to fluoroquinolones by
the early 2000s.The most recent professional guideline for the
treatment of typhoid fever in south Asia was issued by the Indian
Association of Pediatrics (IAP) in October 2006. Although these
guidelines were published for pediatric typhoid fever, the authors
feel that they are also applicable to adult cases. For empiric
treatment of uncomplicated typhoid fever, the IAP recommends
cefixime and, as a second-line agent, azithromycin. For complicated
typhoid fever, they recommend ceftriaxone. Aztreonam and imipenem
are second-line agents for complicated cases.[52]The authors
believe that the IAP recommendations apply to empiric treatments of
typhoid fever in both adults and children.In high-prevalence areas
outside the areas discussed above, the rate of intermediate
sensitivity or resistance to fluoroquinolones is 3.7% in the
Americas (P=.132), 4.7% (P=.144) in sub-Saharan Africa, and 10.8%
(P=.706) in the Middle East. Therefore, for strains that originate
outside of south or Southeast Asia, the WHO recommendations may
still be validthat uncomplicated disease should be treated
empirically with oral ciprofloxacin and complicated typhoid fever
from these regions should be treated with intravenous
ciprofloxacin.[44, 47, 53, 24, 54]Resistance in the United StatesIn
the United States in 2012, 68% ofS typhiisolates and 95% ofS
paratyphiisolates were fully resistant to nalidixic acid. While
full resistance to ciprofloxacin was considerably less,
intermediate susceptibilities to ciprofloxacin in both organisms
closely matched resistance to nalidixic acid. Note that nalidixic
acid is a nontherapeutic drug that is used outside of the United
States as a stand-in for fluoroquinolones in sensitivity assays. In
the United States, it is still used specifically forS
typhiinfection.[44, 22]The rate of multidrug resistance in 2012 was
9% inS typhiand 0% inS paratyphi. (Multidrug-resistantS typhiis, by
definition, resistant to the original first-line agents,
ampicillin, chloramphenicol, and
trimethoprim-sulfamethoxazole.)There have been no cases of
ceftriaxone-resistantS typhiorS paratyphidocumented in the United
States, at least since 2003.[55]Antibiotic resistance is a moving
target. Reports are quickly outdated, and surveys of resistance may
have limited geographic scope. Therefore, any recommendation
regarding antibiotic treatment must be taken with a grain of salt.
However, in the authors' opinion, if the origin of the infection is
unknown, the combination of a first-generation fluoroquinolone and
a third-generation cephalosporin should be used. This allows for
most effective clearance if the organism is
fluoroquinolone-susceptible but still covers strains that are
not.Table 3. Antibiotic Recommendations by Origin and Severity(Open
Table in a new window)LocationSeverityFirst-Line
AntibioticsSecond-Line Antibiotics
South Asia, East Asia[52]
[56, 45]
UncomplicatedCefixime POAzithromycin PO
ComplicatedCeftriaxone IVor
Cefotaxime IV
Aztreonam IVor
Imipenem IV
Eastern Europe, Middle East, sub-Saharan Africa, South
America[53, 57]UncomplicatedCiprofloxacin POor
Ofloxacin PO
Cefixime POor
Amoxicillin POor
TMP-SMZ PO
or Azithromycin PO
ComplicatedCiprofloxacin IVor
Ofloxacin IV
Ceftriaxone IVor
Cefotaxime IVor
Ampicillin IV
or
TMP-SMZ IV
Unknown geographic origin or Southeast Asia[58, 52]
[56, 45, 53, 57]
UncomplicatedCefixime POplus
Ciprofloxacin POor
Ofloxacin PO
Azithromycin PO*
ComplicatedCeftriaxone IVor
Cefotaxime IV,plus
Ciprofloxacin IVor
Ofloxacin IV
Aztreonam IVor
Imipenem IV,plus
Ciprofloxacin IV
or
Ofloxacin IV
*Note that the combination of azithromycin and fluoroquinolones
is not recommended because it may cause QT prolongation and is
relatively contraindicated.
Future directionsA meta-analysis found that azithromycin
appeared to be superior to fluoroquinolones and ceftriaxone with
lower rates of clinical failure and relapse respectively. Although
the data did not permit firm conclusions, if further studies
confirm the trend, azithromycin could become a first-line
treatment.[59]View full drug informationChloramphenicol
(Chloromycetin)Binds to 50S bacterial-ribosomal subunits and
inhibits bacterial growth by inhibiting protein synthesis.
