Epidemic typhus

INTRODUCTION — Epidemic typhus is a potentially lethal, louse-borne, exanthematous disease caused by Rickettsia prowazekii. R. prowazekii is one of two members of the typhus group of Rickettsia known to cause human illness; the other member, Rickettsia typhi, causes murine typhus. Scrub typhus is caused by Orientia tsutsugamushi. Like all rickettsiae, R. prowazekii cannot be grown on cell-free media, and specialized laboratory facilities are required to recover the organism from clinical specimens.

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of epidemic typhus will be discussed here. Topic reviews that discuss murine typhus and scrub typhus are found elsewhere. (See "Scrub typhus" and "Murine typhus".)

BACKGROUND — The first description of epidemic typhus was thought to be made in 1546 by an Italian physician, Girolamo Fracastoro, who separated epidemic typhus from other typhus-like infections. It remains controversial as to whether typhus was imported into Europe from the New World or vice versa [1].

Throughout the Middle Ages and into the early part of the 20th century, periodic epidemics of R. prowazekii infection killed millions of people. As an example, during the eight-year period from 1917 to 1925, over 25 million cases of epidemic typhus occurred in Russia, causing an estimated three million deaths [2]. It has been estimated that epidemic typhus has caused more deaths than all the wars in history [3].

Epidemic typhus is now a rare disease, but subsequent developments illustrate that an understanding of its epidemiology, clinical features, and treatment is still important to clinicians:

●A sylvatic cycle of infection (disease transmitted from wild animals, particularly flying squirrels and their ectoparasites, with secondary transmission to humans) has been reported in the United States [4,5].

●More than 45,000 cases of epidemic typhus occurred in Burundi in association with civil war during the 1990s; in addition, an outbreak of epidemic typhus occurred at a youth center in Rwanda in 2012. In both cases, body louse infestation preceded outbreaks of both epidemic typhus and trench fever due to Bartonella quintana [6,7].

The outbreaks of typhus in Africa illustrate that the words of Hans Zinsser are still applicable today: "Typhus is not dead. It will live on for centuries and it will continue to break into the open whenever human stupidity and brutality give it a chance as most likely they occasionally will" [8].

EPIDEMIOLOGY — Epidemic typhus is a vector-borne disease with a complex epidemiology. The principal vectors are Pediculosis humanus (the body louse) and P. humanus capitis (the head louse) [9]. The human louse was thought to be the sole vector of R. prowazekii and humans were thought to be the sole reservoir of infection until a report in 1975 demonstrated that R. prowazekii infection occurred in flying squirrels in the southeastern United States [10].

Subsequent studies revealed that both the squirrel flea (Orchospea howardii) and the squirrel louse (Neohaemotophinus sciuropteri) are vectors for the transmission of R. prowazekii among flying squirrels. Although N. sciuropteri is host-specific and does not feed on humans, O. howardii will bite humans and transmit R. prowazekii if its principal host, the flying squirrel, is unavailable [11]. In one study, flying squirrels inoculated with R. prowazekii developed a rickettsemia that lasted for two to three weeks. Lice, fleas, and mites feeding on these experimentally-infected squirrels could be infected with R. prowazekii [11].

A limited number of papers about the epidemiology of R. prowazekii infection have been published in recent decades. However, the available data suggest that reporting and detection biases probably exist. Epidemic typhus is likely to be misdiagnosed or completely undiagnosed in areas of the world where poverty, famine, war, and disease occur simultaneously. As an example, seroprevalence studies of patients from North Africa and in homeless people from Marseilles, France suggest that R. prowazekii infection may be occurring far more often than is recognized [12,13]. The incidence of R. prowazekii infection in homeless populations in the United States is unknown. In one study, 2 of 176 homeless people from Houston had serologic evidence of infection with R. prowazekii [14]. In another prospective serological study of febrile patients with exanthems at a single hospital in Algeria, 1 of 14 proven cases of rickettsial infection identified over a six-year time period was due to R. prowazekii. This illustrates that multiple rickettsial pathogens may coexist with R. prowazekii in the same geographic area [15].

Mechanisms of transmission — The body louse typically spends its life on the skin or clothes of humans. Its prevalence is increased by cold weather, humidity, and poor hygiene [1]. Eggs are laid on clothes and hatch in about eight days. After hatching, larvae molt three times before they become adults.

