Anne A. Gershon and Michael Katz
Leptospirosis is a multisystem febrile disease; its underlying pathogenesis is a vasculitis. All leptospires belong to one species of spirochete, Leptospira interrogans. It causes a variety of clinical syndromes including Weil disease (occasionally used to refer to the most severe form of leptospirosis), swamp fever, and field fever in Europe; 7-day fever (nanukayami) and autumnal fever (Hasami-Netsu) in Japan; canefield fever in Australia; and Bushy Creek fever and Fort Bragg fever in the United States; all described before discovery of the causative agent. There is ample epidemiologic evidence that swine, cattle, dogs, and rodents serve as reservoirs.1
All leptospires belong to one species, L interrogans, which consists of two complexes, interrogans and biflexa. The pathogenic strains belong to the interrogans complex, and at least a dozen strains are known to infect humans. Only three, however—the icterohaemorrhagiae serogroup (from rats), the pomona serogroup (from swine), and the canicola serogroup (from cattle and dogs)—do so with any frequency. The hardjo serovariant from cattle has also caused disease in humans.
Although uncommon, leptospirosis is the most common zoonosis in the world and may be an emerging infection. Among the factors most strongly associated with this infection are household use of rainwater catchment systems and contact with animal tissues and cattle.1-3
The reservoir animals retain leptospires in their renal tubules and shed large numbers of these organisms in the urine for months after infection. Humans become infected through contact with animal urine, either directly or secondarily through contaminated soil or water. During the warm seasons, stagnant waters and moist soil are common sources of infection. Infection can be acquired through cut or abraded skin, or through respiratory or conjunctival epithelium with immersion. The disease is associated with farming, abattoirs, and sewers, as well as with camping, fishing, and contact with pet dogs. It is more frequent in summer and early fall, and has a 3:1 predominance of males. Seventy percent of infections occur in individuals between 10 and 40 years of age.1-3
In general, leptospirosis is a biphasic disease that develops after a median incubation period of 1 week, with a range of 2 to 30 days. The initial phase, lasting 4 to 7 days, is the septicemic stage. There is sudden onset of fever, headache, myalgia, and gastrointestinal disturbances, such as abdominal pain, nausea, and vomiting. In this period, the organisms multiply in monocytes. Host defense depends on the cell-mediated and humoral immune responses.3
Physical examination usually reveals an acutely ill patient, who may be confused or delirious. Conjunctivitis, uveitis, pharyngeal infection, lymphadenopathy, hepatosplenomegaly, macular exanthem, and icterus may be seen. In one study, two thirds of the patients had abnormal radiographic findings in the lungs. Small nodular densities predominated, but a few patients had larger areas of consolidation. During this stage, the patient has leptospiremia and proteinuria. The fever ends by lysis. The patient may remain well and comfortable for 1 to 3 days, until the start of the second phase of the disease, which is subclinical in most patients.
In those patients who have symptoms, the second phase begins with meningitis, which may be subclinical, and with fever, which may be of a lower grade than during the first phase. CSF shows features characteristic of aseptic meningitis, with mononuclear pleocytosis, usually not exceeding 500 cells/μL, a normal glucose, and an elevated protein concentration. During this phase, the patient no longer has leptospiremia, but does have leptospiruria. Because the patient has developed antibodies to the organism by now, this phase is also sometimes referred to as the immune stage.
Ten percent of patients develop a severe form of the disease, characterized by prolonged fever, jaundice, azotemia, hemorrhage, vascular collapse, and an altered state of consciousness. The same biphasic pattern of the disease can be seen in this severe form, but the severity of symptoms and their prolongation may last well into the second phase, obscuring the signs that mark the end of the first phase. Thrombocytopenia and renal failure can develop and appear to be correlated, although a causal relationship has not been demonstrated. Other complications include acute acalculous cholecystitis, hydrops of the gallbladder, cholangitis, pancreatitis, and peripheral gangrene.4
Leptospirosis must be considered in patients with aseptic meningitis, hepatitis, generalized malaise with myalgia, and fever of undetermined origin. Those who have recently returned from tropical environments and have an illness resembling hemorrhagic fever should also be suspected of having leptospirosis. Definitive diagnosis involves demonstrating leptospires in the patient’s blood or urine by culture or by inoculation of guinea pigs, hamsters, or mice, but this method is laborious and prolonged. A rapid diagnosis can be made by determining the specific IgM using the DOT-ELISA method, which is accurate and inexpensive, and is therefore preferable to the older, commonly used microagglutinin test.5 The DOT-ELISA method is based on a series of leptospiral antigens, may be performed in a routine laboratory, and is more sensitive and easier to perform than the older method.4 A sensitive assay for Leptospira spp by a polymerase chain reaction (PCR) has been developed. It has been applied to human CSF and urine. It was positive in patients with leptospirosis and negative in uninfected controls. It is considered to be the most efficient and accurate diagnostic test. However, its interpretation should be considered in the light of epidemiologic information.6
Efficacy of antimicrobial therapy remains controversial. In one study, doxycycline was reported beneficial, especially if started early in the disease.7 Two prospective, randomized studies of therapy with penicillin have shown opposite results, one indicating definite benefit and the other no benefit.7,8 Because doxycycline may not be used in children younger than 8 years or in pregnant women, penicillin is the only choice available for these patients. Based on the study that did show benefit, therapy should be given intravenously for 7 days. In a retrospective study of severely ill hospitalized children in Brazil, treatment with penicillin or ampicillin was associated with an accelerated recovery from acute renal failure and thrombocytopenia, but not other complications or the duration of fever. More recent data suggest that the treatment of choice may be ceftriaxone.9 No human vaccine is currently available. An inactivated veterinary vaccine does not prevent leptospiruria. Therefore, vaccinated animals can still be sources of human infection.
The prognosis depends on two principal factors: virulence of the infecting organism and the age of the patient. In anicteric leptospirosis, death is virtually unknown, but in classic Weil disease with jaundice, case fatality may be as high as 20%. Mortality tends to be higher in the oldest age group and lower in children.