Effective against gram-negative and gram-positive bacteria. Since
its introduction in 1948, has proven to be remarkably effective for
enteric fever worldwide. For sensitive strains, still most widely
used antibiotic to treat typhoid fever. In the 1960s,S typhi
strains with plasmid-mediated resistance to chloramphenicol began
to appear and later became widespread in many endemic countries of
the Americas and Southeast Asia, highlighting need for alternative
agents.Produces rapid improvement in patient's general condition,
followed by defervescence in 3-5 d. Reduced preantibiotic-era
case-fatality rates from 10%-15% to 1%-4%. Cures approximately 90%
of patients. Administered PO unless patient is nauseous or
experiencing diarrhea; in such cases, IV route should be used
initially. IM route should be avoided because it may result in
unsatisfactory blood levels, delaying defervescence.View full drug
informationAmoxicillin (Trimox, Amoxil, Biomox)Interferes with
synthesis of cell wall mucopeptides during active multiplication,
resulting in bactericidal activity against susceptible bacteria. At
least as effective as chloramphenicol in rapidity of defervescence
and relapse rate. Convalescence carriage occurs less commonly than
with other agents when organisms are fully susceptible. Usually
given PO with a daily dose of 75-100 mg/kg tid for 14 d.View full
drug informationTrimethoprim and sulfamethoxazole (Bactrim DS,
Septra)Inhibits bacterial growth by inhibiting synthesis of
dihydrofolic acid. Antibacterial activity of TMP-SMZ includes
common urinary tract pathogens, exceptPseudomonas aeruginosa. As
effective as chloramphenicol in defervescence and relapse rate.
Trimethoprim alone has been effective in small groups of
patients.View full drug informationCiprofloxacin
(Cipro)Fluoroquinolone with activity against pseudomonads,
streptococci, MRSA,Staphylococcus epidermidis,and most
gram-negative organisms but no activity against anaerobes. Inhibits
bacterial DNA synthesis and, consequently, growth. Continue
treatment for at least 2 d (7-14 d typical) after signs and
symptoms have disappeared. Proven to be highly effective for
typhoid and paratyphoid fevers. Defervescence occurs in 3-5 d, and
convalescent carriage and relapses are rare. Other quinolones (eg,
ofloxacin, norfloxacin, pefloxacin) usually are effective. If
vomiting or diarrhea is present, should be given IV.
Fluoroquinolones are highly effective against multiresistant
strains and have intracellular antibacterial activity.Not currently
recommended for use in children and pregnant women because of
observed potential for causing cartilage damage in growing animals.
However, arthropathy has not been reported in children following
use of nalidixic acid (an earlier quinolone known to produce
similar joint damage in young animals) or in children with cystic
fibrosis, despite high-dose treatment.Cefotaxime (Claforan)Arrests
bacterial cell wall synthesis, which inhibits bacterial growth.
Third-generation cephalosporin with gram-negative spectrum. Lower
efficacy against gram-positive organisms. Excellent in vitro
activity againstS typhiand other salmonellae and has acceptable
efficacy in typhoid fever. Only IV formulations are available.
