Typhus

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Typhus a group of diseases caused by louse-borne bacteria. The name comes from the Greek typhos, meaning smoky or lazy, describing the state of mind of those affected with typhus. Rickettsia is endemic in rodent hosts, including mice and rats, and spreads to humans through mites, fleas and body lice. The arthropod vector flourishes under conditions of poor hygiene, such as those found in prisons or refugee camps, amongst the homeless, or until the middle of the 20th century, in armies in the field. In tropical countries, typhus is often mistaken for dengue fever.^{[1][2][3][4][5]}

The first description of typhus was given in 1083 at a convent near Salerno, Italy. In 1546, Girolamo Fracastoro, a Florentine physician, described typhus in his famous treatise on viruses and contagion, De Contagione et Contagiosis Morbis. Before a vaccine was developed in World War II, typhus was a devastating disease for humans and has been responsible for a number of epidemics throughout history. These epidemics tend to follow wars, famine, and other conditions that result in mass casualties. The first reliable description of the disease appears during the Spanish siege of Moorish Granada in 1489. These accounts include descriptions of fever and red spots over arms, back and chest, progressing to delirium, gangrenous sores, and the stink of rotting flesh. During the siege, the Spaniards lost 3,000 men to enemy action but an additional 17,000 died of typhus. Typhus was also common in prisons (and in crowded conditions where lice spread easily), where it was known as Gaol fever or Jail fever. Gaol fever often occurs when prisoners are frequently huddled together in dark, filthy rooms. Imprisonment until the next term of court was often equivalent to a death sentence. It was so infectious that prisoners brought before the court sometimes infected the court itself. Following the Assize held at Oxford in 1577, later deemed the Black Assize, over 300 died from Epidemic typhus, including Sir Robert Bell Lord Chief Baron of the Exchequer. The outbreak that followed, between 1557 to 1559, killed about 10% of the English population.^[6]

Typhus is a group of diseases caused by bacteria that are spread to humans by fleas, lice, and chiggers. Typhus fevers include scrub typhus, murine typhus, and epidemic typhus. Chiggers spread scrub typhus, fleas spread murine typhus, and body lice spread epidemic typhus. The most common symptoms are fever, headaches, and sometimes rash.^[7]

Typhus is a zoonotic disease, humans are infected by the bites from parasites such as fleas, lice, mites, and ticks or by the inoculation of infectious fluids or feces from the parasites into the skin. The incubation period of Typhus fever varies from one to two weeks. Following transmission, rickettsia are ingested by macrophages and polymorphonuclear cells. The major pathology is caused by a vasculitis and its complications. This process may cause result in occlusion of blood vessels and initiates an inflammatory response (aggregation of leukocytes, macrophages, and platelets) resulting in small nodules. This vasculitic process causes destruction of the endothelial cells and leakage of the blood leading to volume depletion with subsequent hypovolemia and decreased tissue perfusion and, possibly, organ failure.^{[8][9][10][11][12]}

Typhus is caused by one of two types of bacteria Rickettsia typhi or Rickettsia prowazekii. The form of typhus depends on which type of bacteria causes the infection. Rickettsia typhi causes murine or endemic typhus. Endemic typhus is uncommon in the United States. It is usually seen in areas where hygiene is poor and the temperature is cold. Endemic typhus is sometimes called “jail fever.” Murine typhus occurs in the southeastern and southern United States.^[1][13]

Typhus must be differentiated from other diseases that cause fever, rash, diarrhea and vomiting, such as Ebola, Typhoid fever, Malaria and Lassa fever.^{[14][15][16][17][18]}

