Typhoid Fever

Typhoid fever, or enteric fever, is a potentially fatal multisystemic infection produced primarily by Salmonella enterica serotype typhi and to a lesser extent Salmonella enterica serotypes and paratyphi A, B, and C. Salmonella are motile enterobacteriaceae that can produce a variety of gastrointestinal infections. The most serious of these is typhoid that is primarily produced by Salmonella enterica serotype typhi and, to a lesser extent, S enterica serotypes paratyphi A, B, and C. It presents in a wide variety of ways ranging from an overwhelming septic illness to minor cases of diarrhea with low-grade fever. The classic presentation is one of fever, malaise, diffuse abdominal pain, and constipation. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel perforation, and death within 1 month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications. The term typhoid derived from the ancient Greek word for cloud, was chosen to emphasize the severity and long lasting neuropsychiatric effects among the untreated. Yearly, 21 million people acquire typhoid fever throughout the world. It is fatal in approximately 161,000. Over the years, it has developed increasing resistance to antibiotics. During 2016, extensively drug-resistant typhoid (XDR) were documented in Pakistan. Only three classes of antimicrobial agents, azithromycin, carbapenems, and tigecycline, remain affective among these strains.[1]  

Typhoid thrives in conditions of poor sanitation, crowding, and social chaos.[1]  Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries. The incidence of infections with S paratyphi may be surpassing those due to S typhi. This may be due to the immunologic naïveté of a given population as well as the incomplete coverage provided by current Typhoid vaccines against these pathogens. Non -Typhoidal strains usually produce mild, self-limiting gastroenteritis.[2]

Pathogenic Salmonella species are engulfed by the phagocytic cells of the gut, which then present them to the macrophages of the lamina propria. By means of their toll-like receptor (TLR)–5 and TLR-4/MD2/CD-14 complexes, the macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then mobilize T cells and neutrophils with interleukin 8 (IL-8). Hopefully, the resulting inflammation will be adequate to suppress the infection.[3, 4]

 S typhi and paratyphi enter the host's system primarily through the distal ileum. They have 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 typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation, whereas the most common paratyphi serovar, paratyphi A, does not. This may explain the greater infectivity of Typhi as compared with paratyphi isolates.[5]

In addition,serotypes typhi and paratyphi are able to Quorum Sense. This is a type of intracellular communication by which the organisms coordinate swarming and biofilm production.[6]

Typhoidal salmonella co-opt the macrophages' cellular machinery for their own reproduction[7] 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. When a critical density is reached, the bacteria bring about macrophage apoptosis.This allows salmonella to enter the bloodstream[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 shed in the stool and so become available to infect others.[2, 4]  

Life cycle of Salmonella typhi.

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.[8] The bacteria excreted by a single carrier may have multiple genotypes, making it difficult to trace an outbreak to its origin.[9]

Risk factors

Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms of typhi causes infection in more than 50% of healthy volunteers.[10]  Paratyphi requires 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 individual—a carrier—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).[11, 12, 13]

Paratyphi is more commonly transmitted in food from street vendors. It is believed that some such foods provide a friendly environment for the microbe.

Paratyphi is more common among newcomers to urban areas, probably because they tend to be immunologically naïve to it. Also, travellers get little or no protection against paratyphi from the current typhoid vaccines, all of which target typhi.[14, 15]

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 facilitate S typhi infection.[4]

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 or paratyphi infection are conflicting. If an association exists, it is probably minor.[16, 17, 18, 19]

Other risk factors for typhoid fever 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.[12]

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.[20, 21]

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.[22] American clinicians should keep this in mind, as students from these areas often come to the United States for further education.[23]

Frequency

United States

Since 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.[24]

International

Typhoid 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.[25] 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.[26]

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[24] :

• 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) - 2.2

Mortality/Morbidity

With 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.[24] 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%.[27]

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.[24]

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.[22, 28]

Classic typhoid fever syndrome

S typhi and paratyphi are clinically indistinguishable from each other. Symptoms of disease develop 7-14 days after ingestion of the organism. The peaks and troughs of fever rise progressively in stepwise fashion.

