Rickettsia prowazekii (Epidemic Typhus and Brill-Zinsser Disease)

Authors: Didier Raoult, Max Maurin, M.D., Ph.D.

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Microbiology

Rickettsia species are gram negative, strictly intracellular bacilli that multiply within the cytosol of endothelial cells. Rickettsia prowazekii, a typhus group rickettsia, is the etiologic agent of epidemic or louse-borne typhus and Brill-Zinsser disease (3).

Epidemiology

Epidemic typhus was first considered a disease restricted to the human being, with human to human transmission occurring via the human body louse (Pediculus humanis corporis) (1, 3). The possibility of recurrent infection in humans several years after the initial infection (referred to as Brill-Zinsser disease) suggested man may act as a reservoir for the bacteria and explained the maintenance of the disease between epidemics (49). However, R. prowazekii has been isolated from flying squirrels (Glaucomys volans) in North America (8), and the disease (referred as indigenous epidemic typhus) may be acquired from flying squirrel-parasitizing arthropods. It has also been found in Amblyomma ticks in Ethiopia and Mexico (29).

Epidemic typhus is considered primarily a disease of war, and has made a significant contribution to human history (1, 3, 33, 49). It is still prevalent in areas where poor socioeconomic conditions and a high prevalence of louse infestation prevail. The currently distribution of epidemic typhus is unknown, but since the 1990s, foci of epidemic typhus have been described in Africa, including Algeria (25, 26, 27) and central eastern African countries such as Ethiopia, Zaire, Rwanda and Burundi (30, 34), in mountainous regions of South America (including Peru), in North America, including recently in Texas (36), in the Himalayan regions in Asia, and in Russia (45). An autochthonous case of epidemic typhus has been recently reported in France (2). A reemergence of epidemic typhus in developed countries, especially in the homeless louse-infested population, is a possible threat.

Clinical Manifestations

Most cases of epidemic typhus occur during the cold months, when heavy clothing and poor sanitary conditions allow infestation by body lice. Incubation period of the disease is usually 1 to 2 weeks, but can be shorter in severe forms of the disease. Prodromal symptoms include headache, arthralgia (especially in the large joints), and malaise. Onset is typically abrupt, with persistent headache, chills, a high-grade fever, frequently nausea and vomiting, and prostration of variable degree. Characteristically a cutaneous rash appear after 4 to 5 days of illness, first visible in axillae and in the inner surfaces of the arms, then extending to the trunk but usually not to the face or extremities. Early lesions are maculae which become papulae in a few days, but in more severe cases the rash may become petechial and even hemorrhagic and necrotic. In approximately 20% of cases the rash is absent which hampers clinical diagnosis. In a recent study in Africa, it was found in only 20% of cases in patients with dark skin. Complications may occur and lead to death in about 20% of cases without antibiotic treatment, a figure which may be higher in uncontrolled situations. Complications include neurologic disorders (meningitis, encephalitis, muttering delirium, coma), cardiac failure, respiratory distress, vascular complications (mainly gangrene), intestinal complications, and renal failure.

The clinical manifestations of Brill Zinsser disease are similar to those of epidemic typhus, although usually milder, and the cutaneous rash is most often absent (19, 43, 49). Indigenous epidemic typhus has been described in the Eastern US, where 15 clinical cases have been extensively described by McDade et al. (22), and Duma et al. (9). These cases occurred during the colder months, from November to March. In most cases onset was abrupt with high fever, headache, and myalgia. A cutaneous rash was seen in about half the patients (8/15). Clinical manifestations suggestive of central nervous system involvement, including meningismus, confusion, delirium, and coma, were observed in 40% (6/15) of the cases.

Brill-Zinsser diseases is considered milder than classical epidemic typhus, although it remains potentially life-threatening. On the other hand, because R. prowazekii bacteremia often occur in Brill-Zinsser patients, an epidemic typhus outbreak may supervene when body louse infestation is prevalent in the considered population.

