AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Typhus refers to a group of infectious diseases that are caused by rickettsial organisms and result in an acute febrile illness. Arthropod vectors transmit the etiologic agents to humans. The principle diseases of this group are epidemic or louse-borne typhus and its recrudescent form known as Brill-Zinser disease, murine typhus, and scrub typhus.

Pathophysiology

Epidemic typhus is the prototypical infection of the typhus group of diseases, and the pathophysiology of this illness is representative of the entire category. The arthropod vector of epidemic typhus is the body louse (Pediculus corporis). This is the only vector of the typhus group in which humans are the usual host. Rickettsia prowazekii, which is the etiologic agent of typhus, lives in the alimentary tract of the louse. A Rickettsia-harboring louse bites a human to engage in a blood meal and causes a pruritic reaction on the host's skin. The louse defecates as it eats; when the host scratches the site, the lice are crushed, and the Rickettsia-laden excrement is inoculated into the bite wound. The Rickettsia travel to the bloodstream and rickettsemia develops.

Rickettsia parasitize the endothelial cells of the small venous, arterial, and capillary vessels. The organisms proliferate and cause endothelial cellular enlargement with resultant multiorgan vasculitis. This process may cause thrombosis, and small nodules may develop from the deposition of leukocytes, macrophages, and platelets. Gangrene of the distal portions of the extremities, nose, ear lobes, and genitalia may occur as a result of thrombosis of supplying blood vessels. This vasculitic process may also result in loss of intravascular colloid with subsequent hypovolemia and decreased tissue perfusion and, possibly, organ failure. Loss of electrolytes is common.

Some people may have a recrudescent case typhus (Brill-Zinsser disease). After a patient is treated with antibiotics and the disease has seemingly been cured, Rickettsia may linger in the body tissues. Months, years, or even decades after treatment, organisms may reemerge and cause a recurrence of typhus. How the Rickettsia organisms linger silently in a person and by what mechanism recrudescence is mediated are unknown. The presentation of Brill-Zinsser disease is less severe and mortality is much lower than in epidemic typhus. Risk factors that may predispose a person to recrudescence include improper or incomplete antibiotic therapy and malnutrition.

Murine typhus and scrub typhus share the same pathophysiology as epidemic typhus, although they are somewhat milder. The incubation period is approximately 12 days for the typhus group. Prior infection with Rickettsia typhi provides subsequent and long-lasting immunity to reinfection.

Frequency

United States

Approximately 15 documented sporadic cases of active infection with R prowazekii, the etiologic agent of epidemic typhus, have been reported. These occurred in the central and eastern portions of the United States and have been linked with exposure to flying squirrels (Glaucomys volans). The flying squirrel acts as the host for R prowazekii, and transmission to humans is believed to occur via squirrel fleas or lice. Murine typhus caused by Rickettsia felis is associated with opossums, cats, and their fleas and occurs in southern California and southern Texas. Adults are most commonly affected, but infection may occur in any age group. No indigenous cases of scrub typhus have occurred, although infections have been diagnosed in patients returning from endemic areas.

International

Epidemic typhus occurs in Central and South America, Africa, northern China, and certain regions of the Himalayas. Outbreaks may occur when conditions arise that favor the propagation and transmission of lice. Brill-Zinsser disease may occur in approximately 15% of people with a history of primary epidemic typhus.

Murine typhus occurs in most parts of the world, particularly in subtropical and temperate coastal regions. It occurs mainly in sporadic cases, and incidence is probably greatly underestimated in the more endemic regions. Rats, mice, and cats, which are hosts for the disease, are particularly common along coastal port regions. Temperate climates may have a rise in the flea vector and a subsequent rise in the incidence of murine typhus in the summer months. Prior infection with R typhi provides immunity to subsequent reinfection.