Lice require a blood meal during each of these three stages. During a blood meal, the louse defecates highly infective feces at the site of its feeding. Rickettsiae present in louse feces may then be introduced into abraded or injured skin or mucous membranes by either scratching or hand contamination, since skin irritation commonly occurs at the site of a louse bite. Lice feces may remain infectious for as long as 100 days; as a result, human to human transmission can occur from sharing clothes or transfer of infective lice feces from one human to another.

P. humanus typically spends its entire life on the same host and does not leave unless manually removed or close contact allows transfer to a second human host. However, lice rapidly leave a dying human host and seek a blood meal on an alternate host. The cumulative effect of all these factors is that transmission of epidemic typhus typically occurs in crowded, cold, and unhygienic environments.

The mechanisms of louse infection following feeding on an infected host were explored in an experimental model of human body louse infection with R. prowazekii [16]. The following findings were noted:

●R. prowazekii initially invaded the stomach epithelial cells of lice.

●Rickettsiae first appeared in the feces of infected lice on the fifth day of infection.

●Rickettsiae replicated in the stomach epithelial cells, causing cell rupture six to seven days postinfection. Erythrocytes entered the hemolymph of infected lice following epithelial cell rupture, causing the lice to become bright red and die within four hours.

●Infected lice did not transmit infection to their progeny.

●The life span of infected lice was shortened by 20 to 23 days compared to uninfected controls.

Lice are capable of serially feeding on different humans, but transfer of infected lice directly from one human to another is thought to be uncommon. One possible reason for this is the rapid death of lice following rickettsial infection, as summarized above [16]. However, indirect transmission via infected lice in contaminated clothing or from crowded environmental conditions is known to occur [3]. In experimental conditions, R. prowazekii can also be transmitted via aerosols, and because R. prowazekii can be infectious for prolonged periods (eg, 100 days in louse feces), R. prowazekii remains on the United States Centers for Disease Control and Prevention (CDC) list of potential bioweapons [17].

Transmission of the sylvatic form of epidemic typhus to humans typically occurs when humans have direct contact with infected squirrels or when squirrels that are nesting in the attics or walls of homes are removed or killed and the lice inhabiting their nest are forced to seek alternate hosts. However, transmission of sylvatic typhus may occur in individuals who have no recollection or evidence of recent louse bites [5].

Geographic distribution — Only a few foci of epidemic typhus still exist in the world today [18]. In recent decades, cases of epidemic typhus have been reported in Burundi, Rwanda, Ethiopia and in the rural highlands of South America, Asia, and Algeria [1,8,19-22].

Except for a single case reported from California, almost all cases of epidemic typhus in the United States until 2001 occurred east of the Mississippi River within the range of the eastern flying squirrel (Glaucomys volans). However, in 2001, a patient from New Mexico, who presented with fever and signs and symptoms of meningitis without skin rash, was found to have acute infection with R. prowazekii using PCR amplification of the 17-kDA antigen gene and DNA sequencing of the amplified product [23]. The source of his infection could not be determined. A cluster of four cases of epidemic typhus subsequently occurred between 2004 and 2006 among staff and visitors to a wilderness camp in Pennsylvania; an investigation concluded that the source of infection was flying squirrels nesting in the walls of a cabin adjacent to a specific bunk [24]. Of the 14 flying squirrels trapped in woodlands near the cabin, 71 percent were infected with R. prowazekii. Similar findings were reported in 2009, when an investigation of two cases of epidemic typhus in the same household in New York state found 11 flying squirrels trapped in the attic of this house, and all were seropositive to R. prowazekii antigens [5].

Sylvatic epidemic typhus associated with flying squirrels remains an uncommon disease in the United States. The CDC documented only 47 cases in the US from 1976 to 2010 [4]. However, it is likely that other cases were never recognized or serologically confirmed.

Coinfection — Coinfection with R. prowazekii and another louse-born pathogen, B. quintana, has been reported. The development of "paleomicrobiologic techniques" (ie, using molecular diagnostic methods to examine the dental pulp of long-buried skeletons) has revealed evidence that soldiers dying during Napoleonic military campaigns during the early 19^th century had evidence of simultaneous infection with both pathogens. Similar findings of coinfection were documented in outbreaks in Burundi during a civil war in 1993, and in Rwanda in 2012 [1,7]. A more detailed discussion of B. quintana is found elsewhere. (See "Bartonella quintana infections: Clinical features, diagnosis, and treatment".)

