TYPHOID FEVER

Typhoid fever, also known as Typhoid,[1] is a common worldwide bacterial disease, transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica, serovar Typhi.[2][3] The bacteria then perforate through the intestinal wall and are phagocytosed by macrophages The organism is a Gramnegative short bacillus that is motile due to its peritrichous flagella. The bacterium grows best at 37C / 98.6F human body temperature. This fever received various names, such as gastric fever, abdominal typhus, infantile remittant fever, slow fever, nervous fever, pythogenic fever, etc. The name of "typhoid" comes from the neuropsychiatric symptoms common to typhoid and typhus (from Greek , "stupor").[4] The impact of this disease fell sharply with the application of modern sanitation techniques.

[edit] Signs and symptoms

Typhoid fever is characterized by a slowly progressive fever as high as 40 C (104 F), profuse sweating and gastroenteritis. Less commonly, a rash of flat, rose-colored spots may appear.[5] Classically, the course of untreated typhoid fever is divided into four individual stages, each lasting approximately one week. In the first week, there is a slowly rising temperature with relative bradycardia, malaise, headache, and cough. A bloody nose (epistaxis) is seen in a quarter of cases and abdominal pain is also possible. There is leukopenia, a decrease in the number of circulating white blood cells, with eosinopenia and relative lymphocytosis, a positive reaction and blood cultures are positive for Salmonella typhi or paratyphi. The classic Widal test is negative in the first week. In the second week of the infection, the patient lies prostrate with high fever in plateau around 40 C (104 F) and bradycardia (sphygmothermic dissociation), classically with a dicrotic pulse wave. Delirium is frequent, frequently calm, but sometimes agitated. This delirium gives to typhoid the nickname of "nervous fever". Rose spots appear on the lower chest and abdomen in around a third of patients. There are rhonchi in lung bases. The abdomen is distended and painful in the right lower quadrant where borborygmi can be heard. Diarrhea can occur in this stage: six to eight stools in a day, green with a characteristic smell, comparable to pea soup. However, constipation is also frequent. The spleen and liver are enlarged (hepatosplenomegaly) and tender, and there is elevation of liver transaminases. The Widal reaction is strongly positive with antiO and antiH antibodies. Blood cultures are sometimes still positive at this stage. (The major symptom of this fever is that the fever usually rises in the afternoon up to the first and second week.) In the third week of typhoid fever, a number of complications can occur:

Intestinal hemorrhage due to bleeding in congested Peyer's patches; this can be very serious but is usually not fatal. Intestinal perforation in the distal ileum: this is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicaemia or diffuse peritonitis sets in. Encephalitis Neuropsychiatric symptoms (described as "muttering delirium" or "coma vigil"), with picking at bedclothes or imaginary objects. Metastatic abscesses, cholecystitis, endocarditis and osteitis

The fever is still very high and oscillates very little over 24 hours. Dehydration ensues and the patient is delirious (typhoid state). By the end of third week the fever has started reducing this (defervescence). This carries on into the fourth and final week.

[edit] Transmission
The bacteria which causes typhoid fever may be spread through poor hygiene habits and public sanitation conditions, and sometimes also by flying insects feeding on feces. Public education campaigns encouraging people to wash their hands after defecating and before handling food are an important component in controlling spread of the disease. According to statistics from the United States Centers for Disease Control and Prevention (CDC), the chlorination of drinking water has led to dramatic decreases in the transmission of typhoid fever in the U.S.A. A person may become an asymptomatic carrier of typhoid fever, suffering no symptoms, but capable of infecting others. According to the CDC approximately 5% of people who contract typhoid continue to carry the disease after they recover. The most famous asymptomatic carrier was Mary Mallon (commonly known as "Typhoid Mary"), a young cook who was responsible for infecting at least 53 people with typhoid, three of whom died from the disease.[6] Mallon was the first apparently perfectly healthy person known to be responsible for an "epidemic". Many carriers of typhoid were locked into an isolation ward never to be released in order to prevent further typhoid cases. These people often deteriorated mentally, driven mad by the conditions they lived in.[7]

[edit] Possible protective effects of heterozygosity for cystic fibrosis

It has been hypothesized that cystic fibrosis may have risen to its present levels (1 in 1600 in UK) due to the heterozygous advantage that it confers against typhoid fever.[8] The CFTR protein is present in both the lungs and the intestinal epithelium, and the mutant cystic fibrosis form of the CFTR protein prevents entry of the typhoid bacterium into the body through the intestinal epithelium. However, the heterozygous advantage hypothesis was proposed in one review in which the author himself writes, "Although cellular/molecular evidence presently is not available for this hypothesis, the CF mutation may be one of several mutations that have spread in European populations because they increased resistance to infectious diseases." Since no molecular experimental evidence has been presented in support of this theory, this theory is not accepted by the majority of the scientific community. '

