In this review, the epidemiology and clinical features of leptospirosis are described, recent taxonomic changes affecting the genusLeptospira are discussed, and advances in the diagnosis of leptospirosis by serological and molecular methods are analyzed.
HISTORICAL ASPECTS
Leptospirosis is a zoonosis of ubiquitous distribution, caused by infection with pathogenic
Leptospira species. The spectrum of human disease caused by leptospires is extremely wide, ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality. This syndrome, icteric leptospirosis with renal failure, was first reported over 100 years ago by Adolf Weil in Heidelberg (
624). However, an apparently identical syndrome occurring in sewer workers was described several years earlier (
337,
338). Earlier descriptions of diseases that were probably leptospirosis were reviewed recently (
207,
211). Leptospirosis was certainly recognized as an occupational hazard of rice harvesting in ancient China (
211), and the Japanese name akiyami, or autumn fever, persists in modern medicine. With hindsight, clear descriptions of leptospiral jaundice can be recognized as having appeared earlier in the 19th century, some years before the description by Weil (
211). It has been suggested that
Leptospira interrogans serovar icterohaemorrhagiae was introduced to western Europe in the 18th century by westward extension of the range of of
Rattus norvegicus from Eurasia (
24).
The etiology of leptospirosis was demonstrated independently in 1915 in Japan and Germany (
207). In Japan, Inada and Ido detected both spirochetes and specific antibodies in the blood of Japanese miners with infectious jaundice, and two groups of German physicians studied German soldiers afflicted by “French disease” in the trenches of northeast France. Uhlenhuth and Fromme (
588) and Hubener and Reiter (
289) detected spirochetes in the blood of guinea pigs inoculated with the blood of infected soldiers. Unfortunately, these two groups became so embroiled in arguments over priority that they overlooked the first publications in English (
296) and German of papers by Inada's group, whose initial publications predated their own by 8 months (
207). Confirmation of the occurrence of leptospirosis on both sides of the Western Front was obtained rapidly after the publication in Europe of Inada's work (
131,
145,
543,
630).
Given the initial controversy over nomenclature, it is ironic that the organism had first been described almost 10 years before (
542). Stimson demonstrated by silver staining the presence of clumps of spirochetes in the kidney tubules of a patient who reportedly died of yellow fever. The spirochetes had hooked ends, and Stimson named them
Spirochaeta interrogans because of their resemblance to a question mark. Unfortunately, this sentinel observation was overlooked for many years (
211).
The importance of occupation as a risk factor was recognized early. The role of the rat as a source of human infection was discovered in 1917 (
293), while the potential for leptospiral disease in dogs was recognized, but clear distinction between canine infection with
L. interrogans serovars icterohaemorrhagiae and canicola took several years (
329). Leptospirosis in livestock was recognized some years later (
24). Several monographs provide extensive information on the early development of knowledge on leptospirosis (
24,
211,
213,
596,
634).
EPIDEMIOLOGY
Leptospirosis is presumed to be the most widespread zoonosis in the world (
646). The source of infection in humans is usually either direct or indirect contact with the urine of an infected animal. The incidence is significantly higher in warm-climate countries than in temperate regions (
208,
479); this is due mainly to longer survival of leptospires in the environment in warm, humid conditions. However, most tropical countries are also developing countries, and there are greater opportunities for exposure of the human population to infected animals, whether livestock, domestic pets, or wild or feral animals. The disease is seasonal, with peak incidence occurring in summer or fall in temperate regions, where temperature is the limiting factor in survival of leptospires, and during rainy seasons in warm-climate regions, where rapid dessication would otherwise prevent survival.
The reported incidence of leptospirosis reflects the availability of laboratory diagnosis and the clinical index of suspicion as much as the incidence of the disease. Within the United States, the highest incidence is found in Hawaii (
101). Leptospirosis ceased to be a notifiable infection within the United States after December 1994 (
97).
The usual portal of entry is through abrasions or cuts in the skin or via the conjunctiva; infection may take place via intact skin after prolonged immersion in water, but this usually occurs when abrasions are likely to occur and is thus difficult to substantiate. Water-borne transmission has been documented; point contamination of water supplies has resulted in several outbreaks of leptospirosis (Table
5). Inhalation of water or aerosols also may result in infection via the mucous membranes of the respiratory tract. Rarely, infection may follow animal bites (
55,
158,
244,
360,
525). Direct transmission between humans has been demonstrated rarely (see Other Complications, below). However, excretion of leptospires in human urine months after recovery has been recorded (
46,
307). It is thought that the low pH of human urine limits survival of leptospires after excretion. Transmission by sexual intercourse during convalescence has been reported (
167,
262).