PATHOGENESIS — After transcutaneous entry of infective louse tissues or feces, R. prowazekii spreads throughout the body via the blood stream or lymphatics. Once inside the human host, typhus rickettsiae, like R. rickettsii, enter endothelial cells and proliferate by binary fission. (See "Biology of Rickettsia rickettsii infection".)

The precise mechanism by which R. prowazekii produces cellular injury is still uncertain, but experimental studies suggest that a complex and multifactorial sequence of events results in endothelial injury via both cellular swelling and necrosis. Secondary immune and phagocytic responses to R. prowazekii involve both lymphocytes and macrophages, but R. prowazekii can also injure cells directly in the absence of immune and inflammatory responses. Attachment of R. prowazekii to cell membranes directly increases phospholipase activity, which in turn injures host cell membranes [25]. R. prowazekii may accumulate in vast numbers in individual endothelial cells prior to sudden "burst release", which results in death of the host cell.

The consequence of the above series of cellular events is the pathologic hallmark of epidemic typhus infection: widespread lymphocytic vasculitis with increased vascular permeability, edema, and activation of humoral inflammatory and coagulation mechanisms. This rickettsia-induced vasculitis may also be accompanied by mural and intimal thrombosis and microscopic areas of hemorrhage. Involvement of the microcirculation can produce diffuse myocarditis as well as damage to muscle, spleen, kidneys, and brain. Central nervous system involvement may result in characteristic "typhus nodules" composed of perivascular infiltrates consisting of lymphocytes, macrophages, and plasma and mast cells.

The molecular basis for Brill-Zinsser disease, defined as the recrudescence of epidemic typhus years after the initial episode, remains unclear. In particular, the mechanism by which R. prowazekii remains latent in humans for decades has not been established [26]. (See 'Brill-Zinsser disease' below.)

ACUTE R. PROWAZEKII INFECTION — R. prowazekii infection produces two distinct clinical syndromes: an acute potentially severe infection that occurs 10 to 14 days after exposure to infected lice, and a recrudescent form called Brill-Zinsser disease that may occur 10 to 50 years after primary infection.

Symptoms — The majority of patients with epidemic typhus or sylvatic typhus infection experience the abrupt onset of fever, severe headache, and malaise. Infected patients may also complain of a number of other nonspecific symptoms including cough, abdominal pain, nausea, and diarrhea. They may also have myalgias, which can be severe [1]. The relative frequencies with which these symptoms occur are illustrated by the findings of two studies of 104 patients [19,27]:

●Fever – 100 percent

●Headache – 91 to 100 percent

●Tachypnea – 97 percent

●Chills – 82 percent

●Muscle tenderness – 70 percent

●Rash – 64 percent

●Abdominal tenderness – 60 percent

●Arthralgias – 50 percent

●Cough – 38 percent

●Nausea – 32 percent

Rash — The rash of epidemic typhus classically begins several days after the onset of symptoms, appearing as a red macular or maculopapular eruption on the trunk that later spreads centrifugally to the extremities. The rash, which may be difficult to see in dark-skinned individuals, is classically described as sparing the palms and soles, but many exceptions to this rule occur. In severe cases, the rash may become petechial; gangrene of the distal extremities necessitating amputation is a rare complication.

The rash is usually present on both the trunk and extremities but may be limited to one or the other site in some patients [19,27]. The incidence of the rash becoming petechial is variable, ranging in these two reports from 18 to 55 percent.

Rash may or may not be present in patients with sylvatic typhus. In two separate series describing a total of 15 patients, rash occurred in seven and was petechial in two [28,29]. In another report, none of four patients with sylvatic typhus developed a skin rash [24].

Central nervous system manifestations — The majority of patients with epidemic typhus manifest one or more abnormalities in central nervous system function. Common neurologic symptoms include confusion and drowsiness. Coma, seizures, and focal neurologic signs may develop in a minority of patients. In an outbreak of epidemic typhus in a jail in Burundi, seven of nine patients had one or more neurologic signs or symptoms, including seizures in one and coma in three [8]. Similar symptoms can occur with sylvatic typhus [28].