The Centers for Disease Control and Prevention have documented only 47 cases from 1976 to 2010. According to the World Health Organization, the case fatality rate from typhus is about 1 out of every 5,000,000 people per year. All age groups are at risk for rickettsial infections during travel to endemic areas. The typhus group of infections has no sexual predilection. Scrub typhus, which is transmitted by mites encountered in high grass and brush, is endemic in northern Japan, Southeast Asia, the western Pacific Islands, eastern Australia, China, maritime areas and several parts of south-central Russia, India, and Sri Lanka. R. typhi and R. felis, which are transmitted by fleas, are widely distributed, especially throughout the tropics and subtropics and in port cities and coastal regions with rodents.^[13]Closing </ref> missing for <ref> tag^{[19][20][21][22][23]}

Signs and symptoms of typhus usually appear abruptly, 8–16 days following exposure to infected lice. Illness can vary from mild to severe, and even life-threatening. Symptoms of acute infection are generally non-specific and include fever and chills, headache, rapid breathing, myalgia, rash, cough, nausea, vomiting and altered mental status.^{[1][5][24][25]}

Typhus presents with high-grade fever and a maculopapular rash. Generalized lymphadenopathy is present in majority of the patients. Physical examination usually reveals a combination of several non-specific findings.^[5][24][25]

Diagnosis of typhus is usually based on clinical recognition and serology, the latter requires comparison of acute- to convalescent-phase serology, so is only helpful in retrospect. Etiologic agents can generally only be identified to the genus level by serologic testing. PCR and immunohistochemical analyses may also be helpful.^[26][27][28]

There is no specific X-ray, CT or MRI finding associated with typhus.

Treatments for most rickettsial illnesses are similar and include administration of appropriate antibiotics (e.g., tetracyclines, chloramphenicol, azithromycin, fluoroquinolones, and rifampin) and supportive care. Treatment should usually be given empirically prior to disease confirmation, and the particular antimicrobial agent and the length of treatment are dependent upon the disease and the host.^[1]

Surgical intervention is not recommended for the management of typhus.

No licensed vaccines for prevention of rickettsial infections are commercially available in the United States. With the exception of the louse-borne diseases, for which contact with infectious arthropod feces is the primary mode of transmission (through autoinoculation into a wound, conjunctiva, or inhalation), travelers and health-care providers are generally not at risk for becoming infected via exposure to an ill person. Limiting exposures to vectors or animal reservoirs remains the best means for reducing the risk for disease. Travelers should be advised that prevention is based on avoidance of vector-infested habitats, use of repellents and protective clothing, prompt detection and removal of arthropods from clothing and skin, and attention to hygiene.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

The first description of typhus was probably given in 1083 at a convent near Salerno, Italy. In 1546, Girolamo Fracastoro, a Florentine physician, described typhus in his famous treatise on viruses and contagion, De Contagione et Contagiosis Morbis. Before a vaccine was developed in World War II, typhus was a devastating disease for humans and has been responsible for a number of epidemics throughout history. These epidemics tend to follow wars, famine, and other conditions that result in mass causalties. The first reliable description of the disease appears during the Spanish siege of Moorish Granada in 1489. These accounts include descriptions of fever and red spots over arms, back and chest, progressing to delirium, gangrenous sores, and the stink of rotting flesh. During the siege, the Spaniards lost 3,000 men to enemy action but an additional 17,000 died of typhus. Typhus was also common in prisons (and in crowded conditions where lice spreads easily), where it was known as Gaol fever or Jail fever. Gaol fever often occurs when prisoners are frequently huddled together in dark, filthy rooms. Imprisonment until the next term of court was often equivalent to a death sentence. It was so infectious that prisoners brought before the court sometimes infected the court itself. Following the Assize held at Oxford in 1577, later deemed the Black Assize, over 300 died from Epidemic typhus, including Sir Robert Bell Lord Chief Baron of the Exchequer. The outbreak that followed, between 1557 to 1559, killed about 10% of the English population.

