DISEASES, EPIDEMIOLOGY, AND PATHOGENESIS

A few key concepts form the foundation for understanding leptospirosis and its pathogenesis. First, leptospires often colonize proximal convoluted kidney tubules and may be excreted in urine for extended periods by reservoir hosts without clinical signs (Figure 31-1). The carrier state may be as short as a few days or may extend throughout the life of the animal. This is considered a major means of host-to-host transmission. Indirect exposure depends on environmental moisture, neutral soil pH, and a sufficiently mild climate to favor survival of leptospires. Streams and ponds contaminated by the urine of wild rodents or domestic and wild animals can be a source of infection for domestic animals and humans, as can urine aerosols in milking parlors (especially those of the herringbone configuration). The organism can also be isolated from milk of infected cows, and this probably serves as a means of transmission to humans and calves (Figure 31-2).

FIGURE 31-1 Fluorescent antibody stain of Leptospira interrogans in kidney.

(Courtesy William A. Ellis.)

FIGURE 31-2 Transmission and maintenance of Leptospira interrogans.

(Courtesy Ashley E. Harmon.)

Second, localization in tissues from which the organism cannot be readily shed is common in infection of at least some hosts with specific serovars. In some urban areas more than 90% of Norway rats have serovar icterohaemorrhagiae localized in brain, and horses not infrequently experience localization in the eye.

Third, many serovars of leptospirae can be roughly categorized as host adapted or nonadapted. Infections by the former tend to be relatively mild and sporadic, with venereal transmission and lifelong colonization of the genitourinary tract; serovars hardjo in cattle and bratislava and tarassovi in swine are examples. Nonadapted strains, however, are more likely to produce catastrophic infections, with abortion storms in pregnant animals and, not infrequently, death of adult hosts. The carrier state is generally brief. Serovar pomona is nonadapted for swine and cattle, as is serovar canicola for dogs. Serovars of serogroups Icterohaemorrhagiae and Ballum are adapted to rats, the latter adapted to mice. The relationship between hosts and adapted strains gives rise to a minor but long-lasting serologic response, whereas nonadapted strains provoke high antibody titers. It should be obvious that a serovar may be adapted to one species and not others. It seems reasonable to speculate that most, if not all, species have host-adapted strains, including perhaps humans.

Fourth, certain steps seems to be common to Leptospira-induced disease, although all need not occur in every case and in some infections can lead only to very mild clinical signs. Exposure by mucosal or conjunctival routes, or through broken skin, is followed by invasion and eventual development of leptospiremia. Organisms proliferate in parenchymatous organs, including liver, kidneys, spleen, and meninges. Venereal transmission may result only in colonization of reproductive organs. The period of leptospiremia may be shorter (with host-adapted strains) or longer (with nonadapted strains), but in either case gives rise to circulating antibodies that mediate clearance of leptospirae by complement-mediated bacteriolysis. Damage to the maternal-fetal interface or active invasion beyond the placenta may cause fetal death and abortion, or birth of weak offspring. Fetuses infected in the third trimester (and perhaps earlier) may be born with specific antibodies. Organisms are cleared by the effects of antibodies and complement, or if antimicrobial therapy is applied, but may localize for days to years in kidney, reproductive tract, brain, or other tissues.

Fifth, mechanisms of pathogenesis are largely unknown, although the recently demonstrated ability to genetic transform leptospirae should facilitate detailed analysis of leptospiral virulence genes. Leptospiral endotoxin is of low potency, compared with that of many other gram-negative bacteria. Lipopolysaccharide (LPS) mediates adherence of neutrophils to endothelial cells and platelets, suggesting a role in development of thrombocytopenia. LPS is immunogenic and responsible for serovar specificity. In acute leptospirosis, damage to vascular endothelium is common, with resulting hemorrhage and disseminated intravascular coagulation (DIC). The last may be mediated, at least in part, by endotoxin, but sphingomyelinase hemolysins produced by many serovars may be responsible for this vascular damage and for specific clinical signs such as hemoglobinuria. Hemolysis by organisms of serovar lai is not related to sphingomyelinase activity, but is apparently due to a pore-forming protein. Protein and glycoprotein cytotoxins have been described.

Leptospiral attachment to epithelial cells can be enhanced by antibody. Virulent strains can bind to fibronectin. On the negative side (for the leptospirae), antibodies and complement are opsonizing; the outer envelope may be antiphagocytic. Leptospires induce apoptosis in vivo and in vitro.

Some symptoms may be immune mediated. Immune complexes may be associated with central nervous system (CNS) inflammation, although this apparently does not occur in the kidney. Autoantibodies, including IgG anticardiolipin antibodies, are detected in acute human illness. Antileptospiral antibodies cross-reacting with equine ocular tissues are apparently involved in pathogenesis of recurrent uveitis because retinal damage relates to the presence of B lymphocytes in the retina.

Finally, there is sufficient leptospiral promiscuity in host selection that it is difficult to say with certainty that a given serovar cannot infect a specific host. Certain strains are more commonly associated than others with disease in a given species, but even that varies with geographic region. Thus it is probably best for veterinary practitioners and diagnosticians to become familiar with the serovars infecting animals in the specific locale in which they practice (Table 31-2).

TABLE 31-2 Examples of Leptospira Serovars Associated with Disease in Specific Hosts