Laboratory Diagnosis

Diagnosis of rickettsial diseases is based upon serology (7, 18). An antibody response is usually detected only after 10 days from the onset of systemic symptoms, and antibody titers reach a peak after 3 to 4 weeks or later if an antibiotic therapy has been administered. Thus an appropriate antibiotic therapy should be administered upon suspicion of a rickettsial infection, without waiting for diagnostic confirmation using specific serological tests. Delay in appropriate antibiotic therapy is the main factor for poor prognosis in patients involved with rickettsial diseases, especially for epidemic typhus which is fatal in about 15% of cases when untreated (34). Also, rapid administration of an appropriate treatment in all clinically suspected cases will prevent the occurrence of large epidemics. Before rickettsial antigens were available for diagnosis, the Weil-Felix test was based on the observation that antibodies from patients recovering from rickettsial infections were able to agglutinate antigens from different Proteus vulgaris strains (OX-K, OX-2, OX-19). Sera from patients involved with epidemic typhus displayed cross reacting antibodies against Proteus vulgaris OX-19. More recent serological tests use Rickettsia prowazekii grown in cell culture as antigen (18). Techniques which have been used include complement fixation tests, microagglutination assays, indirect fluorescent antibody (IFA) tests, and ELISA. IFA remains the current reference, allowing determination of IgG and IgM. Using the IFA test, a single IgG antibody titer of > 128, an IgM titer of > 32, or fourfold increase in antibody titers between acute phase and convalescent phase sera are considered diagnostic. However, serology often does not allow accurate determination of the Rickettsia species involved. Absorption assays and western blot may help in such a differentiation. Brill Zinsser disease is characterized by the presence of rising anti-R. prowazekii IgG titers, whereas IgM are lacking and Weil-Felix test is typically negative. Culture of Rickettsia spp. from clinical samples (mainly blood) requires cell culture systems and a level-3 equipped laboratory, and thus is only available in reference laboratories. Sensitivity is low, especially when an appropriate antibiotic therapy has been administered before collecting clinical samples. Only one strain was isolated from patients since 50 years (5). Direct amplification of rickettsial DNA using PCR or real-time PCR methods may be obtained from blood (buffy coat) or rarely from other clinical samples (10, 44). This technique may be especially useful early in the course of a rickettsial disease, before an antibody response is detected (44).

Pathogenesis

R. prowazekii is inoculated into humans through the skin via the bite of the human body louse. Endothelial cells are the primary target cells for rickettsiae leading to a generalized vasculitis. The diversity of the rickettsial microvascular injuries in the infected patient explains the wide spectrum of clinical manifestations and life threatening complications that may be encountered. R. prowazekii is the only rickettsial species which may persist in infected patients for prolonged duration, with the possibility of recurrences several years after the primary infection (i.e. Brill Zinsser disease).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Because of their obligate intracellular life-style, susceptibility of rickettsiae to antibiotics cannot be assessed in conventional microbiological tests. As epidemic typhus is primarily a human disease, no animal model is available. Fever was observed in guinea pigs injected intraperitoneally with R. prowazekii (54). However, this model is not representative of the clinical manifestations or the route of infection of epidemic typhus in humans. Its reliability for epidemic typhus infections has not been established. R. prowazekii-infected lice have been used to test the activity of antibiotics against this rickettsia. The antibiotic susceptibility of R. prowazekii has also been determined in the embryonated egg model, and more recently in cell culture systems.

Arthropod Model

Infected body lice were used as an in vivo model to test the antibiotic susceptibility of R. prowazekii to antibiotics (4, 6, 17). Lice usually die from infection with R. prowazekii. Infected lice received either doxycycline or rifampin. For both antibiotics rickettsial growth inhibition and delay in death of infected body lice were obtained. However such effect was observed only during antibiotic administration which suggests that antibiotics were bacteriostatic and not bactericidal.