• In 1083, typhus was first identified as a disease in Spain.
• In 1489, during the Spanish siege of Moorish Granada, the first reliable description of the disease was made.
• In 1546, Fracastoro extensively described the disease and distinguished it from plague in his book Contagione.
• In 1676, Von Zavorziz wrote a book on typhus called “The Infection of Military Camps”.
• In 1739, Huxham stated typhus and typhoid as two different entities, later in the same year Boissier de Sauvages confirmed this and called it exanthematous typhus.
• In 1829, Louis, French clinician clearly differentiated typhus fever from typhoid fever.
• In 1836, Gerhard(United States) clearly distinguished the two diseases from each other based on pathologic findings.
• In 1909, Charles Nicolle for the first time described the role of lice bite in transmission of typhus. In 1928, he was awarded the Nobel Prize for his discovery.
• In 1916, Weil and Felix reported the isolation of a Proteus that was agglutinated by the sera of patients with typhus, which was the basis for the first serological test for the disease.
• In 1916, DaRocha-Lima isolated and identified Rickettsia prowazekii.
• In 1926, Maxcy described the various forms of typhus.
• In 1938, Starzyk demonstrated that patients are infected by the feces and not the bite of the louse.
• In 1922, Wolbach described the human histopathology of R prowazekii infection.^[1]
• In 1938, Cox was successful in growing cell cultures of R prowazekii in embryonated eggs.^[2]
• In 1940, Cox and Bell prepared an epidemic typhus vaccine based upon the use of tissue culture.
• In 1943–1944, during world war II DDT (a pesticide) was employed to control lice and typhus.
• In 1998, Andersson et al, sequenced the entire genome after much study of the fundamental mechanisms of R prowazekii’s intracellular life and its effects on host cells.^[3]

• 
  Civilian Public Service worker distributes rat poison for typhus control in Gulfport, Mississippi, ca. 1945.
• 
  A U.S. soldier is demonstrating DDT-hand spraying equipment. DDT was used to control the spread of typhus-carrying lice.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Typhus fevers are a group of diseases caused by bacteria that are spread to humans by fleas, lice, and chiggers. Typhus fevers include scrub typhus, murine typhus, and epidemic typhus. Chiggers spread scrub typhus, fleas spread murine typhus, and body lice spread epidemic typhus. The most common symptoms are fever, headaches, and rash.

• Epidemic typhus is so named because the disease often causes epidemics following wars and natural disasters.^[1]
• The causative organism is Rickettsia prowazekii, transmitted by the human body louse (Pediculus humanus humanus).^[2]
• Feeding on a human who carries the bacillus infects the louse. R. prowazekii grows in the louse’s gut and is excreted in its feces.
• The disease is then transmitted to an uninfected human who scratches the louse bite (which itches) and rubs the feces into the wound.
• The abysmally low standards of hygiene enforced in camps such as Theresienstadt and Bergen-Belsen created conditions where diseases such as typhus flourished.
• A possible modern scenario for typhus epidemics would be in refugee camps during a major famine or natural disaster. This form of typhus is also known as “prison fever” or “ship fever” because it becomes prevalent in crowded conditions in prisons and aboard ships.

• Endemic typhus (also called “flea-borne typhus” and “murine typhus” or “rat flea typhus”) is caused by the bacteria Rickettsia typhi, and is transmitted by the fleas that infest rats. ^[3]
• Less often, endemic typhus is caused by Rickettsia felis and transmitted by fleas carried by cats or possums. Symptoms of endemic typhus include headache, fever, chills, myalgia, nausea, vomiting, and cough.
• Endemic typhus is highly treatable with antibiotics.^[3] Most people recover fully, but death may occur in the elderly, severely disabled or patients with a depressed immune system.

