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Thursday, October 25, 2007

Typhoid Fever

Compiled and Summarized by Anthony
Typhoid fever, also known as enteric fever, is an illness caused by the bacterium Salmonella enterica serovar typhi. It is commonly transmitted through the fecal-oral route — the ingestion of food or water contaminated with feces or urine from an infected person. The bacteria then multiplies in the blood stream of the infected person and are absorbed into the digestive tract and eliminated with the waste.

Signs and Symptoms

Typhoid fever is characterized by a sustained fever as high as 40°C (104°F), profuse sweating, gastroenteritis, and diarrhea. Less commonly a rash of flat, rose-colored spots may appear.

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. Epistaxis is seen in a quarter of cases and abdominal pain is also possible. There is leukopenia with eosinopenia and relative lymphocytosis, a positive diazo 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 prostrated with high fever in plateau around 40°C and bradycardia (Sphygmo-thermic 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 1/3 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.

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 non-fatal.
· Intestinal perforation in distal ileum: this is a very serious complication and is frequently fatal. It may occur without alarming symptoms until septicemia or diffuse peritonitis sets in.
· Encephalitis
· 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 defervescence commences that prolongs itself in the fourth week.

Causative Agents

Salmonella typhi, and Salmonella paratyphi, which are subspecies of Salmonella enterica

Mode of Transmission

Fecal-oral route


Diagnosis is made by blood, bone marrow or stool cultures, urine sample, 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 blood cultures.

Incubation Period

The incubation period of typhoid fever varies with the size of the infecting dose and averages 7-14 (range, 3-60) days.


Salmonella organisms penetrate the mucosa of both small and large bowel, coming to lie intracellularly where they proliferate. There is not the same tendency to mucosal damage as occurs with Shigella infections but ulceration of lymphoid follicles may occur. The evolution of typhoid is fascinating. Initially S. typhi proliferates in the second part of the Payer’s patches of the lower small intestine from where systemic dissemination occurs, to the liver, spleen, and reticuloendothelial system. For a period varying from 1 to 3 weeks the organism multiplies within these organs.

Rupture of infected cell occurs, liberating organisms into the bile and for a second time cause infection of the lymphoid tissue of the small intestine paticularly in the ileum. It is this phase of heavy infection that brings the classical bowel pathology of typhoid in its train. Invasion of the mucosa causes the epithelial cells to synthesize and release various proinflammatory cytokines including IL-1, IL-6, IL-8, TNF-β, INF, GM-CSF etc.


After ingestion by the host, S. typhi invades through the gut and multiplies within the mononuclear phagocytic cells in the liver, spleen, lymph nodes, and Peyer patches of the ileum.

In studies of healthy, previously unvaccinated men, ingestion of 107 S. typhi bacilli caused disease in 50% of volunteers. Investigations of outbreaks seem to indicate that an inoculum of as few as 200 organisms may lead to the disease. Perhaps such a discrepancy exists because many who ingest S. typhi are not healthy men and have any one of a number of risk factors* (see below). As the number of organisms increases, the incubation period decreases. The number of bacilli ingested does not change the subsequent clinical syndrome.

After successfully passing through the stomach, any Salmonella subspecies may be phagocytized by the gut's intraluminal dendritic cells, causing inflammation that leads to diarrhea. Only the subspecies S. enterica causes severe disease in the rest of the body. Its specialized fimbriae adhere to the epithelium that overlies Peyer patches. Peyer patches are grossly visible aggregates of 5-100 lymphoid follicles in the small bowel submucosa; these patches are larger and more numerous distally. They are the primary mechanism for sampling antigens in the gut and initiating response. S. enterica enters them via 1 of 3 pathways.

Intraluminal dendritic cells may infiltrate through the gut epithelium while carrying the bacterium. M cells may transport it as well. Immobile and interspersed among regular enterocytes in Peyer patches, M cells are epithelial cells that mature into professional phagocytes. They phagocytize bacteria such as S. enterica and present them to macrophages and T cells in the lamina propria. Most interestingly, S. enterica may convert normally nonphagocytic epithelial cells into bacterially-mediated endocytosis (BME).

In BME, Salmonella uses a type III secretion system—macromolecular channels that gram-negative bacteria such as Salmonella insert into eukaryotic cells and intracellular membranes to inject virulence proteins—to inject proteins SipA and SipC into the epithelial cell. These disrupt the normal brush border and force the cell to form membrane ruffles. The ruffles engulf the bacilli and create vesicles that carry them across the epithelial cell cytoplasm and the basolateral membrane. Salmonella pathogenicity island 1 (SPI-1) in the genome encodes the elements of BME.