[edit] Diagnosis of typhoid

Diagnosis is made by any blood, bone marrow or stool cultures and with the Widal test (demonstration of salmonella antibodies against antigens O-somatic and H-flagellar). In epidemics and less wealthy countries, after excluding malaria, dysentery or pneumonia, a therapeutic trial time with chloramphenicol is generally undertaken while awaiting the results of Widal test and cultures of the blood and stool.[9] The Widal test is time consuming and often times, when a diagnosis is reached, it is too late to start an antibiotic regimen. The term "enteric fever" is a collective term that refers to typhoid and paratyphoid.[10]

[edit] Prevention
Main article: Typhoid vaccine

Doctor administering a typhoid vaccination at a school in San Augustine County, Texas

1939 conceptual illustration showing various ways that typhoid bacteria can contaminate a water well (center) Sanitation and hygiene are the critical measures that can be taken to prevent typhoid. Typhoid does not affect animals and therefore transmission is only from human to human. Typhoid can only spread in environments where human feces or urine are able to come into contact with food or drinking water. Careful food preparation and washing of hands are crucial to preventing typhoid.

There are two vaccines licensed for use for the prevention of typhoid:[11] the live, oral Ty21a vaccine (sold as Vivotif Berna) and the injectable Typhoid polysaccharide vaccine (sold as Typhim Vi by Sanofi Pasteur and Typherix by GlaxoSmithKline). Both are between 50% to 80% protective and are recommended for travellers to areas where typhoid is endemic. Boosters are recommended every five years for the oral vaccine and every two years for the injectable form. There exists an older killed whole-cell vaccine that is still used in countries where the newer preparations are not available, but this vaccine is no longer recommended for use, because it has a higher rate of side effects (mainly pain and inflammation at the site of the injection).[11]

[edit] Medical Treatment

The rediscovery of oral rehydration therapy in the 1960s provided a simple way to prevent many of the deaths of diarrheal diseases in general. Where resistance is uncommon, the treatment of choice is a fluoroquinolone such as ciprofloxacin[10][12] otherwise, a third-generation cephalosporin such as ceftriaxone or cefotaxime is the first choice.[13][14][15] Cefixime is a suitable oral alternative.[16][17] Typhoid fever in most cases is not fatal. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, amoxicillin and ciprofloxacin, have been commonly used to treat typhoid fever in developed countries. Prompt treatment of the disease with antibiotics reduces the case-fatality rate to approximately 1%. When untreated, typhoid fever persists for three weeks to a month. Death occurs in between 10% and 30% of untreated cases[citation needed]. In some communities, however, case-fatality rates may reach as high as 47%.[citation needed]

[edit] Surgical Treatment

Surgery 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.

[edit] Resistance
Resistance to ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole and streptomycin is now common, and these agents have not been used as first line treatment now for almost 20 years.[citation needed] Typhoid that is resistant to these agents is known as multidrug-resistant typhoid (MDR typhoid). Ciprofloxacin resistance is an increasing problem, especially in the Indian subcontinent and Southeast Asia. Many centres are therefore moving away from using ciprofloxacin as first line

for treating suspected typhoid originating in South America, India, Pakistan, Bangladesh, Thailand or Vietnam. For these patients, the recommended first line treatment is ceftriaxone. It has also been suggested azithromycin is better at treating typhoid in resistant populations than both fluoroquinolone drugs and ceftriaxone.[12] Azithromycin significantly reduces relapse rates compared with ceftriaxone. There is a separate problem with laboratory testing for reduced susceptibility to ciprofloxacin: current recommendations are that isolates should be tested simultaneously against ciprofloxacin (CIP) and against nalidixic acid (NAL), and that isolates that are sensitive to both CIP and NAL should be reported as "sensitive to ciprofloxacin", but that isolates testing sensitive to CIP but not to NAL should be reported as "reduced sensitivity to ciprofloxacin". However, an analysis of 271 isolates showed that around 18% of isolates with a reduced susceptibility to ciprofloxacin (MIC 0.1251.0 mg/l) would not be picked up by this method.[18] It is not certain how this problem can be solved, because most laboratories around the world (including the West) are dependent on disk testing and cannot test for MICs.