Other complications — Jaundice, elevated serum aminotransferases, and thrombocytopenia are common findings in patients with epidemic typhus. Clinical and laboratory evidence of myocarditis and diffuse or focal pulmonary infiltrates on chest x-ray occur in a small percentage of patients.

BRILL-ZINSSER DISEASE — Brill-Zinsser disease is defined as the recrudescence of epidemic typhus years after the initial episode [4]. In contrast to acute primary infection, Brill-Zinsser disease is generally a mild illness. Severe symptoms and death are rare, primarily occurring in elderly and debilitated patients [30-32].

The onset of Brill-Zinsser disease is typically abrupt with chills, fever, headache, and malaise. Nonspecific gastrointestinal and pulmonary symptoms are also present in many patients. Because affected patients are often elderly, symptoms such as confusion, dyspnea, or lethargy may be erroneously attributed to preexisting or coexistent cardiac, cerebrovascular, or pulmonary disease [30]. The disease may also occur in patients who previously developed sylvatic epidemic typhus associated with flying squirrels [4].

Rash is present in most patients with Brill-Zinsser disease, typically beginning four to six days after the onset of symptoms. The rash is often scant or evanescent and is only rarely petechial.

The results from a study involving a mouse model of recrudescent typhus suggest that doxycycline treatment given promptly to patients with primary infections due to epidemic typhus may reduce the risk of subsequent Brill-Zinsser disease [33].

DIAGNOSIS — Serologic tests are the mainstay of diagnosis since isolation of R. prowazekii is generally impractical. Two serologic tests are widely available: an indirect immunofluorescent antibody test and an immunoblot technique. Neither can reliably separate acute primary infection from Brill-Zinsser disease [32]. Both forms of R. prowazekii infection are associated with a fourfold increase in antibody titers between acute and convalescent specimens taken at least two weeks apart, similar to other rickettsial diseases.

These tests are available in most state health departments, the United States Centers for Disease Control and Prevention (CDC), and a few specialized research laboratories. The polymerase chain reaction-based assays for detection of R. prowazekii in swabs from eschar, tissue, or whole blood are also available through the CDC [34].

PREVENTION

Delousing — Eradication of human infestation with lice will prevent transmission of epidemic typhus. As noted above, people who live and work in close proximity to louse-infested individuals may secondarily acquire lice even if they regularly wash their clothes and have good hygiene. Thus, all louse-infested persons and individuals in close contact with such persons should use long-acting insecticides.

Human lice can be treated with agents such as DDT, malathion, and lindane, but reports of resistance to one or more of these agents have appeared. Pyrethroid permethrin, when applied as a dust or spray to clothing or bedding, is highly effective against lice and is the delousing agent of choice. Fabric treated with permethrin retains toxicity to lice even after 20 washings, thereby offering significant long-term passive protection against epidemic typhus [35].

Antibiotic prophylaxis — The use of chloramphenicol or tetracycline for prophylaxis may be highly effective in interrupting typhus outbreaks. Since even a single dose of doxycycline provides protection against epidemic typhus, some experts recommend the use of one 200 mg dose of doxycycline once weekly by travelers or health care workers residing in areas in which epidemic typhus is present. Prophylaxis is generally continued for one week after leaving such areas.

Vaccination — Studies performed decades ago showed that an inactivated vaccine provided a moderate degree of protection against experimental R. prowazekii infection [36]. Furthermore, a reduced incidence of typhus occurred among individuals vaccinated with both inactivated and an experimental E-strain vaccine. However, because of licensing concerns and additional concerns that spontaneous reversion of live E-strain may revert to a more virulent strain, the E-strain vaccine is not currently available or in use [19].

Environmental control — In areas where flying squirrels are common, such as cabins in parks and campgrounds, openings in attic vents and roof joists should be sealed with metal screening to prevent squirrels from nesting in areas in close proximity to humans [24].

TREATMENT — As in other rickettsial diseases, tetracyclines and chloramphenicol are the most effective agents for epidemic typhus. The drug of choice is doxycycline. In a small study from Rwanda, for example, a single 200 mg oral dose of doxycycline cured 35 of 37 patients; the two remaining patients had a relapse six and seven days after initial response [20]. While the optimal duration of therapy is unproven, most experts recommend treating for at least seven days or until the patient has been afebrile for at least 48 hours, whichever is longer.

