Rickettsia Prowazekii

Etiology

R. prowazekii belongs to the typhus group of Rickettsia. The genus Rickettsia was divided into spotted fever group (SFG) and typhus group (TG). Gillespie et al. added the transitional group (TRG) and an ancestral group (AG) recently. The spotted fever group has outer membrane protein A and B while the typhus group lacks outer membrane protein (OmpA). Vectors for the spotted fever group are ticks while vectors for the typhus group are fleas and lice.

The vector for epidemic typhus is the human body louse. R. prowazekii multiplies in the gut epithelium of the body louse and explodes into the gastrointestinal (GI) tract, eventually killing the body louse in the process. In this regard, R. prowazekii is unique because no other known members of Rickettsia kill their vector. The R. prowazekii remain viable in the dead louse as well as in the louse feces.  Viable R. prowazekii have been detected in dried feces of the body louse for up to several months.  It is the only member of the genus Rickettsia to cause a latent infection, manifesting years to decades later, known as Brill-Zinsser disease (BZD). BZD was first described in 1913 and occurs because of reactivation of R. prowazekii.[4][5][6]

Epidemiology

Epidemic typhus has been the scourge of humanity for centuries, decimating soldiers in war zones. During peacetime, there are foci of epidemic typhus in resource-limited regions. Charles Nicole discovered the agent of transmission (human body louse or Pediculus humanus corporis) of epidemic typhus. In 1928, he received a Nobel prize for his discovery. In the 1940s, during World War II, vaccines against R. prowazekii were successful in protecting US soldiers. The vaccines are no longer produced for routine clinical use.

Worldwide, there are no reservoirs other than humans. In the United States, the flying squirrel (Glaucomys volans), is the reservoir in nature. The transmission from flying squirrel to human is not explicitly defined. The typhus cases caused by flying squirrels, and not related to body lice as vectors, are known as sylvatic typhus. 

Epidemic typhus due to R. prowazekii is rarely reported among tourists. Refugee populations with a prevalence of body lice have localized outbreaks of epidemic typhus. These outbreaks occur in colder months.

Mortality due to epidemic typhus varies depending on the clinical setting. In untreated primary infection, the mortality can be up to 60%, with the highest mortality occurring in elderly and malnourished patients. Patients afflicted with sylvatic typhus and BZD have much lower mortality rates.  In fact, BZD presents with milder symptoms and is rarely fatal. [7][8]

Pathophysiology

The human body louse is only a vector and not a reservoir because infected lice die five to seven days after they become infected with R. prowazekii. R. prowazekii multiplies in the gut epithelium of the louse which then detaches, ruptures, and releases rickettsiae into the feces. Rickettsiae from the infected feces enter the skin via abrasions or bite site and access the human host.

After entering the host, R. prowazekii enters the microcirculation and the endothelial cells like R. rickettsii. Once inside the cell, R. prowazekii escapes the phagosome and multiplies in the cytoplasm. R. prowazekii seldom gets into the nucleus as it lacks the actin-based directed mobility. R. prowazekii can multiply inside the endothelial cell until the cell bursts, releasing the contents into the extracellular space. 

The injury to the endothelial cells occurs due to the multiplication of the rickettsiae which causes the cells to burst. There is no evidence of endotoxin or exotoxin production by R. prowazekii. Thus, a network of endothelial cells is infected, inviting host cell response. R. prowazekii infection seldom disables the host machinery completely. The host mechanisms to contain Rickettsia prowazekii are like other rickettsial infections. Cytotoxic T-cell lymphocytes, particularly the CD8 group, are essential for the clearance of the rickettsiae. Interferon-gamma and tumor necrosis factor alpha activate the endothelial cells to kill the intracellular rickettsiae. However, despite adequate treatment R. prowazekii is known to cause latent infection (BZD).

Endothelial cell injury leads to increased permeability of vascular endothelium and vasodilation. In severe cases, increased vascular permeability leads to interstitial edema, hypovolemia, hypotension, and hypoalbuminemia. In response to hypovolemia, secretion of antidiuretic hormone causes hyponatremia. Increased vascular permeability in the pulmonary circulation causes noncardiogenic pulmonary edema.  Thus, a picture of severe multi-organ system failure unfolds.

History and Physical

The differential diagnosis for febrile illness with multisystem involvement includes not only epidemic typhus but other entities such as typhoid and relapsing fever. The list is non-exhaustive but includes infections due to other rickettsial species, Ehrlichia, Leptospira, and malaria. Other arthropod-vector borne diseases such as dengue are also in the differential diagnosis. Murine typhus and epidemic typhus are difficult to differentiate due to similar clinical symptoms. Murine typhus occurs predominantly in summer and fall, while epidemic typhus usually occurs during the winter. History of epidemiological exposure is very important for diagnosis.

The incubation period is one to two weeks, with most infections becoming evident after ten to fourteen days. Symptoms of epidemic typhus are high fever (105 F to 106 F) which may last up to two weeks, severe headache, myalgias, dry cough, delirium, stupor, and a dull, red rash that begins on the trunk within several days and spreads peripherally. Palms and soles are spared, which is unlike the rash due to R. rickettsii where palms and soles are typically involved. The illness can progress leading to hypotension, shock, and death. 

In a patient, reactivation of R. prowazekii infection often occurs in the context of malnutrition, chronic illness and in the presence of poor hygiene leading to a greater density of lice. Recrudescent cases (BZD) occur years to decades after the initial infection. There is often a history of prior epidemiological exposure to R. prowazekii. Symptoms of BZD include a severe headache, a sustained high fever, chills, and cough. The rash is often evanescent or absent. Overall BZD is a milder form of epidemic typhus. The circulatory disturbances and hepatic, renal, and central nervous system changes in BZD disease are the same as that of epidemic typhus. A detailed history of exposure and a high index of suspicion are needed to make a diagnosis of BZD.

Evaluation

Like other rickettsial diseases, epidemic typhus is diagnosed clinically and confirmed by serology. A four-fold rise between acute and convalescent titers is diagnostic. These tests include indirect fluorescence antibody (IFA) tests, various agglutination tests (e.g., plate microagglutination, latex agglutination) and enzyme immunoassays. Patients with epidemic typhus have an initial immunoglobulin (IgM) response, then IgG antibodies. However, in BZD, the initial response is a rise in IgG antibody titers. Antibodies due to R. prowazekii can cross-react with R. typhi, the agent of murine typhus. R. prowazekii produces Weil-Felix antibodies, but the test is not recommended anymore.

Treatment / Management

Primary treatment of epidemic typhus is doxycycline 100 mg by mouth twice daily until the patient improves and has been afebrile for 24 to 48 hours. The total duration of treatment is typically between seven and ten days. Chloramphenicol 500 mg orally or intravenously four times daily for seven to ten days is an alternative treatment. In severe cases, supportive therapy with intravenous fluids is recommended. Critically ill patients may have marked capillary permeability and can easily succumb to pulmonary and cerebral edema. Response to therapy is prompt. Clinical failures with azithromycin therapy have been reported. Macrolides are not recommended therapy for R. prowazekii infection.[9][10][11](B3)

Differential Diagnosis

• Epstein-Barr virus

• Fever of unknown origin

• Kawasaki disease

• Leptospirosis

• Malaria

• Meningitis

• Meningococcemia

• Relapsing fever

• Rocky Mountain spotted fever (RMSF)

• Syphilis

• Toxic shock syndrome

• Toxoplasmosis

• Tularemia

• Typhoid fever