Recently, emergence of domestically acquired
ceftriaxone-resistantSalmonellainfections has been described.View
full drug informationAzithromycin (Zithromax)Treats mild to
moderate microbial infections. Administered PO at 10 mg/kg/d (not
exceeding 500 mg), appears to be effective to treat uncomplicated
typhoid fever in children 4-17 y. Confirmation of these results
could provide an alternative for treatment of typhoid fever in
children in developing countries, where medical resources are
scarce.View full drug informationCeftriaxone
(Rocephin)Third-generation cephalosporin with broad-spectrum
gram-negative activity against gram-positive organisms; Excellent
in vitro activity againstS typhiand other salmonellae.Cefoperazone
(Cefobid)Discontinued in the United States. Third-generation
cephalosporin with gram-negative spectrum. Lower efficacy against
gram-positive organisms.View full drug informationOfloxacin
(Floxin)A pyridine carboxylic acid derivative with broad-spectrum
bactericidal effect.View full drug informationLevofloxacin
(Levaquin)For pseudomonal infections and infections due to
multidrug-resistant gram-negative organisms.CorticosteroidsClass
SummaryDexamethasone may decrease the likelihood of mortality in
severe typhoid fever cases complicated by delirium, obtundation,
stupor, coma, or shock if bacterial meningitis has been
definitively ruled out by cerebrospinal fluid studies. To date, the
most systematic trial of this has been a randomized controlled
study in patients aged 3-56 years with severe typhoid fever who
were receiving chloramphenicol therapy. This study compared
outcomes in 18 patients given placebo with outcomes in 20 patients
given dexamethasone 3 mg/kg IV over 30 minutes followed by
dexamethasone 1 mg/kg every 6 hours for 8 doses. The fatality rate
in the dexamethasone arm was 10% versus 55.6% in the placebo arm
(P=.003).[60]Nonetheless, this point is still debated. A 2003 WHO
statement endorsed the use of steroids as described above, but
reviews by eminent authors in theNew England Journal of
Medicine(2002)[4]and theBritish Medical Journal(2006)[61]do not
refer to steroids at all. A 1991 trial compared patients treated
with 12 doses of dexamethasone 400 mg or 100 mg to a retrospective
cohort in whom steroids were not administered. This trial found no
difference in outcomes among the groups.[62]The data are sparse,
but the authors of this article agree with the WHO that
dexamethasone should be used in cases of severe typhoid fever.View
full drug informationDexamethasone (Decadron)Prompt administration
of high-dose dexamethasone reduces mortality in patients with
severe typhoid fever without increasing incidence of complications,
carrier states, or relapse among survivors.Further Inpatient CareIf
treated with well-selected antibiotics, patients with typhoid fever
(enteric fever) should defervesce within 3-5 days. However,
patients with complicated typhoid fever should finish their course
intravenously and should remain in the hospital if unable to manage
this at home.Patients with complicated typhoid fever should be
admitted through the acute phase of the illness. Uncomplicated
cases are generally treated on an outpatient basis unless the
patient is a public health risk or cannot be fully monitored
outside the home.Further Outpatient CareAfter discharge, patients
should be monitored for relapse or complications for 3 months after
treatment has commenced.Five percent to 10% of patients treated
with antibiotics experience relapse of typhoid fever after initial
recovery. Relapses typically occur approximately 1 week after
therapy is discontinued, but relapse after 70 days has been
reported. In these cases, the blood culture results are again
positive, and high serum levels of H, O, and Vi antibodies and rose
spots may reappear.A relapse of typhoid fever is generally milder
and of shorter duration than the initial illness. In rare cases,
second or even third relapses occur. Notably, the relapse rate is
much lower following treatment with the new quinolone drugs, which
have effective intracellular penetration.S typhiandS
paratyphirarely develop antibiotic resistance during treatment. If
an antibiotic has been chosen according to sensitivities, relapse
should dictate a search for anatomic, pathologic, or genetic
predispositions rather than for an alternate antibiotic.Previous
infection does not confer immunity. In any suspected relapse,
infection with a different strain should be ruled out.Depending on
the antibiotic used, between 0% and 5.9% of treated patients become
chronic carriers. In some cases, the organism evades antibiotics by
sequestering itself withingallstonesorSchistosoma
haematobiumorganisms that are infecting the bladder. From there, it
is shed in stool or urine, respectively. If present, these diseases
must be cured before the bacterium can be eliminated.Untreated
survivors of typhoid fever may shed the bacterium in the feces for
up to 3 months. Therefore, after disease resolution, 3 stool
cultures in one-month intervals should be performed to rule out a
carrier state. Concurrent urinary cultures should be
considered.Deterrence/PreventionTravelers to endemic countries
should avoid raw unpeeled fruits or vegetables since they may have
been prepared with contaminated water and should not buy food from
street vendors; in addition, they should drink only boiled water.In
endemic countries, the most cost-effective strategy for reducing
the incidence of typhoid fever is the institution of public health
measures to ensure safe drinking water and sanitary disposal of
excreta. The effects of these measures are long-term and reduce the
incidence of other enteric infections, which are a major cause of
morbidity and mortality in those areas.VaccinesIn endemic areas,
mass immunization with typhoid vaccines at regular intervals
considerably reduces the incidence of infections.Routine typhoid
vaccination is not recommended in the United States but is
indicated for travelers to endemic areas, persons with intimate
exposure to a documentedS typhicarrier (eg, household contacts of
chronic carriers, defined as persons with excretion ofS typhiin
