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 Greek typhos, 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 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)

An inoculum as small as 100,000 organisms causes infection in more than 50% of healthy volunteers.

Pathophysiology
All pathogenic Salmonella species 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 tolllike receptor (TLR)5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogenassociated 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 then through 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.

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 for S 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 and PACGR 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 leprae and 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

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.

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.

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.

Supportive therapy Other treatment steps aimed at managing symptoms include:

Drinking fluids. This helps prevent the dehydration that results from a prolonged fever 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 nutrients you 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. Wash your 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 when water isn't available.

Avoid drinking untreated water. Contaminated drinking water is a particular problem 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.

Avoid raw fruits and vegetables. Because raw produce may have been washed in unsafe 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. Steaming hot 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 keep from 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 and water 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're no 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 own use and wash them frequently in hot, soapy water. Heavily soiled items can be soaked first in disinfectant.

REFERENCES
www.emidicine.com www.medscape.com www.mayoclinic.com