• Scrub typhus (also called “chigger-borne typhus”) is caused by Orientia tsutsugamushi and transmitted by chiggers, which are found in areas of heavy scrub vegetation.
• Symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Typhus is a zoonotic disease, humans are infected by the bites from parasites such as fleas, lice, mites, and ticks or by the inoculation of infectious fluids or feces from the parasites into the skin. The incubation period of typhus fever varies from one to two weeks. Following transmission, rickettsia are ingested by macrophages and polymorphonuclear cells. The major pathology is caused by a vasculitis and its complications. This process may cause result in occlusion of blood vessels and initiates inflammatory response (aggregation of leukocytes, macrophages, and platelets) resulting in small nodules. This vasculitic process causes destruction of the endothelial cells and leakage of the blood leading to volume depletion with subsequent hypovolemia and decreased tissue perfusion and, possibly organ failure.^{[1][2][3][4][5][6]}

The pathophysiology of typhus fever can be described in the following steps:^{[1][2][3][4][5][6]}

• Rickettsial pathogens are harbored by parasites such as fleas, lice, mites, and ticks.
• Organisms are transmitted by the bites from these parasites or by the inoculation of infectious fluids or feces from the parasites into the skin.
• Inhaling or inoculating conjunctiva with infectious material also causes infection.

• Incubation period of typhus fever varies from one to two weeks.

• Following transmission, rickettsia are ingested by macrophages and polymorphonuclear cells. On ingestion, they replicate intracellularly inside the lysed cells and disseminate systemically.

• The major pathology is caused by a vasculitis and its complications.
• On transmission, Rickettsia is actively phagocytosed by the endothelial cells of the small venous, arterial, and capillary vessels.
• It is followed by systemic hematogenous spread resulting in multiple localizing vasculitis.
• This process may cause result in occlusion of blood vessels and initiates inflammatory response (aggregation of leukocytes, macrophages, and platelets) resulting in small nodules.
• Occlusion of supplying blood vessels may cause gangrene of the distal portions of the extremities, nose, ear lobes, and genitalia.
• This vasculitic process causes destruction of the endothelial cells and leakage of the blood leading to volume depletion with subsequent hypovolemia and decreased tissue perfusion and, possibly, organ failure.
• Endothelial damage also leads to activation of clotting system (DIC).

• Tumor necrosis factor α (TNF-α) produce on activation of cell mediated immunity, stimulates T lymphocytes and macrophages, which help in eliminating intracellular rickettsia. Virulent rickettsia tend to suppress the activity of tumor necrosis factor α (TNF-α) and IFN-gamma.
• Cytokines such as interleukin (IL) 12 promote production of Interferon γ (IFN-γ) responses. IFN-γ, which drives TH1-type responses and stimulates macrophage activation. Cytokines, which include , IL-6, IL-4and IL-10, down-regulate the protective response.

There is no known genetic association to typhus fever.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Typhus is caused by one of two types of bacteria Rickettsia typhi or Rickettsia prowazekii. The form of typhus depends on which type of bacteria causes the infection. Rickettsia typhi causes murine or endemic typhus. Endemic typhus is uncommon in the United States. It is usually seen in areas where hygiene is poor and the temperature is cold. Endemic typhus is sometimes called “jail fever.” Murine typhus occurs in the southeastern and southern United States

Typhus is caused by one of two types of bacteria Rickettsia typhi or Rickettsia prowazekii. The form of typus depends on which type of bacteria causes the infection. Rickettsia typhi causes murine or endemic typhus. Endemic typhus is uncommon in the United States. It is usually seen in areas where hygiene is poor and the temperature is cold. Endemic typhus is sometimes called “jail fever.” Murine typhus occurs in the southeastern and southern United States, often during the summer and fall. It is rarely deadly. Risk factors for murine typhus include:

• Exposure to rat fleas or rat feces
• Exposure to other animals (such as cats, opossums, raccoons, skunks, and rats)

Rickettsia prowazekii causes epidemic typhus and Brill-Zinsser disease. Brill-Zinsser disease is a mild form of epidemic typhus. It occurs when the disease re-activates in a person who was previously infected. It is more common in the elderly. Lice and fleas of flying squirrels spread the bacteria.