Over the course of the first week of illness, a wide variety gastrointestinal symptoms of the disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant pain.Inflamed Peyer patches narrow the bowel lumen to the point of causing significant constipation that may persist for the duration of the illness. If untreated the individual may develop a dry cough, dull frontal headache, delirium, and severe malaise associated with marked stupor.[2]

Seven to 10 days into the illness, the fever plateaus at 103-104°F (39-40°C). The patient develop Rose Spots, salmon-colored, blanching, truncal, maculopapules that are 1-4 cm wide and fewer than 5 in number. These generally resolve within 2-5 days.[2]  They are caused by bacterial emboli to the dermis Occsasionally , they may be seen in cases of Shigellosis or nontyphoidal Salmonellosis.[29]

During the second week, 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 lead to 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 asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely.[2, 4, 22, 30, 31]

Various presentations of typhoid fever

The clinical course of an untreated patient with typhoid fever may deviate from that describe above . 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 at least one third of immunocompetent adults who develop typhoid fever develop diarrhea rather than constipation.

Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, 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 as delirium or, in extremely rare cases, parkinsonian symptoms or Guillain-Barré syndrome. Other unusual complications include pancreatitis,[32] meningitis, orchitis, osteomyelitis, and abscesses anywhere on the body.[2]

Table 1. Incidence and Timing of Various Manifestations of Untreated Typhoid Fever ^{[2, 33, 34, 35, 36, 37]} (Open Table in a new window)

Treated typhoid fever

If 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.

See History.

S typhi and Salmonella paratyphi cause typhoid/enteric fever.

See History.

See History.

Any individual with asignificant febrile illness who has traveled to endemic areas or who has been exposed to a case of Typhoid should be ruled out for this disease.

The diagnosis of typhoid fever (enteric fever) is primarily clinical.

Importantly, the reported sensitivities of tests for S typhi vary greatly in the literature, even among the most recent articles and respected journals.

Culture

The criterion standard for diagnosis of typhoid fever has long been culture isolation of the organism. Cultures are considered 100% to be 100% specific.

Culture of bone marrow aspirate is 90% sensitive until at least 5 days after the start of antibiotics. it is quite painful and seldom utilized unless adequate cultures(see below ) were not obtained prior to starting empiric antibiotics.[38]

Blood, intestinal secretions (vomitus or duodenal aspirate), and stool culture results are positive for S typhi in 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 for S typhi several 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.[39]

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% but may remain positive even after administration of antibiotics. A single rectal swab culture upon hospital admission can be expected to detect S typhi in 30%-40% of patients. S typhi has 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 37°C for at least 7 days. Subcultures are made daily to one selective medium (eg, MacConkey agar) and one inhibitory medium (eg, Salmonella-Shigella agar). Identification of the organism with these conventional culture techniques usually takes 48-72 hours from acquisition.

Table 2. Sensitivities of Cultures ^{[2, 39, 40, 41]} (Open Table in a new window)

Polymerase chain reaction

Polymerase 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 of S 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.[42, 43]

Specific serologic tests

Assays that identify Salmonella antibodies 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 of S 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 to S typhi polysaccharide, as well as monoclonal antibodies against S typhi flagellin,[44] are promising, but the success rates of these assays vary greatly in the literature.

In summary, current laboratory tests possess suboptimal sensitivity and specificity. In addition, there are no validated diagnostic methods for detecting asymptomatic carriers.[45]

Other nonspecific laboratory studies

Since the sensitivity of cultures of blood, bone marrow, urine and stool vary with the duration of disease, various nonspecific tests have been studied regarding usefulness in diagnosing typhoid fever.

Most 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 subclinical disseminated intravascular coagulation (DIC).

Liver transaminase and serum bilirubin values usually rise to twice the reference range.

Mild hyponatremia and hypokalemia are common.

A combination of absolute eosinopenia, elevated aspartate aminotransferase levels, and elevated C-reactive protein levels (>40 mg/L) have been shown to be a positive predictor of S typhi and S paratyphi bacteremia.[46]

A serum alanine amino transferase (ALT)–to–lactate 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.[47]

Radiography: 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.

Bone marrow aspiration: The most sensitive method of isolating S typhi is BMA culture (see Lab Studies).

The 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, four 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 of cholecystitis. 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]

The 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).[36]

If a patient presents with unexplained symptoms described in Table 1 within 60 days of returning from a 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 for 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.

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.[48]

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 hepatic infection.

An 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).

Fluids 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.

No 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.