Animals, including humans, can be divided into maintenance hosts and accidental (incidental) hosts. The disease is maintained in nature by chronic infection of the renal tubules of maintenance hosts (
43). A maintenance host is defined as a species in which infection is endemic and is usually transferred from animal to animal by direct contact. Infection is usually acquired at an early age, and the prevalence of chronic excretion in the urine increases with the age of the animal. Other animals (such as humans) may become infected by indirect contact with the maintenance host. Animals may be maintenance hosts of some serovars but incidental hosts of others, infection with which may cause severe or fatal disease. The most important maintenance hosts are small mammals, which may transfer infection to domestic farm animals, dogs, and humans. The extent to which infection is transmitted depends on many factors, including climate, population density, and the degree of contact between maintenance and accidental hosts. Different rodent species may be reservoirs of distinct serovars, but rats are generally maintenance hosts for serovars of the serogroups lcterohaemorrhagiae and Ballum, and mice are the maintenance hosts for serogroup Ballum. Domestic animals are also maintenance hosts; dairy cattle may harbor serovars hardjo, pomona, and grippotyphosa; pigs may harbor pomona, tarassovi, or bratislava; sheep may harbor hardjo and pomona; and dogs may harbor canicola (
69). Distinct variations in maintenance hosts and the serovars they carry occur throughout the world (
266). A knowledge of the prevalent serovars and their maintenance hosts is essential to understanding the epidemiology of the disease in any region.
Human infections may be acquired through occupational, recreational, or avocational exposures. Occupation is a significant risk factor for humans (
609). Direct contact with infected animals accounts for most infections in farmers, veterinarians, abattoir workers (
95,
104,
570), meat inspectors (
65), rodent control workers (
155), and other occupations which require contact with animals (
27,
357). Indirect contact is important for sewer workers, miners, soldiers (
87,
314,
361), septic tank cleaners, fish farmers (
241,
489), gamekeepers, canal workers (
29), rice field workers (
219,
430,
615), taro farmers (
25), banana farmers (
535), and sugar cane cutters (
132).
Miners were the first occupational risk group to be recognized (
86,
296). The occurrence of Weil's disease in sewer workers was first reported in the 1930s (
23,
218,
308,
545). Serovar icterohaemorrhagiae was isolated by guinea pig inoculation from patients, from rats trapped in sewers (
23,
308), and from the slime lining the sewers (
23). In Glasgow, Scotland, a seroprevalence among sewer workers of 17% was reported (
545). The recognition of this important risk activity led to the adoption of rodent control programs and the use of protective clothing, resulting in a significant reduction in cases associated with this occupation. The presence in wastewater of detergents is also thought to have reduced the survival of leptospires in sewers (
610), since leptospires are inhibited at low detergent concentrations (
106).
Fish workers were another occupational group whose risk of contracting leptospirosis was recognized early. Between 1934 and 1948, 86% of all cases in the northeast of Scotland occurred in fish workers in Aberdeen (
532). Recognition of risk factors and adoption of both preventive measures and rodent control have reduced the incidence of these occupational infections greatly. From 1933 to 1948 in the British Isles, there were 139 cases in coal miners, 79 in sewer workers, and 216 in fish workers. However, in the period from 1978 to 1983, there were nine cases in these three occupations combined (
610). More recently, fish farmers have been shown to be at risk (
489), particularly for infection with serovars of serogroup Icterohaemorrhagiae (
241), presumed to be derived from rat infestation of premises. Because of the high mortality rate associated with Icterohaemorrhagiae infections, this was considered an important occupational risk group despite the very small absolute number of workers affected (
240).
