The human pathogens in the family Rickettsiaceae are small bacteria of the genera Rickettsia and Orientia. They are closely related to members of the family Anaplasmataceae that includes the genera Ehrlichia and Anaplasma. These organisms are obligate intracellular parasites that are transmitted to humans by arthropods. Many rickettsiae are transmitted transovarially in the arthropod, which serves as both vector and reservoir. Rickettsial infections, but not the ehrlichioses, typically are manifested by fever, rashes, and vasculitis. They are grouped on the basis of their clinical features, epidemiologic aspects, and immunologic characteristics (Table 26-1). Coxiella burnetii resides in the family Coxiellaceae and is more closely related to the genus Legionella; for convenience, it is discussed at the end of this chapter.

Properties of Rickettsiae

Rickettsiae are pleomorphic coccobacilli, appearing either as short rods (0.3 × 1–2 μm) or as cocci (0.3 μm in diameter). They do not stain well with Gram stain but are readily visible under the light microscope when stained with Giemsa stain, Gimenez stain, acridine orange, or other stains. However, immunohistochemical or immunofluorescence stains performed at a laboratory skilled in rickettsial diagnostics are the most useful methods for confirming a diagnosis of rickettsial infections.

Rickettsiae grow readily in yolk sacs of embryonated eggs. Pure preparations of rickettsiae for use in laboratory testing can be obtained by differential centrifugation of yolk sac suspensions. Many strains of rickettsiae also grow in cell culture, where the generation time is 8–10 hours at 34°C. Cell culture has replaced animal inoculation (except for Orientia species) and yolk sac cultivation for isolation of these organisms. For reasons of biosafety, isolation of rickettsiae should be done only in reference laboratories.

Rickettsiae have gram-negative cell wall structures that include peptidoglycan-containing muramic acid and diaminopimelic acid. The genus is divided into several groups. The typhus group, the spotted fever group, and the transitional group have species that are pathogenic to humans. Rickettsiae contain lipopolysaccharide and the cell wall proteins include the surface proteins OmpA and OmpB. These surface proteins are important in adherence to host cells and in the humoral immune response and also provide the basis for serotyping.

Rickettsiae grow in different parts of the cell. Those of the typhus group are usually found in the cytoplasm, and those of the spotted fever group are usually found in the nucleus. Rickettsial growth is enhanced in the presence of sulfonamides, and rickettsial diseases are made more severe by these drugs. Tetracyclines and chloramphenicol inhibit the growth of rickettsiae and can be therapeutically effective.

Most rickettsiae survive only for short times outside of the vector or host. Rickettsiae are quickly destroyed by heat, drying, and bactericidal chemicals. Dried feces of infected lice may contain infectious Rickettsia prowazekii for months at room temperature.

Rickettsial Antigens and Serology

The direct immunofluorescent antibody test can be used to detect rickettsiae in ticks and sections of tissues. The test has been most useful to detect Rickettsia rickettsii in skin biopsy specimens to aid in the diagnosis of Rocky Mountain spotted fever (RMSF); however, the test is performed in only a few reference laboratories.

Serologic evidence of infection occurs no earlier than the second week of illness for any of the rickettsial diseases. Thus, serologic tests are useful only to confirm the diagnosis, which is based on clinical findings (eg, fever, headache, rash) and epidemiologic information (eg, tick bite). Therapy for potentially severe diseases, such as RMSF and typhus, should be instituted before seroconversion occurs.

A variety of serologic tests have been used to diagnose rickettsial diseases. Most of these tests are performed only in reference laboratories. Antigens for the indirect immunofluorescence, latex agglutination, indirect immunoperoxidase tests, and enzyme immunoassay for RMSF are commercially available. Reagents for other tests are prepared only in public health or other reference laboratories. The indirect fluorescent antibody technique may be the most widely used method because of the availability of reagents and the ease with which it can be performed. The test is relatively sensitive, requires little antigen, and can be used to detect immunoglobulin M (IgM) and IgG. Rickettsiae partially purified from infected yolk sac material are tested with dilutions of a patient’s serum. Reactive antibody is detected with a fluorescein-labeled antihuman globulin. The results indicate the presence of partly species-specific antibodies, but cross-reactions are observed.

Pathology

Rickettsiae multiply in endothelial cells of small blood vessels and produce vasculitis characterized by lymphocytes that surround the blood vessels. The cells become swollen and necrotic; there is thrombosis of the vessel, leading to rupture and necrosis. Vascular lesions are prominent in the skin, but vasculitis occurs in many organs and appears to be the basis of hemostatic disturbances. Disseminated intravascular coagulation and vascular occlusion may develop. In the brain, aggregations of lymphocytes, polymorphonuclear leukocytes, and macrophages are associated with the blood vessels of the gray matter; these are called “typhus nodules.” The heart shows similar lesions of the small blood vessels. Other organs may also be involved.

Immunity

In cell cultures of macrophages, rickettsiae are phagocytosed and replicate intracellularly even in the presence of antibody. The addition of lymphocytes from immune animals stops this multiplication in vitro. Infection in humans is followed by partial immunity to reinfection from external sources, but relapses occur (see the discussion of Brill-Zinsser disease).

Clinical Findings

Rickettsial infections are characterized by fever, headache, malaise, prostration, skin rash, and enlargement of the spleen and liver.

A. Typhus Group

1. Epidemic typhus (R prowazekii)—Disease is transmitted by the body louse in a human–louse cycle. In epidemic typhus, systemic infection and prostration are severe, and fever lasts for about 2 weeks. The disease is more severe and more often fatal in patients older than 40 years of age. During epidemics, the case fatality rate has been 6–30%.

2. Endemic typhus or murine typhus (Rickettsia typhi)—Infected flea feces rubbed into the bite wound is the method of transmission. The clinical picture of endemic typhus has many features in common with that of epidemic typhus, but the disease is milder and is rarely fatal except in elderly patients.

B. Spotted Fever Group

The spotted fever group resembles typhus clinically; however, unlike the rash in other rickettsial diseases, the rash of the spotted fever group usually appears after 3–5 days of illness, first on the extremities, then moves centripetally, and involves the palms and soles. Some, such as Brazilian spotted fever and RMSF, may produce severe infections possibly due to infection of endothelial cells that leads to vascular permeability and consequently complications such as pulmonary edema and hemorrhages; others, such as Mediterranean spotted fever, are mild. The case fatality rate varies greatly. RMSF is life-threatening for all age groups but mortality is usually much greater in elderly persons (up to 50%) than in young adults or children.

C. Transitional Group

Rickettsialpox (Rickettsia akari) is a mild disease with a vesicular rash resembling that of varicella. About 1 week before onset of fever, a firm red papule appears at the site of the mite bite and develops into a deep-seated vesicle that in turn forms a black eschar (see later discussion).

D. Scrub Typhus

Scrub typhus (Orientia tsutsugamushi)—This disease resembles epidemic typhus clinically. One feature is the eschar, the punched-out ulcer covered with a blackened scab that indicates the location of the mite bite. Generalized lymphadenopathy and lymphocytosis are common. Illness can be severe with associated cardiac and cerebral involvement leading to death in about 30% of patients.

Laboratory Findings

Isolation of rickettsiae is technically difficult and is of only limited usefulness in diagnosis. It is also hazardous and must be performed in a biosafety level 3 laboratory. Animal inoculation has been replaced by cell culture methods for cultivation of most of the rickettsiae. Appropriate specimens include heparinized plasma, buffy coat, and skin lesions. Organisms can be detected in cell cultures by molecular methods or by immunofluorescence staining.