urine or stool 1 year), and microbiology laboratory personnel who
frequently work withS typhi. In their 2015 recommendations, the
Advisory Committee on Immunization Practices in the US recommends
that travelers to countries with a high prevalence of typhoid and
recognized risk for exposure toStyphishould be vaccinated against
typhoid, even if they are staying with friends or relatives or only
traveling for a short time.[63]Vaccines are not approved for use in
children younger than 2 years. The efficacy of typhoid fever
vaccinations againstparatyphiserovars has not been firmly
established, but is markedly less than their efficacy
againsttyphi.[64]Travelers should be vaccinated at least one week
prior to departing for an endemic area. Because typhoid vaccines
lose effectiveness after several years, consultation with a
specialist in travel medicine is advised if the individual is
traveling several years after vaccination. In addition, clinicians
should warn travelers to consume only safe foods and beverages,
because typhoid vaccines offer only moderate protection, and large
inocula ofS typhi can overcome vaccine-induced protection.The only
absolute contraindication to vaccination is a history of severe
local or systemic reactions following a previous dose. The typhoid
vaccines available in the United States have not been studied in
pregnant women.Currently, the 3 typhoid fever vaccines include
injected Vi capsular polysaccharide (ViCPS; Typhim Vi, Pasteur
Merieux) antigen, enteric Ty21a (Vivotif Berna, Swiss Serum and
Vaccine Institute) live-attenuated vaccine, and an
acetone-inactivated parenteral vaccine (used only in members of the
armed forces). The efficacy of both vaccines available to the
general public approaches 50%.Vi capsular polysaccharide antigen
vaccineVi capsular polysaccharide antigen vaccine is composed of
purified Vi antigen, the capsular polysaccharide elaborated byS
typhiisolated from blood cultures. The Vi antigen is absent inS
paratyphi A, but this vaccine does provide some in vitro
immunogenicity againstS paratyphi A. This may be due to trace
amounts of other, common antigens in the preparation.[65]Primary
vaccination with ViCPS consists of a single parenteral dose of 0.5
mL (25 g IM) one week before travel. The vaccine manufacturer does
not recommend the vaccine for children younger than 2 years.
Booster doses are needed every 2 years to maintain protection if
continued or renewed exposure is expected.Adverse effects include
fever, headache, erythema, and/or induration of 1 cm or greater. In
a study conducted in Nepal, the ViCPS vaccine produced fewer local
and systemic reactions than the control (the 23-valent pneumococcal
vaccine).[66]Among school children in South Africa, ViCPS produced
less erythema and induration than the control (bivalent vaccine).A
systemic review and meta-analysis of 5 randomized controlled trials
on the efficacy and safety of ViCPS versus placebo or nontyphoid
vaccine found a cumulative efficacy of 55% (95% CI, 30%-70%).The
efficacy of vaccination with ViCPS has not been studied among
persons from areas without endemic disease who travel to endemic
regions or among children younger than 5 years. ViCPS has not been
given to children younger than 1 year.Questions concerning Vi
typhoid vaccine effectiveness in young children (ie, < 5 y) have
inhibited its use in developing countries. Whether the vaccine is
effective under programmatic conditions is also unclear.Sur et al
conducted a phase IV effectiveness trial in slum-dwelling residents
aged 2 years or older in India to determine vaccine protection.
Participants (n=37,673) were randomly assigned to receive a single
dose of either Vi vaccine or inactivated hepatitis A vaccine,
according to geographic clusters. The mean rate of Vi vaccine
coverage was 61% and 60% for the hepatitis A vaccine.Typhoid fever
was diagnosed in 96 subjects in the hepatitis A vaccine group
compared with 34 in the Vi vaccine group (no more than 1 episode
was reported per individual). Protective effect for typhoid with
the Vi vaccine was 61% (P< 0.001) compared with the hepatitis A
vaccine group. Children vaccinated while aged 2-5 years had an 80%
protection level. Unvaccinated members of the Vi vaccine clusters
showed a protection level of 44%. The overall protection level with
all Vi vaccine cluster residents was 57%. The authors concluded
that the Vi vaccine was effective in young children and protected
unvaccinated neighbors of Vi vaccinees.[67]Ty21aTy21a is an oral
vaccine that contains live attenuatedS typhiTy21a strains in an
enteric-coated capsule. The vaccine elicits both serum and
intestinal antibodies and cell-mediated immune responses.In the
United States, primary vaccination with Ty21a consists of one
enteric-coated capsule taken on alternate days to a total of 4
capsules. The capsules must be refrigerated (not frozen), and all 4
doses must be taken to achieve maximum efficacy.The optimal booster
schedule has not been determined; however, the longest reported
follow-up study of vaccine trial subjects indicated that efficacy
continued for 5 years after vaccination. The manufacturer
recommends revaccination with the entire 4-dose series every 5
years if continued or renewed exposure toS typhiis expected. This
vaccine may be inactivated if given within 3 days of
antibiotics.Adverse effects are rare. They include abdominal
discomfort, nausea, vomiting, fever, headache, and rash
orurticaria.The vaccine manufacturer of Ty21a recommends against
use in children younger than 6 years. It should not be administered
to immunocompromised persons; the parenteral vaccines present
theoretically safer alternatives for this group.A systemic review
and meta-analysis of 4 randomized controlled trials on the efficacy
and safety of Ty21a versus placebo or nontyphoid vaccine found a
cumulative efficacy of 51% (95% CI, 36%-62%).The efficacy of Ty21a
has not been studied among persons from areas without endemic
disease who travel to disease-endemic regions.Acetone-inactivated
parenteral vaccineAcetone-inactivated parenteral vaccine is
currently available only to members of the US Armed Forces.