Livestock farming is a major occupational risk factor throughout the world. The highest risk is associated with dairy farming and is associated with serovar hardjo (
66,
458,
500,
609), in particular with milking of dairy cattle (
263,
352,
528). Human cases can be associated with clinical disease in cattle (
263,
500), but are not invariably so (
30,
138). Cattle are maintenance hosts of serovar hardjo (
192), and infection with this serovar occurs throughout the world (
45,
412,
466). Many animals are seronegative carriers (
192,
267,
571). After infection, leptospires localize in the kidneys (
249,
427,
465,
571,
626) and are excreted intermittently in the urine (
189). Serovar hardjo causes outbreaks of mastitis (
196) and abortion (
190). Serovar hardjo is found in aborted fetuses and in premature calves (
188,
194,
238,
268). In addition, hardjo has been isolated from normal fetuses (
191), the genital tracts of pregnant cattle (
191), vaginal discharge after calving (
193), and the genital tract and urinary tract of >50% of cows (
197,
198) and bulls (
185). In Australia, both serovars hardjo and pomona were demonstrated in bovine abortions, but serological evidence suggested that the incidence of hardjo infection was much higher (
182,
305,
529). In Scotland, 42% of cattle were seropositive for hardjo, representing 85% of all seropositive animals (
187). In the United States, serovar hardjo is the most commonly isolated serovar in cattle (
198), but pomona also occurs.
There is a significant risk associated with recreational exposures occurring in water sports (
405), including swimming, canoeing (
306,
517), white water rafting (
482,
591,
627), fresh water fishing, and other sports where exposure is common, such as potholing and caving (
611). The potential for exposure of large numbers of individuals occurs during competitive events (
98,
99,
102,
126,
204). Several outbreaks of leptospirosis associated with water have been reported (Table
5). Many of these outbreaks have followed extended periods of hot, dry weather, when pathogenic leptospires presumably have multiplied in freshwater ponds or rivers. Cases of leptospirosis also follow extensive flooding (
111,
153,
201,
226,
232,
425,
436,
442,
526,
590,
645).
Pathogenic serovars have been isolated from water in tropical regions (
19) and in the United States, where serovars icterohaemorrhagiae, dakota, ballum, pomona, and grippotyphosa have been recovered (
137,
161,
242). Survival of pathogenic leptospires in the environment is dependent on several factors, including pH, temperature, and the presence of inhibitory compounds. Most studies have used single serovars and quite different methodologies, but some broad conclusions may be drawn. Under laboratory conditions, leptospires in water at room temperature remain viable for several months at pH 7.2 to 8.0 (
106,
246), but in river water survival is shorter and is prolonged at lower temperatures (
106,
137). The presence of domestic sewage decreases the survival time to a matter of hours (
106), but in an oxidation ditch filled with cattle slurry, viable leptospires were detected for several weeks (
160). In acidic soil (pH 6.2) taken from canefields in Australia, serovar australis survived for up to 7 weeks, and in rainwater-flooded soil it survived for at least 3 weeks (
531). When soil was contaminated with urine from infected rats or voles, leptospires survived for approximately 2 weeks (
319,
531). In slightly different soil, serovar pomona survived for up to 7 weeks under conditions approximating the New Zealand winter (
274).
Many sporadic cases of leptospirosis in tropical regions are acquired following avocational exposures that occur during the activities of daily life (
205,
454). Many infections result from barefooted walking in damp conditions or gardening with bare hands (
170). Dogs are a significant reservoir for human infection in many tropical countries (
623) and may be an important source of outbreaks (Table
6). A number of outbreaks of leptospirosis have resulted from contamination of drinking water (Table
5) and from handling rodents (
14).
Three epidemiological patterns of leptospirosis were defined by Faine (
211). The first occurs in temperate climates where few serovars are involved and human infection almost invariably occurs by direct contact with infected animals though farming of cattle and pigs. Control by immunization of animals and/or humans is potentially possible. The second occurs in tropical wet areas, within which there are many more serovars infecting humans and animals and larger numbers of reservoir species, including rodents, farm animals, and dogs. Human exposure is not limited by occupation but results more often from the widespread environmental contamination, particularly during the rainy season. Control of rodent populations, drainage of wet areas, and occupational hygiene are all necessary for prevention of human leptospirosis. These are also the areas where large outbreaks of leptospirosis are most likely to occur following floods, hurricanes, or other disasters (
111,
158,
201,
226,
232,
425,
436,
442,
526,
590). The third pattern comprises rodent-borne infection in the urban environment. While this is of lesser significance throughout most of the world, it is potentially more important when the urban infrastructure is disrupted by war or by natural disasters. This type of infection is now rarely seen in developed countries (
157), but is exemplified by the recent rediscovery of urban leptospirosis in Baltimore (
601) and by outbreaks occurring in slum areas in developing countries (
332).