Leptospirosis: A Global Overview of an Important Zoonotic Infection

• Leptospirosis most commonly affects people from low-income populations, resulting in significant morbidity and mortality.
   
• It is estimated that the infection causes one million cases and around 58,900 deaths annually, with a fatality rate of 6.85%.

Adolph Weil first described leptospirosis in 1886 as a febrile illness with jaundice, splenomegaly, renal failure, and conjunctivitis, associated with outdoor occupations where people come into contact with water. Therefore, the severe form was called "Weil’s disease."

There are several descriptions reported much earlier, in ancient texts, that match the clinical characteristics of leptospirosis: “ cane cutter disease ” or “swineherd’s disease” in Europe, “rice field jaundice” in ancient Chinese texts, and, “Akiyami (autumn fever)” in Japan.

The causative organism was first described in 1907 by Stimson, who demonstrated the presence of spirochetes in the kidneys of a patient dying from the disease; the organism was named Spirochaeta interrogans because of the question mark shape of the organism.

Leptospires are spirochetes that live freely in aerobic environments, with characteristic hook-shaped ends, 6 to 20 μm in length, with an approximate diameter of 0.1 μm.

The surface structures of leptospires are composed of a cytoplasmic membrane and an outer cell wall of peptidoglycan, and an outer membrane cover composed of a lipid bilayer, thus showing characteristics of both Gram-negative and Gram-positive bacteria.

The organisms are motile by means of endoflagella. Only certain strains cause disease in mammalian hosts.

The taxonomy is complex. Traditionally, the genus Leptospira was divided into two species: L. interrogans (all pathogenic strains) and L. biflexa (all saprophytic strains). Currently, leptospires are in Sub-Saharan Africa, the Caribbean and Oceania.

It is common among rural and impoverished urban populations, and in semi-urban populations, particularly affecting young men.

Farmers who are in contact with livestock, those exposed to rodents in their workplace, and people who live in areas where sanitation is poor are most at risk. Recreational exposure has also been described in those who practice water sports.

Outbreaks are common in environments where sanitation is poor and rat breeding is high. Incidence rates have generally been stable globally, but numerous major outbreaks have occurred from time to time in certain countries, in some cases related to natural disasters associated with flooding.

Almost all mammals can carry leptospires and can harbor and eliminate the organisms from the proximal tubules of the kidney. The rat is by far the most important carrier responsible for human leptospirosis. This is due to the ubiquitous presence of rats in proximity to human habitats, in addition to the fact that they excrete very high concentrations of organisms, even several months after the initial infection.

The mode of transmission to humans is through abrasions on the skin and mucous membranes, which come into contact with water contaminated with the urine of infected rats. Humans are incidental hosts and are at greatest risk when working or living in environments close to the habitats of keeping hosts, especially rats and farm animals.

Effective control of leptospirosis is difficult due to 2 epidemiological characteristics. First, leptospires are capable of developing a symbiotic relationship with many animal hosts, in which the organisms persist in the renal tubules for a long time, shedding bacteria in the urine without causing disease in the host. Second, wild animals provide an important reservoir, continually reinfecting domestic animals.

Human leptospirosis has various clinical manifestations. The clinical presentation in humans can range from a mild, self-limiting acute febrile illness to a life-threatening severe condition with multiple organ dysfunction. Many organ systems may be involved to varying degrees, with a number of atypical or unusual manifestations; Complications have also been described.

The clinical features of leptospirosis are similar to those seen in many other febrile diseases, especially tropical diseases, such as dengue and other hemorrhagic fevers, such as rickettsiosis, malaria, and bacterial sepsis. Although the majority present without febrile complications, almost 10% develop severe illness.

The classic presentation is Weil syndrome consisting of conjunctival sufusion, jaundice and acute kidney injury. Pulmonary hemorrhage has recently been shown to be an important cause of mortality. The incubation period shows a wide variation, from 2 to 20 days, usually 7 to 12 days. A biphasic disease is seen in some patients.

The clinical course of leptospirosis has classically been divided into a “ leptospyremic phase” or acute phase, followed by a second “immune phase” .

The initial “leptospyremic phase” is said to last 3 to 9 days, and presents as an acute, nonspecific febrile illness.

There is fever, chills, myalgia and headache. Conjunctival sufusion is a characteristic finding, developing on the third or fourth day. Myalgia can be severe and is usually located in the calves, abdomen (mimicking acute abdomen), and paraspinal muscles (resulting in meningismus). The “leptospyremic” or “septicemic” phase is followed by the immune phase, with the appearance of IgM antibodies, and the excretion of organisms in the urine.

It is presumed that during this phase, the organisms settle in higher concentrations in the proximal tubules of the kidney and other organs). Depending on the degree of involvement of the organs and the virulence of the organism, serious manifestations occur in this context.

In practice, this differentiation into phases is arbitrary, and, while there may be a brief period of defervescence between these phases, the two often overlap. Until most patients recover, a small number have persistent high fever and develop jaundice, acute kidney injury, and other serious organ dysfunction.