Efficacy rates for this vaccine range from 75%-94%. Booster doses
should be administered every 3 years if continued or renewed
exposure is expected.The parenteral heat-phenolinactivated vaccine
(Wyeth-Ayerst) has been discontinued.No information has been
reported concerning the use of one vaccine as a booster after
primary vaccination with a different vaccine. However, using either
the series of 4 doses of Ty21a or 1 dose of ViCPS for persons
previously vaccinated with parenteral vaccine is a reasonable
alternative to administration of a booster dose of parenteral
inactivated vaccine.A more effective vaccine may be on the horizon.
An investigational vaccine using ViCPS conjugated to the nontoxic
recombinant pseudomonas exotoxin A (Vi-rEPA) has been studied in a
randomized controlled trial. The vaccine was given to children aged
2-5 years and showed an efficacy of 89% (95% CI, 76%-97%) after 3.8
years. Vi-rEPA has not been approved for use in the United
States.ComplicationsIn the past 2 decades, reports from
disease-endemic areas have documented a wide spectrum of
neuropsychiatric manifestations of typhoid fever. Potential
neuropsychiatric manifestations of typhoid fever include the
following: A toxic confusional state, characterized by
disorientation, delirium, and restlessness, is characteristic of
late-stage typhoid fever. In some cases, these and other
neuropsychiatric features dominate the clinical picture at an early
stage. Facial twitching or convulsions may be the presenting
feature. Meningismus is not uncommon, but frank meningitis is rare.
Encephalomyelitis may develop, and the underlying pathology may be
that of demyelinating leukoencephalopathy. In rare cases,
transverse myelitis, polyneuropathy, or cranial mononeuropathy
develops. Stupor, obtundation, or coma indicates severe disease.
Focal intracranial infections are uncommon, but multiplebrain
abscesseshave been reported.[68] Other less-common neuropsychiatric
manifestations events have included spastic paraplegia, peripheral
or cranial neuritis, Guillain-Barr syndrome, schizophrenialike
illness, mania, and depression.Respiratory complications may
include the following: Cough Ulceration of posterior pharynx
Occasional presentation as acute lobar pneumonia
(pneumotyphoid)Cardiovascular complications may include the
following: Nonspecific electrocardiographic changes occur in
10%-15% of patients with typhoid fever. Toxic myocarditis occurs in
1%-5% of persons with typhoid fever and is a significant cause of
death in endemic countries. Toxic myocarditis occurs in patients
who are severely ill and toxemic and is characterized by
tachycardia, weak pulse and heart sounds, hypotension, and
electrocardiographic abnormalities. Pericarditis is rare, but
peripheral vascular collapse without other cardiac findings is
increasingly described. Pulmonary manifestations have also been
reported in patients with typhoid fever.[69]Hepatobiliary
complications may include the following: Mild elevation of
transaminases without symptoms is common in persons with typhoid
fever. Jaundice may occur in persons with typhoid fever and may be
due to hepatitis,cholangitis,cholecystitis, or hemolysis.
