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 Medscape Reference article Pediatric Scrub Typhus in the Pediatric: General Medicine volume.)
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.
R prowazekii is also thought to be transmitted by fleas associated with flying squirrels and their nesting material, by inhaling dried louse feces, or by rubbing Rickettsia -containing louse feces inadvertently into eyes, mucous membranes, or in insect bite–associated wounds.[1]
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.
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).[2] 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,[3] 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.
In 2013, 12 patients with murine typhus were identified in Galveston, Texas, which may reflect a re-emergence of R typhi in the rat population and/or a cycle involving opossums and cats with R felis.[4] Murine typhus is most common in adults, but infection may occur in any age group.[5] 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. The homeless are particularly vulnerable.[6] 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.[7]
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.
GeoSentinel, a global network that monitors travel-related morbidity, reported no fatalities in 16 cases of murine typhus and 13 cases of scrub typhus that occurred in international travellers from 1996-2011.[8]
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.
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.
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
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, as follows:
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
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.
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
Generalized lymphadenopathy may occur.
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.
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
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.[2]
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
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
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.
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.
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)
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.[9]
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.[10]
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.
Chest radiography may be a complementary tool to evaluate the clinical course of scrub typhus. Chest radiographic examinations should be obtained during the first week after the onset of illness.[11]
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.
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.
Clinical Context:
Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria. No dose adjustment is necessary in renal impairment.
Clinical Context:
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.
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.[12] Azithromycin and rifampicin have been shown to be effective in small trials conducted in areas with known doxycycline resistance.[13]
Jason F Okulicz, MD, FACP, FIDSA, Director, HIV Medical Evaluation Unit, Infectious Disease Service, San Antonio Military Medical Center; Associate Professor of Medicine, F Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences; Clinical Associate Professor of Medicine, University of Texas Health Science Center at San Antonio; Adjunct Clinical Instructor, Feik School of Pharmacy, University of the Incarnate Word
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Gilead Sciences.
Coauthor(s)
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
Disclosure: Nothing to disclose.
Mark S Rasnake, MD, FACP, 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
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Thomas M Kerkering, MD, Chief of Infectious Diseases, Virginia Tech Carilion School of Medicine
Disclosure: Nothing to disclose.
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; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Disclosure: Nothing to disclose.
Additional Contributors
John M Leedom, MD, Professor Emeritus of Medicine, Keck School of Medicine of the University of Southern California
Disclosure: Nothing to disclose.
Acknowledgements
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
