Leptospirosis: A challenging diagnosis (2024)

Leptospirosis is a bacterial infection produced by spirochetes in the genus Leptospira. Leptospira are aerobic but are difficult to cultivate and take many days to grow. They stain poorly with Gram’s stain and are best visualized with silver stain, dark field microscopy or fluorescent microscopy.

Leptospirosis is a zoonosis and occurs worldwide, mainly in tropical and subtropical climates. Animals such as rats, mice, dogs, cattle, swine and wildlife are reservoirs for leptospirosis in terms of transmission to humans. The Leptospira cause renal infection in these animals, which persists for long periods of time (sometimes for life), and they are excreted in urine intermittently. The infected urine of the animal, especially rodents, serves as the usual vehicle for infection in humans. Leptospira are subdivided by species and by serovars. The main species that produces illness in humans is Leptospira interrogans. There are more than 250 serovars of Leptospira that can cause disease in humans.

Epidemiology

It is estimated that about 1 million cases of leptospirosis occur worldwide each year, with about 60,000 deaths. About 100 to 150 cases are reported yearly in the United States, mainly from Puerto Rico and Hawaii. However, it is safe to assume that many cases go unreported. Outbreaks are particularly likely to occur following floods, hurricanes and heavy rainfall in tropical and subtropical areas with poor sanitation. Very large outbreaks have been reported, affecting thousands of people. In industrialized countries, farmers, slaughterhouse workers, veterinarians and sewer workers are particularly at risk.

Pathogenesis

Infection occurs following exposure to fresh water or soil contaminated by infected animal urine, or exposure to the urine itself (eg, veterinarians, pets). The exposure may occur by contact with skin or ingestion of contaminated water. The Leptospira penetrate through mucous membranes or abrasions in the skin and then disseminate throughout the body. The infection causes a vasculitis with endothelial damage and hemorrhage. Focal hepatocellular necrosis may result in liver failure, and tubular epithelial necrosis may result in renal failure. Patchy hemorrhagic pneumonia may also occur.

Clinical manifestations

Many cases of leptospirosis are asymptomatic or mildly symptomatic. Symptomatic cases typically follow an incubation period of 2 to 20 days. They present as a viral-like illness usually marked by abrupt onset of fever, headache and myalgias. The headache and myalgias can be severe, and muscle tenderness may occur. In fact, during outbreaks in Salvador, Brazil, a telltale sign was severe pain when the gastrocnemius muscle was compressed. Another helpful sign is conjunctival suffusion often associated with photophobia.

PAGE BREAK

In about 10% of cases of clinical leptospirosis, the disease may present as a biphasic illness with a period of improvement followed by a second phase with recurrence of illness, which may be severe and associated with hemorrhage, pulmonary insufficiency, renal failure and/or hepatitis, which can lead to liver failure. Aseptic meningitis may also occur, becoming prominent. Combined liver and renal failure is referred to as Weil’s disease. One interesting finding in Weil’s disease is scleral jaundice combined with conjunctival suffusion, which results in a golden color of the sclera, often with hemorrhage. In the second phase of the disease, also called the immune phase, leptospiral organisms are difficult to find. Many of the manifestations of the second phase are thought to be due to immunological reactions. With severe disease, the mortality rate is between 5% and 15%.

Diagnosis

The clinical diagnosis of leptospirosis is challenging, and it can easily be missed unless there is an epidemic or the patient develops Weil’s disease.

Laboratory diagnosis of leptospirosis is difficult and usually retrospective. Serological testing for antibodies using acute and convalescent blood is the classical way of making the diagnosis. The standard test is the microscopic agglutination test (MAT), which is available only at the CDC and certain specialized laboratories. A significant rise in antibody titer in serum is considered diagnostic. A single high titer (eg, >1/800) suggests recent leptospirosis infection. Antigen detection tests have been developed and show promise for diagnosis using serum, urine or spinal fluid. PCR testing is also available at the CDC and some specialized labs. It is specific but depends on the presence of Leptospira. A negative PCR of serum, urine or spinal fluid does not rule out leptospirosis because the Leptospira are present in blood for only the initial days of infection, and in the urine, the presence of the organisms is intermittent. Leptospira are frequently absent in the spinal fluid of patients with meningitis. Although culture techniques are available, the organisms are fastidious and grow very slowly, requiring many days of incubation.

Commercially available rapid diagnostic serologic tests are available, but these are considered only screening tests, and infection should be confirmed by the MAT. The tests are of greatest use in areas with high rates of leptospirosis.

PAGE BREAK

Therapy

Therapy in the early stages of suspected leptospirosis is recommended, recognizing that few patients will have a definitive diagnosis at that time. Doxycycline (100 mg orally twice a day) is the treatment for most patients. Azithromycin or amoxicillin has also been used. For those who are severely ill, penicillin (1.5 million units IV every 6 hours) or ceftriaxone (1 g IV every 24 hours) is recommended. A Jarisch-Herxheimer reaction may occur within several hours of initiation of antimicrobial therapy. This acute reaction is believed to be an inflammatory response with release of cytokines due to the destruction of spirochetes. It is manifested by sudden onset of fever and hypotension. This happens less frequently than with syphilis — found to occur in 9% of patients with leptospirosis in one review. With severe leptospirosis, supportive care is critical, with dialysis and ventilatory support as needed. With proper supportive care, end organ damage is usually reversible.

Prevention

The primary approach to prevention of leptospirosis is avoidance of exposure to potentially contaminated sources such as flood waters. If such contact is unavoidable, barrier protection such as high rubber boots and protective gloves should be used. Control of rat and mouse populations is helpful.

Some studies have shown that chemoprophylaxis with doxycycline might be effective in preventing clinical disease and could be considered for people at high risk and with short-term exposures. The recommended dosage is 200 mg weekly for the duration of the exposure.

There are vaccines available to prevent leptospirosis in dogs and cattle, but no vaccine is available in the U.S. to prevent leptospirosis in humans. There are vaccines available for humans in some other countries.

• References:
• Budihal SV, Perwez K. J Clin Diagn Res. 2014;doi:10.7860/JCDR/2014/6593.3950.
• Bajani MD, et al. J Clin Microbiol. 2003;doi:10.1128/jcm.41.2.803-809.2003.
• CDC. Leptospirosis fact sheet for clinicians. https://www.cdc.gov/leptospirosis/pdf/fs-leptospirosis-clinicians-eng-508.pdf. Accessed October 6, 2019.
• CDC. Leptospirosis. https://www.cdc.gov/leptospirosis/index.html, Accessed October 6, 2019.
• Cunha JP, Shiel WC. Leptospirosis. emedicinehealth. https://www.emedicinehealth.com/leptospirosis_facts/article_em.htm. Accessed October 6, 2019.
• Galloway RN, et al. Traveler’s Health---Leptospirosis. Yellow Book. https://wwwnc.cdc.gov/travel/yellowbook/2020/travel-related-infectious-diseases/leptospirosis. Accessed October 6, 2019.
• Gamage C, et al. J Immunol Methods. 2018;doi:10.1016/j.jim.2018.09.006.
• Guerrier G, D’Ortenzio E. PLoS One. 2013;doi:10.1371/journal.pone.0059266.
• Xu Y, Ye Q. Hum Vaccin Immunother. 2018;doi:10.1080/21645515.2017.1405884.

• For more information:
• Donald Kaye, MD, MACP, is a professor of medicine at Drexel University College of Medicine, associate editor of the International Society for Infectious Diseases’ ProMED-mail, section editor of news for Clinical Infectious Diseases and an Infectious Disease News Editorial Board Member.

Disclosure: Kaye reports no relevant financial disclosures.