eMedicine Specialties > Infectious Diseases > Bacterial Infections

Typhus

Jason F Okulicz, MD, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Staff, Infectious Disease Service, Brooke Army Medical Center
Mark S Rasnake, MD, Assistant Professor of Medicine, Program Director, Internal Medicine Residency, University of Tennessee Graduate School of Medicine; Consulting Staff, Department of Infectious Diseases, University of Tennessee Medical Center at Knoxville; Eric A Hansen, DO, Fellow, Clinical Instructor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook; Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Updated: Sep 18, 2008

Introduction

Background

Typhus refers to a group of infectious diseases that are caused by rickettsial organisms and that 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-Zinsser disease, murine typhus, and scrub typhus. (For more information on pediatric scrub typhus, see the eMedicine article Scrub Typhus in the Pediatric: General Medicine volume.)

Pathophysiology

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 the deposition of leukocytes, macrophages, and platelets may result in small nodules. Thrombosis of supplying blood vessels may cause gangrene of the distal portions of the extremities, nose, ear lobes, and genitalia. 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 with a history of typhus may develop a recrudescent type of typhus known as Brill-Zinsser disease. After a patient with typhus is treated with antibiotics and the disease appears to be 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 than epidemic typhus, and the associated mortality rate is much lower. Risk factors that may predispose to recrudescent typhus 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).¹ 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 infection with Rickettsia felis is associated with opossums,² cats, and their fleas and occurs in southern California and southern Texas. Most cases of murine typhus in Texas occur in spring and summer, whereas, in California, the illness is most common in the summer and fall. Murine typhus is most common in adults, but infection may occur in any age group.³ No indigenous cases of scrub typhus have occurred in the United States, 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 develops 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. Murine typhus 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. Populations of the flea vector may rise during the summer months in temperate climates, subsequently increasing the incidence of murine typhus. Prior infection with R typhi provides immunity to subsequent reinfection.

Scrub typhus occurs in the western Pacific region, northern Australia, and the Indian subcontinent. The 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, one study found that the incidence of scrub typhus in Malaysia was approximately 3% per month, and multiple infections in the same individual are possible because of a lack of cross-immunity among the various strains of its causative organism, Orientia tsutsugamushi.⁴

Mortality/Morbidity

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

Sex

The typhus group of infections has no sexual predilection.

Age

The typhus group of infections has no age predilection. However, in the United States, murine typhus and sporadic cases of epidemic typhus have mainly occurred in adults.

Clinical

History

Patients with typhus may have a history that includes the following:

• Patients may have had exposure to an endemic area
• Occupational exposure: Medical and military personnel are potentially at higher risk for typhus 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 include nonproductive cough and deafness/tinnitus.
• The duration of most clinical symptoms and signs in untreated typhus is approximately 2 weeks. Several months may pass before complete recovery from fatigue and malaise.
• 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 of typhus 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 leads to many undiagnosed cases of scrub typhus.

Physical

• Fever
  • Fever rises to 39-41ºC and is persistent in patients with untreated typhus.
  • Patients with typhus 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.
• Other features
  • 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 epidemic typhus.
  • 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.¹
  • 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 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 above (see Pathophysiology).
• Murine typhus is caused by R typhi, and the vector is the rat or cat flea (Xenopsylla cheopis, Ctenocephalides felis).
  • Rats (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.

Differential Diagnoses

Other Problems to Be Considered

Rubella
Measles
Rickettsial diseases

Workup

Laboratory 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 diagnoses.
• 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 one 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 that is capable of causing various abnormal laboratory values. Any organ may be affected, and multiorgan system dysfunction or 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 evaluate 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 of typhus 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.⁵

Imaging Studies

• No imaging studies are specifically indicated to aid in diagnosing typhus. Imaging studies are indicated only 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

Medical Care

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

Activity

Activity is as tolerated.

Medication

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

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.⁶ Azithromycin and rifampicin have been shown to be effective in small trials conducted in areas with known doxycycline resistance.⁷

Follow-up

Further Inpatient Care

• Inpatient care may be required for ill patients with typhus 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 of typhus.

Inpatient & Outpatient Medications

• See Medications.

Deterrence/Prevention

• Avoid exposure to areas known to be endemic for typhus.
• Avoid overcrowding.
• Insecticides may be helpful in controlling the arthropod vectors that spread typhus.
• 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 of typhus are due to hematogenous spread of organisms with 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.
• Vasculitis may result in hypovolemia, electrolyte disturbances, and digital gangrene.
• Hemodynamic status and fluid/electrolyte replacement should be diligently monitored.
• Secondary infections, such as bacterial pneumonia, should be treated appropriately.

Prognosis

• Uncomplicated cases of typhus that are diagnosed promptly and antibiotic therapy initiated early generally carry an excellent prognosis. Mortality rates are greatly reduced when appropriate antibiotics are initiated promptly (see Mortality/Morbidity).
• Complicated cases of typhus generally carry a good prognosis, but this varies depending on the severity of the specific complications and the health status of the patient at the time of disease onset.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Failure to adequately educate patients regarding measures to prevent typhus

References

1. Reynolds MG, Krebs JS, Comer JA, et al. Flying squirrel-associated typhus, United States. Emerg Infect Dis. Oct 2003;9(10):1341-3. [Medline].