The pathogenesis of severe leptospirosis is poorly understood. It is believed to be due to a form of vasculitis. As with other bacterial infections, both direct tissue damage by leptospires and immune-mediated mechanisms are responsible for tissue and organ damage, tissue microcirculation, and endothelial dysfunction. Although jaundice is a prominent feature, death usually results from complications of acute kidney injury, myocardial compromise, or pulmonary hemorrhage.

Along with lung involvement, in extreme forms with pulmonary hemorrhage, other hemorrhagic manifestations and myocarditis are important, causing high mortality.

Countless atypical or unusual manifestations have been reported , including nervous system involvement (acute disseminated encephalomyelitis, intracranial hydrocephalus and hypertension, encephalitis-induced coma, intracranial vascular events, intracranial hemorrhage and thrombosis, cerebellar syndrome, transverse myelitis, Guillain-Barré syndrome, mononeuritis and mononeuritis multiplex including cerebral palsy); ocular manifestations (uveitis, optic neuritis, retinal phlebitis); hematological disorders (pancytopenia, hemolytic anemia, hemolytic uremic syndrome and thrombotic thrombocytopenic purpura) and gastrointestinal involvement (pancreatitis, cholecystitis).

The diagnosis of leptospirosis is largely based on clinical suspicion, with a history of risk exposure.

Leptospirosis should be suspected in any patient with a history of exposure to risk and any of the following symptoms or signs: headache, myalgia, prostration, jaundice, conjunctival suffusion, oliguria, signs of meningeal irritation, hemorrhage, heart failure or arrhythmia, cough , dyspnea, skin rash or any other evidence of organ involvement or dysfunction.

There are many diagnostic tests available for leptospirosis, although availability is lower in resource-poor settings. Diagnostic accuracy is also variable, especially for serological tests. Cutoff values ​​for seropositivity in a single sample are likely to depend on regional seroprevalence.

Results may be further confounded by cross-reactivity with other infections. Broadly speaking, diagnostic tests are divided into those that provide direct evidence of infection (demonstration of leptospires or their DNA or culture) and tests that provide indirect evidence of infection (demonstration of anti-leptospire antibodies).

Patients with suspected or confirmed leptospirosis, with mild clinical symptoms and no comorbidities can be managed on an outpatient basis, with regular follow-up to detect complications. Patients with clinical evidence of organ involvement, or those with comorbidities, should be hospitalized. Early initiation of antibiotic treatment is likely to improve outcome.

For mild disease (i.e., no organ involvement):

• Administer doxycycline 100 mg, 2/day for 7 days.

• Do a complete blood count; determine C-reactive protein, creatinine, urea, electrolytes, transaminases.

• Bilirubin, complete urine report.

• Control diuresis.

• Review every 48 hours.

• Hospital admission if there is jaundice, oliguria, hematuria, cough or dyspnea, or if clinically very ill.

For those who require hospital admission:

• Do the following investigations: complete blood count, C-reactive protein, creatinine, urea, electrolytes, transaminases, bilirubin, complete urine report, coagulation tests and blood chart (to identify disseminated intravascular coagulopathy), ECG, chest x-ray.

• Start intravenous antibiotics: penicillin G 1.5 million units every 6 hours or ceftriaxone 1 g, 2/day for 7 days. For those with an allergy to penicillin or cephalosporin, prescribe doxycycline or a macrolide (azithromycin or clarithromycin).

• Control fluid intake and diuresis.

• Fluid intake according to the clinical level of hydration. In adults, intake should be around 2.0-2.5 liters/24 hours.

• If oliguria is present, the daily intake should be equal to the previous day’s urine output plus the estimated insensible loss (generally about 500 ml). If the previous day’s output is not known, the hourly intake should be calculated as the previous hour’s urine output plus 25 ml.

• All nephrotoxic and hepatotoxic drugs should be discontinued. Anticoagulant and antiplatelet medications may need to be discontinued if hemorrhagic manifestations are present.

• Patients in critical condition (hemodynamic instability, respiratory compromise, hemoptysis, reduced consciousness, or other signs of organ dysfunction) require care in a high dependency or intensive care unit.

• Those who require intensive care should be managed in accordance with standard protocols and guidelines for the management of critical conditions.

• Mechanical ventilatory support may be required, especially in cases of pulmonary hemorrhage and acute respiratory distress syndrome.

• The use of high doses of corticosteroids for the treatment of leptospirosis is not supported by high-quality evidence, and its routine use is not recommended. There are reports of possible adjuvant benefits with high doses of corticosteroids in severely ill patients.

• Plasmapheresis has been used in severe leptospirosis; Some non-randomized trials show benefits, but the evidence is low quality.

Supportive care and antibiotics remain the mainstay of leptospirosis management, and there are still no therapies that influence the outcome.

Prevention of leptospirosis is done by avoiding exposure to potential infection, and by using pharmacological prophylaxis in high-risk individuals.

It is recommended to start doxycycline 200 mg weekly, 1 week before exposure, continuing during the exposure period.

There is currently no vaccine available for humans.

Currently, there are no reliable scoring systems or predictive models to determine which leptospirosis patients are most likely to develop severe disease. This is an area for future research.

The pathogenesis of severe leptospirosis is poorly understood and basic science research should focus on identifying biomarkers of severity and possible target therapeutics.

More randomized trials are required to evaluate potentially beneficial interventions that could prevent progression to the severe phase of the disease.