• 
  Image depicts a dorsal view of a female head louse, Pediculus humanus var. capitis. From Public Health Image Library (PHIL). ^[1]
• 
  Image depicts an adult female body louse, Pediculus humanus, and two larval young. From Public Health Image Library (PHIL). ^[1]
• 
  Dorsal view of a male body louse, Pediculus humanus var. corporis. From Public Health Image Library (PHIL). ^[1]
• 
  Dorsal view of a male body louse, Pediculus humanus var. corporis. From Public Health Image Library (PHIL). ^[1]
• 
  Lateral view of a female body louse, Pediculus humanus var. corporis, as it was obtaining a blood-meal from a human host. From Public Health Image Library (PHIL). ^[1]
• 
  Dorsal view of a male body louse, Pediculus humanus var. corporis. From Public Health Image Library (PHIL). ^[1]
• 
  Magnified photograph of ventral view of a male body louse, Pediculus humanus var. corporis, focusing on the insects cephalic and thoracic regions. From Public Health Image Library (PHIL). ^[1]
• 
  Scanning electron micrograph (SEM) reveals the distal tip of the abdominal region of a female body louse, Pediculus humanus var. corporis from a dorsal perspective (152X mag). From Public Health Image Library (PHIL). ^[1]
• 
  Scanning electron micrograph (SEM) depicted an enlarged dorsal view of the right flexed foreleg of a female body louse, Pediculus humanus var. corporis (309X mag). Leg segments are very stout, and end in claws, which it used to firmly grasp clothing, or a host’s hair shafts. From Public Health Image Library (PHIL). ^[1]
• 
  Scanning electron micrographic (SEM) image focused on the head region of a female body louse, Pediculus humanus var. corporis from a ventral perspective. SEM reveals some of the insect’s exoskeletal morphology exhibited by its cephalic, or head region, thoracic, and proximal abdominal regions. From Public Health Image Library (PHIL). ^[1]
• 
  Scanning electron micrographic (SEM) image focused on the head region of a female body louse, Pediculus humanus var. corporis from a ventral perspective. SEM reveals some of the insect’s exoskeletal morphology exhibited by the cephalic region (307X mag). From Public Health Image Library (PHIL). ^[1]
• 
  Scanning electron micrographic (SEM) depicts enlarged view of the chitinous, exoskeletal surface of a female louse, Pediculus humanus var. corporis, in the region where the organism’s forelegs and hean attached to its thoracic region. (151X mag). From Public Health Image Library (PHIL). ^[1]
• 
  Illustration depicts a photomicrographic view of a culture specimen revealing the presence of numerous Borrelia recurrentis bacteria, which cause European relapsing fever. This bacterium is transmitted from person-to-person by way of the human body louse, Pediculus humanus var. corporis. From Public Health Image Library (PHIL). ^[1]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Typhus must be differentiated from other diseases that cause fever, rash, diarrhea and vomiting, such as Ebola, Typhoid fever, Malaria and Lassa fever.^{[1][2][3][4][5]}

The table below summarizes the findings that differentiate Typhus from other conditions that cause fever, diarrhea and abdominal pain.^{[1][2][3][4][5]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

The Centers for Disease Control and Prevention have documented only 47 cases from 1976 to 2010. According to the World Health Organization, the case fatality rate from typhus is about 1 out of every 5,000,000 people per year. All age groups are at risk for rickettsial infections during travel to endemic areas. The typhus group of infections has no sexual predilection. Scrub typhus, which is transmitted by mites encountered in high grass and brush, is endemic in northern Japan, Southeast Asia, the western Pacific Islands, eastern Australia, China, maritime areas and several parts of south-central Russia, India, and Sri Lanka. R. typhi and R. felis, which are transmitted by fleas, are widely distributed, especially throughout the tropics and subtropics and in port cities and coastal regions with rodents.^[1][2]

• The Centers for Disease Control and Prevention have documented only 47 cases from 1976 to 2010.

• According to the World Health Organization, the case fatality rate from typhus is about 1 out of every 5,000,000 people per year.

• All age groups are at risk for rickettsial infections during travel to endemic areas.

• The typhus group of infections has no sexual predilection.