Pancreatitis and accompanying acute renal failure and hepatitis
with hepatomegaly have been reported.[70]Intestinal manifestations
may include the following: The 2 most common complications of
typhoid fever include intestinal hemorrhage (12% in one British
series) and perforation (3%-4.6% of hospitalized patients). From
1884-1909 (ie, preantibiotic era), the mortality rate in patients
with intestinal perforation due to typhoid fever was 66%-90% but is
now significantly lower. Approximately 75% of patients have
guarding, rebound tenderness, and rigidity, particularly in the
right lower quadrant. Diagnosis is particularly difficult in the
approximately 25% of patients with perforation and peritonitis who
do not have the classic physical findings. In many cases, the
discovery of free intra-abdominal fluid is the only sign of
perforation.Genitourinary manifestations may include the following:
Approximately 25% of patients with typhoid fever excreteS typhiin
their urine at some point during their illness. Immune complex
glomerulitis[71]andproteinuriahave been reported, and IgM, C3
antigen, andS typhiantigen can be demonstrated in the glomerular
capillary wall. Nephritic syndrome may complicate chronicS
typhibacteremia associated with urinaryschistosomiasis. Nephrotic
syndromemay occur transiently in patients withglucose-6-phosphate
dehydrogenase deficiency. Cystitis: Typhoid cystitis is very rare.
Retention of urine in the typhoid state may facilitate infection
with coliforms or other contaminants.Hematologic manifestations may
include the following: Subclinical disseminated intravascular
coagulation is common in persons with typhoid fever.
Hemolytic-uremic syndromeis rare.[72] Hemolysis may also be
associated with glucose-6-phosphate dehydrogenase
deficiency.Musculoskeletal and joint manifestations may include the
following: Skeletal muscle characteristically shows Zenker
degeneration, particularly affecting the abdominal wall and thigh
muscles. Clinically evidentpolymyositismay occur.[73] Arthritisis
very rare and most often affects the hip, knee, or ankle.Late
sequelae (rare in untreated patients and exceedingly rare in
treated patients) may include the following: Neurologic -
Polyneuritis, paranoid psychosis, orcatatonia[74] Cardiovascular -
Thrombophlebitis of lower-extremity veins Genitourinary -Orchitis
Musculoskeletal - Periostitis, often abscesses of the tibia and
ribs; spinal abscess (typhoid spine; very rare)PrognosisThe
prognosis among persons with typhoid fever depends primarily on the
speed of diagnosis and initiation of correct treatment. Generally,
untreated typhoid fever carries a mortality rate of 10%-20%. In
properly treated disease, the mortality rate is less than 1%.An
unspecified number of patients experience long-term or permanent
complications, including neuropsychiatric symptoms and high rates
of gastrointestinal cancers.Patient EducationBecause vigilant hand
hygiene, vaccination, and the avoidance of risky foods and
beverages are mainstays of prevention, educating travelers before
they enter a disease-endemic region is important.Because the
protection offered by vaccination is at best partial, close
attention to personal, food, and water hygiene should be
maintained. The US Centers for Disease Control and Prevention
dictum to "boil it, cook it, peel it, or forget it" is a good rule
in any circumstance. If disease occurs while abroad despite these
precautions, one can usually call the US consulate for a list of
recommended doctors.For excellent patient education resources, see
eMedicineHealth's patient education articleForeign Travel.Case
studyA wealthy middle-aged man presented to his physician a few
days after the onset of flulike symptoms, including fever,
myalgias, chills, severe abdominal pain, and a cough, in addition
to severe abdominal pain. Over the next 2 weeks, he lost a great
deal of weight. He had intermittent but ever-increasing fevers.
About 3 weeks after the onset of symptoms, he developed a few pale,
salmon-colored macules on his trunk. His cough became much more
frequent and severe. He became delirious, listlessly wandering
around the house fiddling with doorknobs. During the fourth week of
his illness, he rapidly declined with increasing somnolence. After
nearly 4 weeks of illness, he died surrounded by his loving
family.The patient was Prince Albert, the Consort to Queen
Victoria. He was diagnosed with typhoid fever. His personal
physician, Sir William Jenner, a leading expert on the disease,
diagnosed typhoid fever. Prince Albert received the best therapy of
the day.For the most up-to-date information, visit the Centers for
Disease Control and Prevention Travelers' Health Typhoid resource
(www.cdc.gov/travel) or call the Travelers' Health automated
information line at 877-FYI-TRIP. The World Health Organizations
site (www.who.int/ith), International Society of Travel Medicine
site (www.istm.org), and Travel Doctor
(www.traveldoctor.co.uk/diseases.htm) contain useful information as
well, though the authors disagree with some of the WHOs antibiotic
guidelines.
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