Embryonated Egg Model

In the embryonated egg model, rickettsiae were injected into the yolk sac of the eggs. This resulted in death of the embryo usually within a few days following infection. Antibiotics were administered by the same route and usually within the first hour following rickettsial inoculation. Antibiotic activity was deduced from the difference in mean survival time (DMST) of infected embryos receiving antibiotics as compared to infected untreated controls. A rickettsiostatic effect of antibiotics allowed the embryos to survive up to the last day of experiments, usually day 14. The rickettsiacidal activity of antibiotics was assessed by subculture of yolk sacs from surviving eggs at 14 days post infection. Direct smear examination prepared from infected tissues and stained with the Gimenez technique has also been used to evaluate the action of antibiotics. Such a model did not however allow direct evaluation of the growth rate of rickettsiae. In the embryonated egg model, penicillin G and the aminoglycosides streptomycin and gentamicin were not effective at doses used in patients (40, 50) (Table 1). However, at higher doses, penicillin is effective, and R. prowazekii forms sphéroplastes when exposed to high penicillin concentrations (53). PABA was poorly effective at concentrations > to 10,000 µg/egg (40). Chloromycetin allowed a DMST > 2.5 days at concentrations > 250 µg/egg (39). Oxytetracycline (Terramycin), and to a lesser extent chlortetracycline (Aureomycin) and chloramphenicol were considered rickettsiostatic (28, 42). Erythromycin was found to be effective against R. prowazekii. However, Weiss et al. (48) demonstrated that, in vitro, R. prowazekii could readily become resistant to this antibiotic after only 3 passages in embryonated eggs in the presence of progressively increasing erythromycin concentrations. Such results suggested the possibility of the in vivo emergence of resistant strains.

Cell Culture Models

The primary target cells for rickettsiae are endothelial cells. However a number of eukaryotic cell lines can be infected with rickettsiae in vitro, including fibroblasts, macrophages, primary chick embryo cells, and human endothelial cells. The plaque formation in infected cell cultures was first used for numeration of viable rickettsiae (20, 21, 23, 47, 51), and then adapted to determine their in vitro antibiotic susceptibility (20, 23, 53). The plaque assay system is currently the recommended technique allowing evaluation of both the bacteriostatic and the bactericidal activity of antibiotics. Cell monolayers (usually Vero cells) grown in tissue culture Petri dishes are acutely infected by rocking incubation with a rickettsial inoculum. Infected cells are then overlaid with Eagle MEM with 2% fetal calf serum and 0.5 % agar. Antibiotics are added at different concentrations at the same time, whereas no antibiotics are added in drug-free controls. Petri dishes are incubated 4 days at 37°C in a 5% CO2 atmosphere. Cell monolayers are then stained with neutral red dye, allowing visualization of the plaques. The MICs are defined as the lowest antibiotic concentration allowing complete inhibition of plaque formation, as compared to a drug-free growth control. A disk assay was proposed as a convenient modification of the plaque assay. In this model antibiotic disks are placed on the surface of the agar overlay. The diameter of the plaque formation inhibition zone around the antibiotic disk represents a measure of the antirickettsial activity of the antibiotic. Ives et al. (14) recently described a new cell culture system in which inhibition of Rickettsia proliferation by antibiotics was determined by comparing rickettsial growth in infected Vero cell cultures incubated in the presence of the antibiotic tested to that in drug-free controls. Infected cells were revealed by an indirect fluorescent antibody (IFA) test.

Using the in vitro infected cell model authors have shown that chloramphenicol, doxycycline, tetracycline, minocycline, and rifampin are effective against R. prowazekii, with MICs ranging from 0.005 to 1 µg/ml (24) (Table 1). Penicillins and cephems were considered poorly effective (24) for human usage, although Wisseman et al (52) demonstrated partial inhibition of rickettsial growth and spheroplast formation in cell culture systems using high doses of penicillin G. Erythromycin was found to be effective against Breinl strain of R. prowazekii, whereas the Madrid E strain was resistant (48). The newer macrolide compounds, roxithromycin, azithromycin, and clarithromycin, were recently tested in the immunofluorescent antibody assay (14) against the same R. prowazekii. Clarithromycin was the most effective compound, with MICs ten times inferior to that of erythromycin (0.25 and 2 µg/ml, respectively). The new ketolide compound, telithromycin, displayed an MIC of 0.5µg/ml (37). Nalidixic acid produces only partial inhibition of plaque formation by R. prowazekii (20), whereas the fluoroquinolone compounds were more effective (15, 24, 38).

