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Typhoid fever
Background
Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness
caused primarily by Salmonella typhi. The protean manifestations of typhoid fever make this
disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse
abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may
progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within
one month of onset. Survivors may be left with long-term or permanent neuropsychiatric
complications.
S typhi has 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. The name S typhi is 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.
Transmission
S typhi has no nonhuman vectors. The following are modes of transmission:
Oral transmission via food or beverages handled by an individual who chronicallysheds the bacteria through stool or, less commonly, urine
Hand-to-mouth transmission after using a contaminated toilet and neglecting handhygiene
Oral transmission via sewage-contaminated water or shellfish (especially in thedeveloping world)
An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy
volunteers.
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Pathophysiology
All pathogenicSalmonellaspecies 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.
In contrast to the nontyphoidal salmonellae, S typhi enters the host's system primarily
through the distal ileum. S typhi has 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. S typhi has a Vi capsular
antigen that masks PAMPs, avoiding neutrophil-based inflammation. The bacteria then
induce their host macrophages to attract more macrophages.
It co-opts the macrophages' cellular machinery for their own reproduction as it is
carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and thenthrough to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes.
Once there, the S typhi bacteria 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.
The gallbladder is then infected via either bacteremia or direct extension of S typhi
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.
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Life cycle of Salmonella typhi.
Risk factors
S typhi 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 facilitate S typhi infection.
HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella
infection; however, the data and opinions in the literature as to whether this is true forS typhi
infection are conflicting. If an association exists, it is probably minor.
Other risk factors for clinical S typhi infection include various genetic
polymorphisms. These risk factors often also predispose to other intracellular pathogens. For
instance,PARK2 andPACGR code 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 with
Mycobacterium lepraeand S typhi.
On the other hand, protective host mutations also exist. The fimbriae of S typhi bind
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 to
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cholera and tuberculosis. 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 as malaria maintains sickle cell disease in Africa.
Environmental and behavioral risk factors that are independently associated with
typhoid fever include eating food from street vendors, living in the same household with
someone who has new case of typhoid fever, washing the hands inadequately, sharing food
from the same plate, drinking unpurified water, and living in a household that does not have a
toilet. 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 hygeine. American clinicians should keep this in mind, as
members of this cohort often come to the United States for higher degrees.
Symptoms
Although children with typhoid fever sometimes become sick suddenly, signs and
symptoms are more likely to develop gradually often appearing one to three weeks after
exposure to the disease.
First week of illness
Once signs and symptoms do appear, you're likely to experience:
Fever, often as high as 103 or 104 F (39.4 or 40 C) Headache Weakness and fatigue Sore throat Abdominal pain Diarrhea or constipation Rash
Children are more likely to have diarrhea, whereas adults may become severely
constipated. During the second week, you may develop a rash of small, flat, rose-colored
spots on your lower chest or upper abdomen. The rash is temporary, usually disappearing in
two to five days.
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Second week of illness
If you don't receive treatment for typhoid fever, you may enter a second stage during which
you become very ill and experience:
Continuing high fever Either diarrhea that has the color and consistency of pea soup, or severe constipation Considerable weight loss Extremely distended abdomen
Third week of illness
By the third week, you may:
Become delirious Lie motionless and exhausted with your eyes half-closed in what's known as the
typhoid state
Life-threatening complications often develop at this time.
Fourth week of illness
Improvement may come slowly during the fourth week. Your fever is likely to
decrease gradually until your temperature returns to normal in another week to 10 days. But
signs and symptoms can return up to two weeks after your fever has subsided.
When to see a doctor
See a doctor immediately if you suspect you have typhoid fever. If you become ill
while traveling in a foreign country, call the U.S. Consulate for a list of doctors. Better yet,
find out in advance about medical care in the areas you'll visit, and carry a list of the names,
addresses and phone numbers of recommended doctors.
If you develop signs and symptoms after you return home, consider consulting a
doctor who focuses on international travel medicine or infectious diseases. A specialist may
be able to recognize and treat your illness more quickly than can a doctor who isn't trained in
these areas.