Scrub typhus occurs in the western Pacific region, northern Australia, and the Indian subcontinent. Incidence of scrub typhus is largely unknown. Many cases are undiagnosed because of its nonspecific manifestations and the lack of laboratory diagnostic testing in endemic areas. However, a report of incidence of scrub typhus in Malaysia was approximately 3% per month, and multiple infections in the same individual may occur because of a lack of cross-immunity among the various strains of Orientia tsutsugamushi.

Mortality/Morbidity

Epidemic typhus has the most severe clinical presentation of the typhus group of rickettsial infections. In severe disease, gangrene may occur and lead to loss of digits, limbs, or other appendages. The vasculitic process may also lead to CNS dysfunction, ranging from dullness of mentation to coma, multiorgan system failure, and death. The mortality rate in untreated persons may be as low as 20% in healthy individuals and as high as 60% in elderly or debilitated persons. Since the advent of widely available antibiotic treatment, mortality rates have fallen to approximately 3-4%. The mortality rate for treated patients with murine typhus is 1-4% and less than 1% for scrub typhus.

Sex

The condition has no predilection for either sex.

Age

The typhus group of infections may occur in people of all ages. In the United States, murine typhus and sporadic cases of epidemic typhus have mainly occurred in adults.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Exposure to an endemic area
• Occupational exposure: Medical and military personnel are potentially at higher risk than the general population in endemic areas.
• Overcrowding leads to close personal contact and spread of arthropod vectors (particularly lice) among individuals.
• Lack of personal hygiene: Infrequent bathing and changing of clothes provides a hospitable environment for body lice.
• Appropriate season: Cold weather may lead to overcrowding indoors and infrequent bathing and changing of clothes, which are advantageous for lice. Flea vectors are more abundant in warmer weather when their hosts are more plentiful.
• Abrupt onset of fever, headache, and rash are common symptoms in rickettsial infections.
• Patients may have a history of flea bite.
• History may include exposure to natural disaster or war.
• Other less common symptoms of typhus are nonproductive cough and deafness/tinnitus.
• The duration of most clinical symptoms and signs in untreated patients is approximately 2 weeks. Several months may pass before complete recovery from fatigue and malaise occurs.
• Epidemic typhus is the prototypical infection of the typhus group. As described in the Pathophysiology section, typhus is a multisystem vasculitis and may cause a wide array of clinical manifestations.
• • Fever is characterized by abrupt onset.
  • Headache is characterized by abrupt onset and is unremitting.
  • A maculopapular/petechial rash occurs on days 4-7 and may begin on the axilla and trunk and spread peripherally. The rash of Rocky Mountain spotted fever (RMSF) typically begins on the extremities and spreads centrally.
  • Other symptoms may include rigors, myalgias, malaise, and CNS symptoms (ranging from mental dullness to coma).
• Scrub typhus may be difficult to recognize and diagnose because the symptoms and signs of the illness are often nonspecific.
• • A painless papule develops at the site of the chigger bite and subsequently undergoes central necrosis with formation of an eschar.
  • Regional lymphadenopathy, with development of large and tender lymph nodes, occurs at the site of the bite and may lead to generalized lymphadenopathy.
  • The nonspecific presentation and lack of the characteristic eschar in 40% of patients makes the underdiagnosis of scrub typhus common.

Physical

• Fever
• • Fever rises to 39-41ºC and is persistent in untreated patients.
  • Patients have relative bradycardia with the fever.
  • Fever may persist for 24-72 hours after initiation of antibiotic therapy.
• Tachypnea and cough: This is most common in scrub typhus because of frequent pulmonary involvement.
• Rash
• • The macular, maculopapular, or petechial rash initially occurs on the trunk and axilla and spreads to involve the rest of the body except for the face, palms, and soles.
  • Rash may be petechial in patients with epidemic or murine typhus.
• Regional lymphadenopathy
• • This occurs in scrub typhus in the region of the arthropod bite and inoculation. Generalized lymphadenopathy may follow.
  • Lymph nodes are often tender and enlarged.
• Generalized lymphadenopathy
• Eschar
• • This is found in the scrub form of typhus and is essential in confirming a clinical diagnosis. It occurs in up to 60% of cases.
  • Eschar occurs at the site of the arthropod bite. It starts as a painless papule, and the lesion becomes indurated and enlarged. The center of the lesion becomes necrotic and develops into a black scab.
• Mild splenomegaly may occur.
• Mild hepatomegaly may occur.
• Conjunctival suffusion may occur in scrub typhus.