• Scrub typhus, which is transmitted by mites encountered in high grass and brush, is endemic in northern Japan, Southeast Asia, the western Pacific Islands, eastern Australia, China, maritime areas and several parts of south-central Russia, India, and Sri Lanka.
• Most travel-acquired cases of scrub typhus occur during visits to rural areas in endemic countries for activities such as camping, hiking, or rafting, but urban cases have also been described.
• R. typhi and R. felis, which are transmitted by fleas, are widely distributed, especially throughout the tropics and subtropics and in port cities and coastal regions with rodents.
• Humans exposed to flea-infested cats, dogs, and peridomestic animals while traveling in endemic regions, or who enter or sleep in areas infested with rodents, are at most risk for fleaborne rickettsioses.
• Murine typhus has been reported among travelers returning from Asia, Africa, and the Mediterranean Basin and has also been reported from Hawaii, California, and Texas in the United States.
• Epidemic typhus is rarely reported among tourists but can occur in communities and refugee populations where body lice are prevalent.
• Travelers at most risk for epidemic typhus include those who may work with or visit areas with large homeless populations, impoverished areas, refugee camps, and regions that have recently experienced war or natural disasters.
• Active foci of epidemic typhus are known in the Andes regions of South America and some parts of Africa (including but not limited to Burundi, Ethiopia, and Rwanda).
• Louseborne epidemic typhus does not regularly occur in the United States, but a zoonotic reservoir occurs in the southern flying squirrel, and sporadic sylvatic epidemic typhus cases are reported.
• Tick-associated reservoirs of R. prowazekii have been described in Ethiopia, Mexico, and Brazil, but documented human cases are rare.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Travelers are at risk for exposure to agents of rickettsial diseases if they engage in occupational or recreational activities which bring them into contact with habitats that support the vectors or animal reservoir species associated with these pathogens. Immunocompromised patients are also at risk.^[1][2][3]

• Travelers visiting affected countries
• Patients on prosthetic heart valve
• Immunocompromised
• Living in residence with poor sanitation
• Exposure to rat fleas, lice and fleas of flying squirrels.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Rickettsioses range in severity from diseases that are usually relatively mild (rickettsialpox, cat scratch disease, and African tick-bite fever) to those that can be life-threatening (epidemic and murine typhus, Rocky Mountain spotted fever, scrub typhus and Oroya fever), and they vary in duration from those that can be self-limiting to chronic (Q fever and bartonelloses) or recrudescent (Brill-Zinsser disease). Without treatment, fever may last 2 weeks, followed by a prolonged recovery time and a significantly greater chance of developing complications. Possible complications include renal insufficiency, pneumonia, meningitis. Without treatment, death may occur in 10 – 60% of patients with epidemic typhus. Patients over age 60 have the highest risk of death.^{[1][2][3][4][5][6]}

• The clinical severity and duration of illnesses associated with different rickettsial infections vary considerably, even within a given antigenic group.
• Rickettsioses range in severity from diseases that are usually relatively mild (rickettsialpox, cat scratch disease, and African tick-bite fever) to those that can be life-threatening (epidemic and murine typhus, Rocky Mountain spotted fever, scrub typhus and Oroya fever), and they vary in duration from those that can be self-limiting to chronic (Q fever and bartonelloses) or recrudescent (Brill-Zinsser disease).
• Without treatment, fever may last 2 weeks, followed by a prolonged recovery time and a significantly greater chance of developing complications.
• Delay in treatment may result in advanced disease, including neurologic manifestations such as confusion, seizures, or coma, and widespread vasculitis (damage to the endothelial cells that line blood vessels).

Possible complications include:

• Renal insufficiency
• Pneumonia
• Hearing loss
• Myocarditis
• Vasculitis
• Aseptic meningitis

Without treatment, death may occur in 10 – 60% of patients with epidemic typhus. Patients over age 60 have the highest risk of death. Patients who receive treatment quickly should completely recover. Less than 2% of untreated patients with murine typhus may die. Most patients with rickettsial infections recover with timely use of appropriate antibiotic therapy.^[3]

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