Class Summary

Since 2016, Salmonella typhi, and to a lesser extent Salmonella paratyphi, have progressively developed resistance to the previously effective antibiotics. Multi-drug-resistant (MDR) typhoid is resistant to ampicillin, trimethoprim sulfamethoxazole, and chloramphenicol. XDR – typhoid has become resistant to chloramphenicol ampicillin, floroquinolones, and third generation cephalosporins. Only azithromycin, members of the carbapenem class, and tigecycline remain effective against XDR isolates.

Since recognition of XDR typhoid fever has been documented in the United States among those who did not travel internationally, appropriate treatment for this disease should consist of azithromycin with or without addition of a carbapenem depending on the severity of the clinical presentation.[49, 50, 51]

Development of MDR and XDR strains has occurred primarily in Pakistan. Most likely, poor sanitation and overuse of antibiotics for the treatment of other infections have been the major reasons for the rapid rise of resistance in Pakistan and other similar countries.The marked increase in density of the urban population in Karachi and other cities clearly facilitates spread of these variants.

The medical complications of COVID-19 have already stressed the medical resources of Pakistan. Many do not want to risk perceived, possible exposure to this virus at various healthcare sites. The marked increase in population density in large cities such as Karachi has facilitated the spread of this pathogen.

Mass immunization campaigns to control typhoid have been thwarted because of religious and cultural prejudices. 

Azithromycin (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.

Class Summary

Dexamethasone 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).[52]

Nonetheless, this point is still debated. A 2003 WHO statement endorsed the use of steroids as described above, but reviews by eminent authors in the New England Journal of Medicine (2002)[4] and the British Medical Journal (2006)[53] 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.[54]

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.

Dexamethasone (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.

Tigecycline (Tygacil)

100mg IVloading

After 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 after treatment with the new quinolone drugs, which have effective intracellular penetration.

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 within gallstones or Schistosoma haematobium organisms 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.

If 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.

Travelers 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.

Vaccines

In 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 documented S typhi carrier (eg, household contacts of chronic carriers, defined as persons with excretion of S typhi in urine or stool ≥1 year), and microbiology laboratory personnel who frequently work with S 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 to Styphi should be vaccinated against typhoid, even if they are staying with friends or relatives or only traveling for a short time.[55]

Vaccines are not approved for use in children younger than 2 years. The efficacy of typhoid fever vaccinations against paratyphi serovars has not been firmly established, but is markedly less than their efficacy against typhi.[56]

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 of S t yphi 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 vaccine

Vi capsular polysaccharide antigen vaccine is composed of purified Vi antigen, the capsular polysaccharide elaborated by S typhi isolated from blood cultures. The Vi antigen is absent in S paratyphi A, but this vaccine does provide some in vitro immunogenicity against S paratyphi A. This may be due to trace amounts of other, common antigens in the preparation.[57]

Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 µg 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).[58] 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.

[59]

Ty21a

Ty21a 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.

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. 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 or urticaria.

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 vaccine

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.

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.

A more effective vaccine is on the horizon. Vi polysaccharide-tetanus typhoid conjugate vaccine (TCV) is a combination of the 1 polysaccharide antigen and tetanus toxoid. It appears to be more immunogenic and longer acting other typhoid vaccines.[60]

Targeted use of vaccines in areas of the world with high rates of typhoid fever and/or resistant Salmonella isolates makes economic sense in reducing the disease burden and associated costs.[61]

In 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 multiple brain abscesses have been reported.[62]

• Other less-common neuropsychiatric manifestations events have included spastic paraplegia, peripheral or cranial neuritis, Guillain-Barré 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.[63]

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.[64]

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 excrete S typhi in their urine at some point during their illness.

• Immune complex glomerulitis[65] and proteinuria have been reported, and IgM, C3 antigen, and S typhi antigen can be demonstrated in the glomerular capillary wall.

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

• Nephrotic syndrome may occur transiently in patients with glucose-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 syndrome is rare.[66]

• 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 evident polymyositis may occur.[67]

• Arthritis is 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, or catatonia[68]

• Cardiovascular - Thrombophlebitis of lower-extremity veins

• Genitourinary -Orchitis

• Musculoskeletal - Periostitis, often abscesses of the tibia and ribs; spinal abscess (typhoid spine; very rare)

The 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 15%-30%. 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.[69]

Because 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 article Foreign Travel

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.