Rickettsial Diseases

History

Epidemic typhus was described by Fracastorius in Italy in 1546; RMSF, by Maxey in Idaho in 1899; and boutonneuse fever, by Conor in Tunisia in 1910. A rickettsial agent was first identified in 1906 in the Bitterroot Valley of western Montana by Howard Ricketts, who also recognized its transmission by ticks. In 1916, S. Burt Wolbach visualized this agent, later named Rickettsia rickettsii , within endothelial cells. Charles Nicolle discovered in 1909 that lice transmit epidemic typhus, which was subsequently found to be caused by Rickettsia prowazekii . Epidemic louse-borne typhus influenced the outcome of most European wars after 1500, including Napoleon's failed Russian invasion in 1812 and World War I, during and after which typhus affected 25 million persons and caused 3 million deaths in Russia. In 1934, recrudescent typhus (Brill–Zinsser disease) was determined to be caused by reactivation of latent R. prowazekii infection. Endemic or murine typhus was shown during the 1930s to have a rat reservoir and flea vector.

Epidemiology

Spotted fever group rickettsiae (SFGR) are maintained in nature principally via transmission of the bacteria in infected ova from one generation of tick, mite, or flea to the next (see Table 76.1 ; Fig. 76.1 ). During feeding, infected arthropods instill saliva containing rickettsiae into their host's skin. Thus, the seasonal and geographic distribution of each disease ( Fig. 76.2 ) depends upon the range and the host-seeking activity of the particular vector. For example, RMSF usually occurs during tick season, from late spring until the end of summer.

Typhus group rickettsiae are deposited on the host's skin in the feces of feeding human body lice ( R. prowazekii ) or fleas ( R. typhi). The organisms are subsequently scratched into the skin, rubbed into mucous membranes, or inhaled. Humans who recover from louse-borne typhus remain latently infected and years later may develop recrudescent illness (Brill–Zinsser disease) and associated rickettsemia. Such individuals can infect feeding lice, which may then spread the disease to another person and ignite an epidemic. In addition, a zoonotic cycle of R. prowazekii is maintained in flying squirrels and their fleas and lice. R. typhi is maintained in natural cycles, classically in rats and oriental rat fleas as well as in opossums and cat fleas . Murine (endemic) typhus caused by R. typhi is prevalent in tropical and subtropical coastal regions worldwide, representing an increasingly recognized cause of febrile illness in travelers .

Pathogenesis

After entry into the dermis, rickettsiae spread throughout the body via the bloodstream. They attach to vascular endothelial cells by outer membrane protein B and, in the case of SFGR, outer membrane protein A as well. The organisms enter the cells by induced phagocytosis and then escape from the phagosome into the cytosol, where they obtain amino acids, nucleotides, and other building blocks for growth from the host cell and divide by binary fission. SFGR move intra- and intercellularly by stimulating propulsion via the host cell's actin, resulting in a contiguous network of infected endothelial cells that represent the source of the vascular-based disease manifestations, including skin lesions. Whereas SFGR injure the host endothelium by stimulating these cells to produce toxic reactive oxygen species, typhus group rickettsiae replicate within the infected endothelial cells until they burst.

The major pathophysiologic effect of rickettsial infection is increased vascular permeability, which can result in edema, hypovolemia, and hypotension . Although endothelial cells of the microcirculation are infected in every organ, the critical target organs in life-threatening infections are the lung and brain. A fatal outcome can result if increased vascular permeability leads to non-cardiogenic pulmonary edema, acute respiratory distress syndrome (ARDS), and meningoencephalitis.

As the infection progresses, macrophages and lymphocytes infiltrate the walls of affected vessels and act as effector cells, secreting cytokines such as interferon-γ and tumor necrosis factor-α. Infected endothelial cells and macrophages themselves are activated by cytokines, resulting in killing of intracellular rickettsiae by mechanisms involving nitric oxide, reactive oxygen species, and tryptophan starvation (via enzymatic degradation of this amino acid). Recruited cytotoxic T cells are critical to the apoptotic elimination of infected endothelial cells, which occurs through perforin-dependent pathways. A combination of rickettsicidal mechanisms and killing of infected endothelial cells ultimately leads to clearance of the infection. Antibodies to rickettsiae play a role in the prevention of reinfection.