ANTIMICROBIAL THERAPY

Drug of Choice

The conventional antibiotic regimen for typhus group rickettsiosis is a 7 to 14 day oral course of doxycycline 200 mg daily (Table 2). Tetracyclines are contraindicated in children less than 8 years old because of the possibility of tooth discoloration (41). They are also contraindicated during pregnancy. Tetracyclines may be toxic to the fetus, including bone toxicity and discoloration of deciduous teeth when given after week 16 of gestation (41). Tetracyclines have also been reported to cause serious hepatotoxicity, often with pancreatitis, in pregnant women (11). These antibiotics may also induce gastric intolerance and photosensitization as general side effects (41). A single dose of 100 or 200mg doxycycline, however, has been reported to be as effective as the conventional therapy for epidemic typhus (12, 13, 16, 31). The single dose doxycycline regimen may represent the current best alternative in children less than 8 years old, both because it's very effective to prevent complications of epidemic typhus, and it's well tolerated. This regimen was recently administered successfully, without any relapse, in patients suffering epidemic typhus in Burundi (34, 35). It is particularly useful in epidemic situations when medications and treatment facilities are limited, especially in developing countries and in refugee camps. In these situations, the administration of doxycycline in all clinically suspected cases of epidemic typhus may allow controlling rapid epidemic spread of the disease.

Monotherapy or Combination Therapy

Antibiotic combinations have not been tested in vitro against R. prowazekii. Combination therapy is not indicated, since most patients can be treated easily by the single dose doxycycline regimen. Early administration of doxycycline is critical, allowing prevention of both severe illnesses and epidemic extension of the disease.

Special Situations

In severely diseased patients, doxycycline should be administered first by the intravenous route at 200 mg daily, and 14 days duration should be considered. There is no evidence that other drugs are more effective than tetracyclines, even in patients with neurological complications.

Alternative Therapy

Chloramphenicol (administered for at least 1 week) has long been considered the main alternative for rickettsial infections (Table 2). In developing countries, such as in Ethiopia, chloramphenicol rather than tetracycline was administered as the first line antibiotic therapy because of its activity against both epidemic typhus and enteric fever. These two diseases are difficult to differentiate clinically, and antibody tests may not be available (16, 31). Moreover, in these countries, when antibiotic therapy should be administered parenterally, chloramphenicol is commonly the only available drug, whereas doxycycline is often lacking. However, chloramphenicol presents the potential risk of aplastic anemia, and is also contraindicated in pregnant women. Moreover, recent in vitro and in vivo data indicate that chloramphenicol has only moderate rickettsiostatic activity. Death has been reported in patients with severe epidemic typhus receiving chloramphenicol therapy (12). Erythromycin is effective in vitro against R. prowazekii. However, as suggested by in vitro data (48), rapid in vivo selection of erythromycin-resistant mutants is possible. Failures have been reported in patients receiving erythromycin therapy (C.L. Wisseman, personal communication). Extensive clinical data are lacking for newer macrolide compounds and fluoroquinolones for treatment of epidemic typhus. However, a patient died from epidemic typhus while he was receiving ciprofloxacin for suspected typhoid fever (55). Also, failures have been recently reported in patients with Brill Zinsser disease treated with azithromycin (46). Selection of resistant mutants to newer macrolides may be expected as has been the case for erythromycin. Cotrimoxazole has been reported to be less active than chloramphenicol or doxycycline for treatment of epidemic typhus (12).