[edit] Epidemiology

Incidence of typhoid fever Strongly endemic Endemic Sporadic cases

Death rates for typhoid fever in the U.S. 19061960 With an estimated 1633 million cases of annually resulting in 216,000 deaths in endemic areas, the World Health Organization identifies typhoid as a serious public health problem. Its incidence is highest in children and young adults between 5 and 19 years old.[19]

[edit] History
Around 430424 BC, a devastating plague, which some believe to have been typhoid fever, killed one third of the population of Athens, including their leader Pericles. The balance of power shifted from Athens to Sparta, ending the Golden Age of Pericles that had marked Athenian dominance in the Greek ancient world. Ancient historian Thucydides also contracted the disease, but he survived to write about the plague. His writings are the primary source on this outbreak and modern academics and medical scientists consider epidemic typhus the most likely cause; a 2006 study detected DNA sequences similar to those of the bacterium responsible for typhoid fever.[20] However the cause of the plague has long been disputed and other scientists have disputed the findings, citing serious methodologic flaws in the dental pulp-derived DNA study.[21] The disease is most commonly transmitted through poor hygiene habits and public sanitation conditions; during the period in question, the whole population of Attica was besieged within the Long Walls and lived in tents.

Mary Mallon ("Typhoid Mary") in a hospital bed (foreground). She was forcibly quarantined as a carrier of typhoid fever in 1907 for three years and then again from 1915 until her death in 1938. Some historians believe that in the English colony of Jamestown, Virginia, died out from typhoid. Typhoid fever killed more than 6000 settlers between 1607 and 1624.[22] During the American Civil War, 81,360 Union soldiers died of typhoid or dysentery.[23] In the late 19th century, typhoid fever mortality rate in Chicago averaged 65 per 100,000 people a year. The worst year was 1891, when the typhoid death rate was 174 per 100,000 people.[24] The most notorious carrier of typhoid feverbut by no means the most destructivewas Mary Mallon, also known as Typhoid Mary. In 1907, she became the first American carrier to be identified and traced. She was a cook in New York. She is closely associated with fifty-three cases and three deaths.[25] Public health authorities told Mary to give up working as a cook or have her gall bladder removed. Mary quit her job but returned later under a false name. She was detained and quarantined after another typhoid outbreak. She died of pneumonia after 26 years in quarantine. In 1880 Karl Joseph Eberth described a bacillus that he suspected was the cause of typhoid. In 1884 pathologist Georg Theodor August Gaffky (18501918) confirmed Eberth's findings, and the organism was given names such as Eberth's bacillus, Eberthella typhi and Gaffky-Eberth bacillus. Today the bacillus that causes typhoid fever goes by the scientific name of Salmonella enterica enterica, serovar Typhi.

Almroth Edward Wright developed an effective inactivated whole-cell typhoid vaccine that was introduced in 1896.[11] In 1909, Frederick F. Russell, a U.S. Army physician, developed an American typhoid vaccine and two years later his vaccination program became the first in which an entire army was immunized. It eliminated typhoid as a significant cause of morbidity and mortality in the U.S. military. Most developed countries saw declining rates of typhoid fever throughout the first half of the 20th century due to vaccinations and advances in public sanitation and hygiene. Antibiotics were introduced in clinical practice in 1942, greatly reducing mortality. Today, incidence of typhoid fever in developed countries is around 5 cases per 1,000,000 people per year. An outbreak in the Democratic Republic of Congo in 200405 recorded more than 42,000 cases and 214 deaths.[19] Typhoid fever was also known as suette milliaire in nineteenth-century France.

Typhoid fever facts

Typhoid fever usually is caused by Salmonellae typhi bacteria. Typhoid fever is contracted by the ingestion of contaminated food or water. Diagnosis of typhoid fever is made when the Salmonella bacteria is detected with a stool culture. Typhoid fever is treated with antibiotics. Typhoid fever symptoms are poor appetite, headaches, generalized aches and pains, fever, and lethargy. Approximately 3%-5% of patients become carriers of the bacteria after the acute illness.

What is typhoid fever? What is the history of typhoid fever?