In the submucosa, Salmonella enters macrophages via bacteria-triggered pinocytosis or via macrophage receptor–mediated phagocytosis. The intravacuolar environment activates the PhoP/PhoQ regulon, leading to modification of protein and lipopolysaccharide elements of the bacterial inner and outer membranes. Thus, Salmonella resists lysis and decreases host proinflammatory signaling. The bacterium also produces homocysteine to inactivate nitric oxide and enzymes against other microbicides. Finally, with the Vi antigen, a polysaccharide capsule, S. typhi and S. paratyphi further protect themselves from lysis within the macrophage and from neutrophils and complement without.

The newly described Salmonella pathogenicity island 2 (SPI-2) encodes a type III secretion system that carries bacterial proteins across the vacuole membrane and into the cytosol. Other virulence factors from SPI-2 prevent or alter fusion of the Salmonella-containing vacuole with other intracellular compartments, rearrange the actin cytoskeleton around the vacuole, and may prevent the implantation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and nitric oxide synthase into the vacuole membrane.

The infected macrophage provides Salmonella a vehicle safe from other elements of the immune system and in which it can multiply and travel. It passes through the mesenteric lymph nodes into the thoracic duct and the lymphatics beyond to seed the reticuloendothelial tissues—liver, spleen, bone marrow, and lymph nodes. In these havens, it multiplies until some critical density is reached. It causes the apoptosis in the macrophages and enters the bloodstream to attack the rest of the body. At this stage, the Vi antigen comes into play. It forms a capsule to protect the bacterium from complement and from phagocytic immune cells.

From blood or from the liver via bile ducts, it infects the gallbladder and reenters the gastrointestinal tract in the bile, spreading to other hosts via stool. In addition, it occasionally invades the urinary tract and spreads via urine.

After primary intestinal infection, further seeding of the Peyer patches occurs through infected bile. They may become hyperplastic and necrotic with infiltration of mononuclear cells and neutrophils, forming ulcers that may hemorrhage through eroded blood vessels or perforate the bowel wall, causing peritonitis.

The host recognizes the invader with toll-like receptors 2, 4, and 5. These induce cytokines such as interferon alpha, interleukin (IL)–12, and tumor necrosis factor-alpha, which recruit macrophages and cause the high fevers of the disease. Macrophages and neutrophils suppress the active infection. Later, humoral and CD4 T-cell–mediated immunity clears it.

*Risk Factors

Salmonella has mechanisms against acidic environments, but a pH level of 1.5 or less kills most of the bacilli. People who continually ingest antacids, histamine-2 receptor antagonists (H2 blockers), or proton pump inhibitors; who have undergone gastrectomy; or who have achlorhydria due to aging or other factors require fewer bacilli to produce clinical disease. Acquired immune deficiencies or hereditary deficiencies in immune modulars such as IL-12 and IL-23 increase risk for infection, complications, and death.


Travelers to endemic countries should avoid raw unpeeled fruits or vegetables since they may have been prepared with contaminated water; 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. In the absence of such a strategy, mass immunization with typhoid vaccines at regular intervals also considerably reduces the incidence of infections.

Routine typhoid vaccination is not recommended in the United States. Vaccination is indicated for travelers to endemic areas, persons with intimate exposure (eg, household contact) to a documented S. typhi carrier, and microbiology laboratory personnel who frequently work with S. typhi.

Travelers should be vaccinated at least 1 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.

The only absolute contraindication to vaccination is a history of severe local or systemic reactions following a previous dose. No data have been reported on pregnant women who receive any of the typhoid vaccines available in the United States.

The following 3 typhoid vaccines are used:

o Vi capsular polysaccharide (ViCPS) antigen vaccine (Typhim Vi, Pasteur Merieux) is composed of purified Vi antigen, the capsular polysaccharide elaborated by S. typhi isolated from blood cultures. In recent studies, one 25-mg injection of purified ViCPS produced seroconversion (ie, at least a 4-fold rise in antibody titers) in 93% of healthy US adults. Similar results were observed in Europe. Two field trials in disease-endemic areas showed overall protection rates of 72% in Nepal and 50-64% in South Africa.

· + 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.

· + Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 mg 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, or induration greater than or equal to 1 cm. In a study conducted in Nepal, the ViCPS vaccine produced fewer local and systemic reactions than the control (the 23-valent pneumococcal vaccine). Among school children in South Africa, ViCPS produced less erythema and induration than the control bivalent vaccine.

o Ty21a (Vivotif Berna, Swiss Serum and Vaccine Institute) is an oral vaccine that contains live attenuated S. typhi Ty21a strains in an enteric-coated capsule. The vaccine elicits both serum and intestinal antibodies and cell-mediated immune responses.