Causes

• Typhus is an acute febrile illness caused by rickettsial organisms. Rickettsia are pleomorphic bacteria that may appear as cocci or bacilli and are obligate intracellular parasites.
• Epidemic typhus is caused by the bacterium R prowazekii, and the vector is the body louse.
• • P corporis is the most common louse vector; however, Pediculus capitis and Phthirus pubis also transmit the disease.
  • Humans are the host in epidemic typhus, but the flying squirrel has also been linked with the disease in several cases in the United States.
  • The louse becomes infected with R prowazekii after feeding on a rickettsemic person with a primary case of typhus or during a recrudescent case (Brill-Zinsser disease).
  • Of all the typhus vectors, the louse is the only arthropod that dies as a result of this infection. Rickettsia live in the alimentary tract and cause obstruction and subsequent death of the louse after 2-3 weeks of infection.
  • All arthropod vectors cause inoculation of Rickettsia into the host by the same mechanism described previously (see Pathophysiology).
• Murine typhus is caused by R typhi, and the vector is the rat or cat flea (Xenopsylla cheopis, Ctenocephalides felis).
• • The rat (Rattus rattus), mice, and cats are the usual hosts; human infection is accidental.
  • Fleas become infected after engaging in a blood meal of a rickettsemic host; however, the fleas are not affected by the bacteria as are the lice in epidemic typhus.
  • Infected fleas may subsequently cause disease by direct inoculation or by indirect inoculation of the infected feces into the site of the bite wound.
  • Aerosolization of the feces and inoculation into the respiratory tract or into a mucous membrane are other possible routes of infection.
• Scrub typhus is caused by O tsutsugamushi (formerly Rickettsia tsutsugamushi) via the mite, Leptotrombidium akamushi, and possibly Leptotrombidium deliense.
• • The life cycle of the mite involves 4 stages of development, but only the larval stage (chigger) requires a blood meal and is infectious to humans and other mammals.
  • Once the mite is infected, it acts as a reservoir for Rickettsia.
  • The infection is maintained in mites from generation to generation by transovarial transmission.
  • Humans are accidental hosts in scrub typhus; rats, mice, and larger mammals are the usual hosts.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Rubella
Measles
Rickettsial diseases

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Laboratory studies are not particularly helpful in confirming a diagnosis of typhus. These studies assist the clinician in assessing the degree of severity of the illness and in helping exclude other diseases in the differential diagnosis.
• The diagnosis of typhus is clinically suggested when the appropriate historical elements are elicited from a patient who presents with the characteristic symptoms and signs.
• • Antibiotic therapy should begin promptly when the diagnosis is suspected; thereafter, appropriate laboratory studies can be serially performed as needed.
  • Diagnosis may be confirmed using laboratory tests; however, more than 1 week may pass before patients mount a demonstrable immune response that can be measured serologically.
  • Laboratory confirmation of typhus is obtained irrespective of the clinical presentation.
• Typhus is a vasculitic process, and a variety of abnormal laboratory values may be present. Any organ may be affected, and multiorgan system dysfunction/failure may occur if the illness is not diagnosed and treated in the early stages. These abnormalities, listed by organ system, may include the following:
• • Renal - Azotemia/proteinuria
  • Hematologic
  • • Leukopenia (common in the early stages of disease)
    • WBC count normal/mildly elevated later
    • Thrombocytopenia
  • Hepatic - Mild transaminase elevations
  • Metabolic - Hypoalbuminemia/electrolyte abnormalities (particularly hyponatremia)
• Indirect immunofluorescence assay (IFA) or enzyme immunoassay (EIA) testing can be used to look for a rise in the immunoglobulin M (IgM) antibody titer, which indicates an acute primary disease.
• Brill-Zinsser disease can be confirmed in a patient with a history of primary epidemic typhus who has recurrent symptoms and signs and a rise in the immunoglobulin G (IgG) antibody titer, which indicates a secondary immune response.
• IFA and EIA tests can be used to confirm a diagnosis of typhus, but they do not identify the various rickettsial species.
• Polymerase chain reaction (PCR) amplification of rickettsial DNA of serum or skin biopsy specimens can be used for diagnosing typhus.
• The complement fixation (CF) test is a serological test that can be used to demonstrate which specific rickettsial organism is causing disease by detection of specific antibodies.
• Rapid diagnostic assays for scrub typhus, such as latex agglutination tests, are currently under development.