Typhoid fever is an acute illness associated with fever that is most often caused by the Salmonella typhi bacteria. It can also be caused by Salmonella paratyphi, a related bacterium that usually leads to a less severe illness. The bacteria are deposited in water or food by a human carrier and are then spread to other people in the area. Typhoid fever is rare in industrial countries but continues to be a significant public-health issue in developing countries. The incidence of typhoid fever in the United States has markedly decreased since the early 1900s. Today, approximately 400 cases are reported annually in the United States, mostly in people who recently have traveled to endemic areas. This is in comparison to the 1920s, when over 35,000 cases were reported in the U.S. This improvement is the result of improved environmental sanitation. Mexico and South America are the most common areas for U.S. citizens to contract typhoid fever. India, Pakistan, and Egypt are also known high-risk areas for developing this disease. Worldwide, typhoid fever affects more than 13 million people annually, with over 500,000 patients dying of the disease. If traveling to endemic areas, you should consult with your health-care professional and discuss if you should receive vaccination for typhoid fever.

How do patients get typhoid fever?

Typhoid fever is contracted by the ingestion of the bacteria in contaminated food or water. Patients with acute illness can contaminate the surrounding water supply through stool, which contains a high concentration of the bacteria. Contamination of the water supply can, in turn, taint the food supply. About 3%-5% of patients become carriers of the bacteria after the acute illness. Some patients suffer a very mild illness that goes unrecognized. These patients can become long-term carriers of the bacteria. The bacteria multiplies in the gallbladder, bile ducts, or liver and passes into the bowel. The bacteria can survive for weeks in water or dried sewage. These chronic carriers may have no symptoms and can be the source of new outbreaks of typhoid fever for many years.

How does the bacteria cause disease, and how is it diagnosed?

After the ingestion of contaminated food or water, the Salmonella bacteria invade the small intestine and enter the bloodstream temporarily. The bacteria are carried by white blood cells in the liver, spleen, and bone marrow. The bacteria then multiply in the cells of these organs and reenter the bloodstream. Patients develop symptoms, including fever, when the organism reenters the bloodstream. Bacteria invade the gallbladder, biliary system, and the lymphatic tissue of the bowel. Here, they multiply in high numbers. The bacteria pass into the intestinal tract and can be identified for diagnosis in cultures from the stool tested in the laboratory. Stool cultures are sensitive in the early and late stages of the disease but often must be supplemented with blood cultures to make the definite diagnosis.

What are the symptoms of typhoid fever?

The incubation period is usually one to two weeks, and the duration of the illness is about four to six weeks. The patient experiences

poor appetite; abdominal pain; headaches; generalized aches and pains; fever, often up to 104 F; lethargy (usually only if untreated); intestinal bleeding or perforation (after two to three weeks of the disease); diarrhea or constipation.

People with typhoid fever usually have a sustained fever as high as 103 F-104 F (39 C-40 C). Chest congestion develops in many patients, and abdominal pain and discomfort are common. The fever becomes constant. Improvement occurs in the third and fourth week in those without complications. About 10% of patients have recurrent symptoms (relapse) after feeling better for one to two weeks. Relapses are actually more common in individuals treated with antibiotics.

What is the treatment for typhoid fever, and what is the prognosis?
Typhoid fever is treated with antibiotics that kill the Salmonella bacteria. Prior to the use of antibiotics, the fatality rate was 20%. Death occurred from overwhelming infection, pneumonia, intestinal bleeding, or intestinal perforation. With antibiotics and supportive care, mortality has been reduced to 1%-2%. With appropriate antibiotic therapy, there is usually improvement within one to two days and recovery within seven to 10 days. Several antibiotics are effective for the treatment of typhoid fever. Chloramphenicol was the original drug of choice for many years. Because of rare serious side effects, chloramphenicol has been replaced by other effective antibiotics. The choice of antibiotics needs to be guided by identifying the geographic region where the organism was acquired and the results of cultures once available. (Certain strains from South America show a significant resistance to some antibiotics.) Ciprofloxacin (Cipro) is the most frequently used drug in the U.S. for nonpregnant patients. Ceftriaxone (Rocephin), an intramuscular injection medication, is an alternative for

pregnant patients. Ampicillin (Omnipen, Polycillin, Principen) and trimethoprimsulfamethoxazole (Bactrim, Septra) are frequently prescribed antibiotics although resistance has been reported in recent years. If relapses occur, patients are retreated with antibiotics. The carrier state, which occurs in 3%-5% of those infected, can be treated with prolonged antibiotics. Often, removal of the gallbladder, the site of chronic infection, will cure the carrier state.

Can typhoid fever be prevented?

For those traveling to high-risk areas, vaccines are now available. The vaccine is usually not recommended in the U.S. There are two forms of the vaccine available an oral and an injectable form. The vaccination needs to be completed at least one week prior to travel and, depending on the type of vaccine, only protects from two to five years. The oral vaccine is contraindicated in patients with depressed immune systems. Details of the vaccination and the vaccine you chose should be discussed with your health-care provider.