· + No prospective randomized trials have been performed in the United States. Several field trials were conducted among school children in Chile. Using 3 doses on alternate days, investigators produced a 66% protection rate that lasted for 5 years (95% CI, 50-77%). In another trial in Chile, the incidence of clinical typhoid fever significantly decreased among persons who received 4 doses of vaccine compared with persons who received 2 doses (P <.001) or 3 doses (P = .002). However, an efficacy rate of only 42% was recorded in Indonesia, suggesting that the vaccine may not be effective in areas where exposure is intense. The efficacy of vaccination with Ty21a has not been studied among persons from areas without endemic disease who travel to disease-endemic regions. · + 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 to S. typhi is expected.

· + Adverse effects are rare. They include abdominal discomfort, nausea, vomiting, fever, headache, and rash or urticaria.

· + The vaccine manufacturer recommends that Ty21a not be administered to children younger than 6 years. It should not be used among immunocompromised persons. The parenteral vaccines present theoretically safer alternatives for this group.

o Acetone-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.

o Of note, the parenteral heat-phenol–inactivated 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.


Typhoid fever in most cases is not fatal. Antibiotics, such as ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole, 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. Vaccines for typhoid fever are available and are advised for persons traveling in regions where the disease is common (especially Asia, Africa and Latin America). Typhim Vi is an intramuscular killed-bacteria vaccination and Vivotif is an oral live bacteria vaccination, both of which protect against typhoid fever. Neither vaccine is 100% effective against typhoid fever and neither protects against unrelated typhus.


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. 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 centers are therefore moving away from using ciprofloxacin as first line for treating suspected typhoid originating in India, Pakistan, Bangladesh, Thailand or Vietnam. For these patients, the recommended first line treatment is 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 0.125–1.0 mg/l) would not be picked up by this method. It not certain how this problem can be solved, because most laboratories around the world (including the West) are dependent disc testing and cannot test for MICs.


Intestinal manifestations

o The 2 most common complications of enteric fever are intestinal hemorrhage (12% in one British series) and perforation (3-4.6% of hospitalized patients).

o From 1884-1909 (ie, preantibiotic era), the mortality rate in patients with intestinal perforation in typhoid fever was 66-90% but now is significantly lower. Approximately 75% of patients have guarding, rebound tenderness, and rigidity, particularly in the right lower quadrant.

o Diagnosis is particularly difficult in the approximately 25% of patients with perforation and peritonitis who do not have the classic physical findings. Often, the discovery of free intra-abdominal fluid may be the only sign of perforation.

Hepatobiliary manifestations

o Mild elevation of transaminases without symptoms is common in persons with typhoid fever.

o Jaundice may occur in persons with enteric fever and may be due to hepatitis, cholangitis, cholecystitis, or hemolysis.

o Pancreatitis and simultaneous acute renal failure and hepatitis with hepatomegaly have been reported.

Cardiopulmonary manifestations

o Nonspecific electrocardiographic changes occur in 10-15% of patients with typhoid. Toxic myocarditis occurs in 1-5% of persons with typhoid and is a significant cause of death in disease-endemic countries.

o 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.

o Pericarditis rarely occurs, but peripheral vascular collapse without other cardiac findings is increasingly described. Pulmonary manifestations have also been reported in patients with typhoid fever.

Neuropsychiatric manifestations

o In the past 2 decades, reports from the disease-endemic areas have documented a wide spectrum of neuropsychiatric manifestations of typhoid fever.

o A toxic confusional state, characterized by disorientation, delirium, and restlessness, is characteristic of late-stage typhoid. Occasionally, these and other neuropsychiatric features may dominate the clinical picture at an early stage.

o Facial twitching or convulsions may be the presenting feature; sometimes, paranoid psychosis or catatonia may develop during convalescence. Meningismus is not uncommon, but frank meningitis is rare. Encephalomyelitis may develop, and the underlying pathology may be that of demyelinating leukoencephalopathy. Rarely, transverse myelitis, polyneuropathy, or cranial mononeuropathy may develop.

o Other less commonly reported events are spastic paraplegia, peripheral or cranial neuritis, Guillain-Barré syndrome, schizophrenia-like illness, mania, and depression.

Hematologic manifestations

o Subclinical disseminated intravascular coagulation occurs commonly in persons with typhoid fever.

o Hemolytic-uremic syndrome is rare.

o Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency.

Genitourinary manifestations

o Approximately 25% of patients excrete S. typhi in their urine at some point during their illness.

o Immune complex glomerulitis and proteinuria have been reported, and IgM, C3 antigen, and S. typhi antigen can be demonstrated in the glomerular capillary wall.

o Nephritic syndrome may complicate chronic S. typhi bacteremia associated with urinary schistosomiasis.

Musculoskeletal manifestations

o Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal wall and thigh muscles.

o Clinically evident polymyositis may occur.

CNS manifestations

o Focal intracranial infections are uncommon.

o Recently, multiple brain abscesses have been reported.


Served as Primary Source. Typhoid Fever by John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Served as Secondary Source.

Provided information on Pathogenesis.

Served as extra reference.

Served as extra reference.

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