Imaging Studies

• No imaging studies are specifically indicated to aid in diagnosing typhus. Imaging studies are only indicated on a case-by-case basis to evaluate potential complications or as needed.

Histologic Findings

Rickettsia may be observed in tissue sections using Giemsa or Gimenez staining techniques.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Antibiotics are the standard of care in the treatment of typhus.
• • Continue antibiotics for 48-72 hours after the fever has resolved.
  • For cases of recrudescent disease, a second course of antibiotic therapy is usually curative.
• Other supportive measures may be employed as necessary.

Activity

Activity is as tolerated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity, prevent complications, and eradicate infection.

Drug Category: Antibiotics

Specific antimicrobial therapy effective against rickettsia should be used. Doxycycline and chloramphenicol are used as antirickettsial agents for the treatment of typhus.

In Thailand, the emergence of doxycycline-resistant scrub typhus has caused clinicians to seek alternative antimicrobials. Azithromycin and rifampicin have been shown to be effective in small trials conducted in areas with known doxycycline resistance.

Drug Name	Chloramphenicol (Chloromycetin)
Description	Generally bacteriostatic to most susceptible microorganisms; binds to the 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Not preferred therapy for treating patients with typhus.
Adult Dose	0.5-1 g IV q6h; not to exceed 4 g/d
Pediatric Dose	80-100 mg/kg/d IV divided q6h
Contraindications	Documented hypersensitivity
Interactions	May increase the level/effects of anticoagulants, barbiturates, cyclophosphamide, phenytoin, and sulfonylureas; may reduce effects of iron salts and vitamin B-12; barbiturates, phenytoin, and rifampin may reduce chloramphenicol levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	At term or during labor, may cause gray baby syndrome in neonates, optic atrophy, ophthalmoplegia, peripheral neuritis, and disulfiramlike reaction; should only be used to treat serious infections; may cause blood dyscrasias such as granulocytopenia, thrombocytopenia, reticulocytopenia, anemia; discontinue upon appearance of these dose-related findings; aplastic anemia is an idiosyncratic response to chloramphenicol and is not dose related, and may occur after the antibiotic is discontinued; prolonged therapy can be toxic in patients with severely impaired liver function

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Inpatient care may be required for ill patients who cannot maintain adequate oral hydration/intake or enteral antibiotic therapy.
• Patients with complications from typhus may need inpatient care for further diagnosis, evaluation, and management for these disorders (see Complications).
• Decisions regarding the need for inpatient care should be assessed on a case-by-case basis.

Further Outpatient Care

• No further outpatient care is usually necessary in uncomplicated cases.

In/Out Patient Meds

• See Medications.

