6/19/2014

Typhoid Fever Follow-up

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Typhoid Fever Follow-up

Author: John L Brusch, MD, FACP; Chief Editor: Michael Stuart Bronze, MD more...
Updated: Apr 1, 2014

Further Inpatient Care

If treated with well-selected antibiotics, patients with typhoid fever (enteric fever) should defervesce within 35 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.

Further Outpatient Care

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 following
treatment with the new quinolone drugs, which have effective intracellular penetration.
S typhi and S paratyphi rarely develop antibiotic resistance during treatment. If an antibiotic has been
chosen according to sensitivities, relapse should dictate a search for anatomic, pathologic, or
genetic predispositions rather than for an alternate antibiotic.
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.

Deterrence/Prevention
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
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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
contact), and microbiology laboratory personnel who frequently work with S typhi. Vaccines are not approved for
use 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.[62]
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.
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 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.[63]
Primary vaccination with ViCPS consists of a single parenteral dose of 0.5 mL (25 g 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).[64] 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.
Sur et al conducted a phase IV effectiveness trial in slum-dwelling residents aged 2 years or
older in India to determine vaccine protection. Participants (n=37,673) were randomly
assigned to receive a single dose of either Vi vaccine or inactivated hepatitis A vaccine,
according to geographic clusters. The mean rate of Vi vaccine coverage was 61% and 60%
for the hepatitis A vaccine.
Typhoid fever was diagnosed in 96 subjects in the hepatitis A vaccine group compared with
34 in the Vi vaccine group (no more than 1 episode was reported per individual). Protective
effect for typhoid with the Vi vaccine was 61% (P < 0.001) compared with the hepatitis A
vaccine group. Children vaccinated while aged 2-5 years had an 80% protection level.
Unvaccinated members of the Vi vaccine clusters showed a protection level of 44%. The
overall protection level with all Vi vaccine cluster residents was 57%. The authors concluded
that the Vi vaccine was effective in young children and protected unvaccinated neighbors of Vi
vaccinees.[65]
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
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frozen), and all 4 doses must be taken to achieve maximum efficacy.

The optimal booster schedule has not been determined; however, the longest reported followup 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 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-phenolinactivated 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 may be on the horizon. An investigational vaccine using ViCPS conjugated
to the nontoxic recombinant pseudomonas exotoxin A (Vi-rEPA) has been studied in a randomized
controlled trial. The vaccine was given to children aged 2-5 years and showed an efficacy of 89%
(95% CI, 76%-97%) after 3.8 years. Vi-rEPA has not been approved for use in the United States.

Complications
Neuropsychiatric manifestations (In the past 2 decades, reports from disease-endemic areas have
documented a wide spectrum of neuropsychiatric manifestations of typhoid fever.)
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.[66]
Other less-common neuropsychiatric manifestations events have included spastic paraplegia,
peripheral or cranial neuritis, Guillain-Barr syndrome, schizophrenialike illness, mania, and
depression.
Respiratory
Cough
Ulceration of posterior pharynx
Occasional presentation as acute lobar pneumonia (pneumotyphoid)
Cardiovascular
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.[67]
Hepatobiliary
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,
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cholecystitis, or hemolysis.
Pancreatitis and accompanying acute renal failure and hepatitis with hepatomegaly have been
reported.[68]
Intestinal manifestations
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
Approximately 25% of patients with typhoid fever excrete S typhi in their urine at some point during
their illness.
Immune complex glomerulitis [69] 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
Subclinical disseminated intravascular coagulation is common in persons with typhoid fever.
Hemolytic-uremic syndrome is rare.[70]
Hemolysis may also be associated with glucose-6-phosphate dehydrogenase deficiency.
Musculoskeletal and joint manifestations
Skeletal muscle characteristically shows Zenker degeneration, particularly affecting the abdominal
wall and thigh muscles.
Clinically evident polymyositis may occur.[71]
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)
Neurologic - Polyneuritis, paranoid psychosis, or catatonia[72]
Cardiovascular - Thrombophlebitis of lower-extremity veins
Genitourinary -Orchitis
Musculoskeletal
Periostitis, often abscesses of the tibia and ribs
Spinal abscess (typhoid spine; very rare)

Prognosis
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 10%-20%. 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.

Patient Education
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.
Case study
A wealthy middle-aged man presented to his physician a few days after the onset of flulike
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symptoms, including fever, myalgias, chills, severe abdominal pain, and a cough, in addition to
severe abdominal pain. Over the next 2 weeks, he lost a great deal of weight. He had intermittent but
ever-increasing fevers. About 3 weeks after the onset of symptoms, he developed a few pale,
salmon-colored macules on his trunk. His cough became much more frequent and severe. He
became delirious, listlessly wandering around the house fiddling with doorknobs. During the fourth
week of his illness, he rapidly declined with increasing somnolence. After nearly 4 weeks of illness,
he died surrounded by his loving family.
The patient was Prince Albert, the Consort to Queen Victoria. He was diagnosed with typhoid fever.
His personal physician, Sir William Jenner, a leading expert on the disease, diagnosed typhoid fever.
Prince Albert received the best therapy of the day.
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-FYITRIP. The World Health Organizations site (www.who.int/ith), International Society of Travel Medicine site
(www.istm.org), and Travel Doctor (www.traveldoctor.co.uk/diseases.htm) contain useful information as well,
though the authors disagree with some of the WHOs antibiotic guidelines.

Contributor Information and Disclosures

Author
John L Brusch, MD, FACP Assistant Professor of Medicine, Harvard Medical School; Consulting Staff,
Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
John L Brusch, MD, FACP is a member of the following medical societies: American College of Physicians and
Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Coauthor(s)
Thomas Garvey, MD, JD Primary Care Physician, Burlington Medical Associates; Co-chair, Medical Advisory
Committee for the Elimination of Tuberculosis
Thomas Garvey, MD, JD is a member of the following medical societies: American College of Legal Medicine,
American College of Physicians, and American Society of Law, Medicine & Ethics
Disclosure: Nothing to disclose.
Roberto Corales, DO Vice President, Chief Medical Officer and Principal Investigator, AIDS Care
Roberto Corales, DO is a member of the following medical societies: American Medical Association, American
Osteopathic Association, and International AIDS Society
Disclosure: Nothing to disclose.
Steven K Schmitt, MD Staff Physician, Department of Infectious Disease, Cleveland Clinic
Steven K Schmitt, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Nothing to disclose.
Specialty Editor Board
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
Richard B Brown, MD, FACP Chief, Division of Infectious Diseases, Baystate Medical Center; Professor,
Department of Internal Medicine, Tufts University School of Medicine
Richard B Brown, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American
College of Chest Physicians, American College of Physicians, American Medical Association, American
Society for Microbiology, Infectious Diseases Society of America, and Massachusetts Medical Society
Disclosure: Nothing to disclose.
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Chief Editor
Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G
Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science
Center
Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American
College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious
Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical
Investigation
Disclosure: Nothing to disclose.

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