2. Boostrom A, Beier MS, Macaluso JA, et al. Geographic association of Rickettsia felis-infected opossums with human murine typhus, Texas. Emerg Infect Dis. Jun 2002;8(6):549-54. [Medline].

3. Civen R, Ngo V. Murine typhus: an unrecognized suburban vectorborne disease. Clin Infect Dis. Mar 15 2008;46(6):913-8. [Medline].

4. Saah AJ. Orientia tsutsugamushi (Scrub typhus). In: Principles and Practice of Infectious Diseases. 2000:2056-2057.

5. Wongchotigul V, Waicharoen S, Riengrod S, et al. 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].

6. Watt G, Kantipong P, Jongsakul K, et al. Doxycycline and rifampicin for mild scrub-typhus infections in northern Thailand: a randomised trial. Lancet. Sep 23 2000;356(9235):1057-61. [Medline].

7. Kim YS, Yun HJ, Shim SK, et al. 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].

8. Christie AB. Rickettsial disease: typhus. In: Infectious Diseases: Epidemiology and Clinical Practice. 2. 1987:1070-1097.

9. Dumler JS, Walker DH. Rickettsia typhi (Murine typhus). In: Principles and Practice of Infectious Diseases. 2000:2053-55.

10. Fergie JE, Purcell K, Wanat D. Murine typhus in South Texas children. Pediatr Infect Dis J. Jun 2000;19(6):535-8. [Medline].

11. Higgins JA, Azad AF. Murine flea-borne typhus. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8^th ed. Philadelphia, Pa: WB Saunders and Co; 2000:434-5.

12. 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].

13. Olson JG. Typhus: general principles. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8^th ed. Philadelphia, Pa: WB Saunders and Co; 2000:430-3.

14. Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin Microbiol Rev. Oct 1997;10(4):694-719. [Medline].

15. Saah AJ. Rickettsia prowazekii (epidemic or louse-borne typhus). In: Principles and Practice of Infectious Diseases. 2000:2050-2053.

16. Watt G, Olson JG. Scrub typhus. In: Hunter GW, Thomas SG, eds. Hunter's Tropical Medicine and Emerging Infectious Diseases. 8^th ed. Philadelphia, Pa: WB Saunders and Co; 2000:443-5.

17. Watt G, Parola P. Scrub typhus and tropical rickettsioses. Curr Opin Infect Dis. Oct 2003;16(5):429-36. [Medline].

Keywords

typhus, epidemic typhus, rickettsemia, louse-borne typhus, classic typhus, Brill-Zinsser disease, recrudescence of epidemic typhus, murine typhus, flea-borne typhus, endemic typhus, scrub typhus, tsutsugamushi fever, rickettsial infection, Pediculus corporis, Rickettsia prowazekii, R prowazekii, Rickettsia felis, R felis, Pediculus capitis, Phthirus pubis, Xenopsylla cheopis, Ctenocephalides felis, Leptotrombidium akamushi, Leptotrombidium deliense, Dermacentor andersoni, Dermacentor variabilis, Amblyomma americanum, Orientia tsutsugamushi, O tsutsugamushi, Rickettsia typhi, R typhi, Rickettsia tsutsugamushi, R tsutsugamushi, Rocky Mountain spotted fever, RMSF

Contributor Information and Disclosures

Author

Jason F Okulicz, MD, Assistant Professor of Medicine, Uniformed Services University of the Health Sciences; Staff, Infectious Disease Service, Brooke Army Medical Center
Jason F Okulicz, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Coauthor(s)

Mark S Rasnake, MD, Assistant Professor of Medicine, Program Director, Internal Medicine Residency, University of Tennessee Graduate School of Medicine; Consulting Staff, Department of Infectious Diseases, University of Tennessee Medical Center at Knoxville
Mark S Rasnake, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Eric A Hansen, DO, Fellow, Clinical Instructor, Department of Internal Medicine, Division of Infectious Diseases, Winthrop-University Hospital, State University of New York at Stony Brook
Eric A Hansen, DO is a member of the following medical societies: American Medical Association, American Osteopathic Association, Infectious Diseases Society of America, and Undersea and Hyperbaric Medical Society
Disclosure: Nothing to disclose.

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

John M Leedom, MD, Professor of Medicine, Keck School of Medicine, University of Southern California; Chief, Division of Infectious Diseases, Department of Internal Medicine, Los Angeles County, University of Southern California Medical Center
John M Leedom, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, American Society for Microbiology, Infectious Diseases Society of America, International AIDS Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Thomas M Kerkering, MD, Chief of Infectious Diseases, Virginia Tech, Carilion School of Medicine, Roanoke, Virginia
Thomas M Kerkering, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Public Health Association, American Society for Microbiology, American Society of Tropical Medicine and Hygiene, Infectious Diseases Society of America, Medical Society of Virginia, and Wilderness Medical Society
Disclosure: Nothing to disclose.

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, Professor, Stewart G Wolf 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 Physician Executives, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Association of Professors of Medicine, Association of Program Directors in Internal Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

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