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Race
Typhoid fever has no racial predilection.
Sex
Fifty-four percent of typhoid fever cases in the United States reported between 1999
and 2006 involved males.
Age
Most 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 the S typhi infection 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.
Treatments and drugs
Antibiotic therapy is the only effective treatment for typhoid fever.
Commonly prescribed antibiotics
In the United States, doctors often prescribe ciprofloxacin for nonpregnant adults.
Ceftriaxone an injectable antibiotic is an alternative for women who are pregnant and
for children who may not be candidates for ciprofloxacin. These drugs can cause side effects,
and long-term use can lead to the development of antibiotic-resistant strains of bacteria.
Problems with antibiotic resistance
In the past, the drug of choice was chloramphenicol. Doctors no longer commonly use
it, however, because of side effects, a high relapse rate and widespread bacterial resistance. In
fact, the existence of antibiotic-resistant bacteria is a growing problem in the treatment of
typhoid, especially in the developing world. In recent years, S. typhi also has proved resistant
to trimethoprim-sulfamethoxazole and ampicillin.
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Supportive therapy
Other treatment steps aimed at managing symptoms include:
Drinking fluids. This helps prevent the dehydration that results from a prolongedfever and diarrhea. If you're severely dehydrated, you may need to receive fluids
through a vein in your arm (intravenously).
Eating a healthy diet. Nonbulky, high-calorie meals can help replace the nutrientsyou lose when you're sick.
Prevention
In many developing nations, the public health goals that can help prevent and control
typhoid safe drinking water, improved sanitation and adequate medical care may be
difficult to achieve. For that reason, some experts believe that vaccinating high-risk
populations is the best way to control typhoid fever.
Two vaccines are currently in use one is injected in a single dose, and the other is
given orally over a period of days. Neither vaccine is 100 percent effective, and both require
repeat immunizations as vaccine effectiveness diminishes over time.
If you're traveling to an area where typhoid fever is endemic, consider being vaccinated.
But because the vaccine won't provide complete protection, be sure to follow these guidelines
as well:
Wash your hands. Frequent hand washing is the best way to control infection. Washyour hands thoroughly with hot, soapy water, especially before eating or preparing
food and after using the toilet. Carry an alcohol-based hand sanitizer for times whenwater isn't available.
Avoid drinking untreated water. Contaminated drinking water is a particularproblem in areas where typhoid is endemic. For that reason, drink only bottled water
or canned or bottled carbonated beverages, wine and beer. Carbonated bottled water is
safer than uncarbonated bottled water is. Wipe the outside of all bottles and cans
before you open them. Ask for drinks without ice. Use bottled water to brush your
teeth, and try not to swallow water in the shower.
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Avoid raw fruits and vegetables. Because raw produce may have been washed inunsafe water, avoid fruits and vegetables that you can't peel, especially lettuce. To be
absolutely safe, you may want to avoid raw foods entirely.
Choose hot foods. Avoid food that's stored or served at room temperature. Steaminghot foods are best. And although there's no guarantee that meals served at the finest
restaurants are safe, it's best to avoid food from street vendors it's more likely to be
contaminated.
To prevent infecting others
If you're recovering from typhoid, these measures can help keep others safe:
Wash your hands often. This is the single most important thing you can do to keepfrom spreading the infection to others. Use plenty of hot, soapy water and scrub
thoroughly for at least 30 seconds, especially before eating and after using the toilet.
Clean household items daily. Clean toilets, door handles, telephone receivers andwater taps at least once a day with a household cleaner and paper towels or disposable
cloths.
Avoid handling food. Avoid preparing food for others until your doctor says you'reno longer contagious. If you work in the food service industry or a health care facility,
you won't be allowed to return to work until tests show that you're no longer shedding
typhoid bacteria.
Keep personal items separate. Set aside towels, bed linen and utensils for your ownuse and wash them frequently in hot, soapy water. Heavily soiled items can be soaked
first in disinfectant.
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REFERENCES
www.emidicine.com
www.medscape.com www.mayoclinic.com
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