However, medical facilities are often inadequate in areas of the world in which epidemic typhus is seen. An alternative to doxycycline is the empiric administration of chloramphenicol 500 mg orally or intravenously four times daily for five days. While inferior, this regimen is effective for epidemic typhus and simultaneously covers meningococcemia and typhoid fever, infections that can mimic many or all of the clinical features of R. prowazekii infection. Other alternate agents with some reported activity against R. prowazekii include azithromycin and rifampin; however, failures with these agents are well documented, and they are clearly inferior to standard therapy with doxycycline [37,38].

Most patients treated with doxycycline or chloramphenicol improve markedly within 48 hours following the initiation of therapy. In the series from Rwanda, 29 of 37 patients were afebrile 48 hours after therapy was started [20]. Supportive care, including fluids, vasopressors, oxygen, and even dialysis, may be required in patients with severe illness.

PROGNOSIS — The prognosis is dependent upon a number of factors, including the age, underlying nutritional status, and health of the patient and the speed with which therapy is administered. In the preantibiotic era, the mortality rates for epidemic typhus were related to age and gender, being higher in older patients and males. In the modern era, mortality is uncommon if either tetracycline or chloramphenicol is given. In a series of 60 hospitalized patients, for example, none of those treated with chloramphenicol or tetracycline died [27]. Most patients remained ill during the first 48 hours of therapy but rapidly improved thereafter. However, in another report of an outbreak of epidemic typhus, two of nine patients died despite receiving chloramphenicol therapy [8].

The prognosis of Brill-Zinsser disease is generally good. However, rare fatalities have been described [30].

SUMMARY AND RECOMMENDATIONS

●Epidemic typhus is a potentially lethal, louse-borne, exanthematous disease caused by Rickettsia prowazekii. The principal vectors are Pediculosis humanus (the body louse) and P. humanus capitis (the head louse), although the squirrel flea (Orchospea howardii) can transmit the sylvatic form of disease from infected flying squirrels to humans. (See 'Introduction' above and 'Epidemiology' above.)

●Only a few foci of epidemic typhus still exist in the world today. In recent decades, cases of epidemic typhus have been reported in Burundi, Rwanda, Ethiopia and in the rural highlands of South America, Asia, and Algeria. A sylvatic form of R. prowazekii infection has been reported in the United States. (See 'Geographic distribution' above.)

●R. prowazekii infection produces two distinct clinical syndromes: an acute potentially severe infection that occurs 7 to 14 days after exposure to infected lice, and a rare recrudescent form called Brill-Zinsser disease that may occur 10 to 50 years after primary infection. Brill-Zinsser disease is generally a mild illness. (See 'Acute R. prowazekii infection' above and 'Brill-Zinsser disease' above.)

●The majority of patients with epidemic typhus or sylvatic typhus infection experience the abrupt onset of fever, severe headache, and malaise. Infected patients may also complain of a number of other nonspecific symptoms including cough, abdominal pain, nausea and diarrhea. (See 'Symptoms' above.)

●The rash of epidemic typhus classically begins several days after the onset of symptoms, appearing as a red macular or maculopapular eruption on the trunk that later spreads centrifugally to the extremities. (See 'Rash' above.)

●Serologic tests are the mainstay of diagnosis since isolation of R. prowazekii is generally impractical. Both forms of R. prowazekii infection are associated with a fourfold rise in antibody titers between acute and convalescent specimens taken at least two weeks apart. (See 'Diagnosis' above.)

●As in other rickettsial diseases, tetracyclines and chloramphenicol are the most effective agents for epidemic typhus. The drug of choice is doxycycline, although chloramphenicol is often used in the developing world. (See 'Treatment' above.)

●Eradication of human infestation with lice will prevent transmission of epidemic typhus. All louse-infested persons and individuals in close contact with such persons should use long-acting insecticides. (See 'Delousing' above.)

●The use of chloramphenicol or tetracyclines for prophylaxis may be highly effective in interrupting typhus outbreaks. Some experts recommend the use of one 200 mg dose of doxycycline once weekly by travelers or health care workers residing in areas in which epidemic typhus is present. (See 'Antibiotic prophylaxis' above.)