Deterrence/Prevention

• Avoid exposure to endemic areas.
• Avoid overcrowding.
• Insecticides may be helpful in controlling the arthropod vectors that spread the disease.
• Reduce the rodent host population.
• Wear protective clothing (eg, long-sleeved shirts, long pants) in endemic areas.
• Practice good personal hygiene, including frequent bathing and frequent changing of clothes.
• Vaccination for typhus is not recommended, and manufacturing of the vaccine has been discontinued in the United States.

Complications

• Signs, symptoms, and potential complications are manifestations of rickettsemia and resultant endothelial proliferation and vasculitis.
• The central nervous, musculoskeletal, and cardiovascular systems may be involved, as well as the skin, lungs, and kidneys. Multiorgan system involvement is possible.
• Hypovolemia, electrolyte disturbances, and digital gangrene may occur as a result of the vasculitis.
• Diligent monitoring of the hemodynamic status and fluid/electrolyte replacement should be performed carefully.
• Secondary infections, such as bacterial pneumonia, should be treated appropriately.

Prognosis

• Prognosis in uncomplicated cases of typhus is generally excellent when the disease is diagnosed promptly and antibiotic therapy is initiated early in the course of the illness. Mortality rates are greatly reduced when appropriate antibiotics are initiated promptly (see Mortality/Morbidity).
• Prognosis in complicated cases of typhus is generally good but varies depending on the severity of the specific complication and the health status of the patient at the time of disease onset.

Patient Education

• Education should be focused on the preventive measures (see Deterrence/Prevention).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to adequately educate patients regarding preventive measures

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Boostrom A, Beier MS, Macaluso JA. Geographic association of Rickettsia felis-infected opossums with human murine typhus, Texas. Emerg Infect Dis. Jun 2002;8(6):549-54. [Medline].
• Christie AB. Rickettsial disease: typhus. In: Infectious Diseases: Epidemiology and Clinical Practice. 1987;2:1070-1097.
• Dumler JS, Walker DH. Rickettsia typhi (Murine typhus). In: Principles and Practice of Infectious Diseases. 2000;2053-55.
• Fergie JE, Purcell K, Wanat D. Murine typhus in South Texas children. Pediatr Infect Dis J. Jun 2000;19(6):535-8. [Medline].
• Higgins JA, Azad AF. Murine flea-borne typhus. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa:. WB Saunders and Co;2000:434-5.
• Kim YS, Yun HJ, Shim SK. A comparative trial of a single dose of azithromycin versus doxycycline for the treatment of mild scrub typhus. Clin Infect Dis. Nov 1 2004;39(9):1329-35. [Medline].
• La Scola B, Raoult D. Laboratory diagnosis of rickettsioses: current approaches to diagnosis of old and new rickettsial diseases. J Clin Microbiol. Nov 1997;35(11):2715-27. [Medline].
• Olson JG. Typhus: general principles. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa:. WB Saunders and Co;2000:430-3.
• Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev. Oct 1997;10(4):694-719. [Medline].
• Reynolds MG, Krebs JS, Comer JA. Flying squirrel-associated typhus, United States. Emerg Infect Dis. Oct 2003;9(10):1341-3. [Medline].
• Saah AJ. Orientia tsutsugamushi (Scrub typhus). In: Principles and Practice of Infectious Diseases. 2000;2056-2057.
• Saah AJ. Rickettsia prowazekii (epidemic or louse-borne typhus). In: Principles and Practice of Infectious Diseases. 2000;2050-2053.
• Watt G, Olson JG. Scrub typhus. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8th ed. Philadelphia, Pa:. WB Saunders and Co;2000:443-5.
• Watt G, Kantipong P, Jongsakul K. Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet. Sep 23 2000;356(9235):1057-61. [Medline].
• Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. Oct 2003;16(5):429-36. [Medline].
• Wongchotigul V, Waicharoen S, Riengrod S. Development and evaluation of a latex agglutination test for the rapid diagnosis of scrub typhus. Southeast Asian J Trop Med Public Health. Jan 2005;36(1):108-12. [Medline].

Article Last Updated: May 12, 2006