ENDPOINTS FOR MONITORING THERAPY

Successful therapy is associated with rapid defervescence and apyrexia usually 3 to 5 days following initiation of treatment. Antibiotic treatment should be continued at least 48 hours following apyrexia. Delay in obtaining apyrexia may be observed in patients with severe diseases, especially those with multi-organ involvement. Failure to respond promptly to the antibiotic therapy has never been associated with antibiotic resistance. It should raise the suspicion of an alternate diagnosis, especially in patients with atypical clinical presentation. There are no useful laboratory parameters of successful treatment. Epidemic typhus is the only rickettsial disease with possible spontaneous recurrences (i.e. Brill Zinsser disease).

VACCINES

There are no vaccines available for Rickettsia prowazekii. The major prophylactic measures to control and eradicate epidemic typhus are eradication of the body lice in the affected population, and monitoring of late disease relapses (Brill-Zinsser disease) (32).

PREVENTION

Doxycycline prophylaxis may be used in epidemic situations. Prevention of epidemic typhus using delousing procedures is efficient, and should be implemented as soon as an outbreak is suspected. Louse infestation is dramatically reduced by the regular changing and washing of clothing. The World Health Organization also recommended insecticides such as permethrin (1%) dusting powder when the prevalence of louse infestation is high. The powder should be applied in a dose of 30 to 50 g per adult (125-250 mg/m2 of clothing). All clothing should be dusted inside and outside. Bedding should also be treated. Lice usually succumb to the insecticide within a few hours. When louse infestation is endemic, the treatment should be repeated every 6 weeks.

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Tables

Table 1. In vitro antibiotic susceptibility of R. prowazekii, Breinl (ATCC VR-142) and Madrid E (ATCC VR-233) strains. The minimum antibiotic doses or MAD (mg/egg) allowing a DMST > 2.5 days in the embryonated egg model, and MICs (mg/L) obtained in cell culture models are presented.

Antibiotics	embryonated eggs MAD (mg/egg)	cell cultures MICs (mg/L)	Strain	References
Penicillin G	162	128	Breinl Breinl	(28, 38)
Amoxicillin		128	Breinl	(38)
Streptomycin	10,000		Breinl	(40)
Gentamicin		16	Breinl	(38)
Chloramphenicol		1	Breinl	(53)
Thiamphenicol		1	Breinl	(38)
Chlortetracycline	129		Breinl	(28)
Oxytetracycline	30 10		Breinl Breinl	(28, 42)
Tetracycline		0.01-0.1	Breinl	(53)
Doxycycline		0.1	Breinl	(53)
Minocycline		0.01-0.1	Breinl	(53)
Rifampin		0.008	Breinl	(53)
Sulfamethoxazole		>4	Breinl	(38)
Erythromycin	15	0.06 2	Breinl Breinl Madrid E	(14, 28, 53)
Dirithromycin		16	Madrid E	(14)
Roxithromycin		1	Madrid E	(14)
Azithromycin		0.25	Madrid E	(14)
Clarithromycin		0.125 1	Madrid E Breinl	(14, 38)
Josamycin		1	Breinl	(38)
Telithromycin		0.5	Breinl	(37)
Pefloxacin		1	Breinl	(38)
Ciprofloxacin		0.5 2.8	Breinl Breinl	(38)
Ofloxacin		1 9	Breinl Madrid E	(15, 38)
Levofloxacin		7.4	Madrid E	(15)
Sparfloxacin		1	Madrid E	(15)

Table 2. Recommendations for antibiotic treatment of R. prowazekii infections.

Condition	Antibiotic	Dose	Duration	References
epidemic typhus in adult and in child > 8 years and Brill Zinsser disease	1. doxycycline	100 mg b.i.d. p.o. (i.v. in case of severe disease)	7-14 days	(12, 16, 19, 41)
	2. doxycycline	100-200 mg p.o.	single dose	(12, 13, 16, 31)
	3. chloramphenicol	500mg every 6 hours	7-14 days	(12, 16)
epidemic situation	doxycycline to all suspected cases	100 mg b.i.d. p.o.	2 days	(34, 35)
child of less than 8 years old	1. doxycycline	100-200 mg p.o.	single dose
child of less than 8 years old	2. chloramphenicol	50mg/Kg/day in divided doses every 6 hours	7-14 days