Leptospirosis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Leptospirosis? What should you expect to find?

The clinical manifestations of leptospirosis are variable and nonspecific. The nonspecific initial presentation and absence of a reliable point of care screening test make this disease a diagnostic challenge.

The traditional course of illness is biphasic, with an initial period of fever, myalgias, and mild symptoms that last about 1 week. During the initial phase, the patient is bacteremic. After the initial phase, also called the leptospiremic or bacteremic phase, the patient will symptomatically improve for 3-4 days. Then the patient may progress to the second phase, also called the leptospiruric or immune phase, marked by return of symptoms, presence of leptospira in urine, and potential progression to meningitis, myocarditis, renal failure, and respiratory failure.

An estimated 90% of cases are subclinical. The 5-10% of infections that cause a clinically significant illness constitutes the majority of recognized cases. If untreated, leptospirosis may rapidly progress to severe and life threatening illness.

Any patient with concern for leptospirosis should be evaluated for potential exposure. In endemic regions, exposure to unsanitary water or close contact with animal urine represents potential exposure.

Leptospirosis often presents as a febrile illness of sudden onset. Because of an incubation period of a few days to weeks (2-20 days), initial presentation may be removed from original exposure. Common initial symptoms of leptospirosis are fever, myalgias, and gastrointestinal (GI) complaints. In the majority of reported cases, the acute phase progresses to severe illness without an asymptomatic interval.

In a retrospective case series in Turkey, the most common symptoms were respiratory symptoms (72%), muscle pain (66%), and nausea and vomiting (65%). The most common physical exam findings were scleral icterus (75%), fever (61%), tachycardia (53%), and conjunctival suffusion (32%). Renal insufficiency is also a common manifestation. In another retrospective case series, 48% of patients with serologically confirmed leptospirosis presented with non-oliguric renal failure that progressed to oliguric renal failure by the fourth hospital day. Even among confirmed cases, clinical presentation is variable. Table I presents frequency of commonly reported symptoms from case series; Table II presents physical exam findings; and Table III presents laboratory findings.

Table I.

Symptoms	Cases	Respiratory(%)	Myalgias(%)	Gastrointestinal(%)	Headache(%)	Oliguria(%)
Esen et al.	72	72.1	65.7	65.3	39.4	38.0
Sejvar et al.	80	–	50	33	47	–
Katz et al.	353	–	91	73	89	26
Vickery et al.	15	27	73	58	47	53
Cengiz et al.	27	–	100	100	–	48
Ko et al.	193	–	93.8	–	74.6	–
Karande et al.	12	16.7	–	75	75	16.7
Lin et al.	23	63	48	53	61	–
Yang et al.	22	47	73	–	–	13

Table II.

Signs	Cases	Icterus /jaundice(%)	Fever(%)	Tachycardia(%)	Conjunctival Suffusion (%)
Esen et al.	72	75.0	61.1	52.9	31.9
Sejvar et al.	189	–	49	–	–
Katz et al.	353	39	99	–	28
Vickery et al.	15	13	73	67	60
Cengiz et al.	–	–	100	–	–
Ko et al.	193	92.7	93.8	–	28.5
Karande et al.	12	8.3	–	–	50
Lin et al.	23	–	100	–	22
Yang et al.	22	64	95	–	27

Table III.

Objective	Cases	Elevated Cr (%)	Elev. ALT or AST (%)	CXR abnormality (%)	Leukocytosis (%)	Thrombocytopenia (%)
Esen et al.	72	58.3	87.8	31.9	38.9	75
Im et al.	58	–	–	63.7	–	–
Katz et al.	353	54	73	–	39	58
Vickery	15	–	–	66	47	53
Cengiz	27	100	–		84	73
Karande	12	–	–	–	–	0
Lin	23	39	57	52	22	39
Yang	22	86	–	–	–	86

How did the patient develop Leptospirosis? What was the primary source from which the infection spread?

Leptospirosis is a zoonosis caused by spirochetes from the genus Leptospira spread by direct or indirect contact with urine from infected animals. Incidence of leptospirosis varies from sporadic cases in temperate climates to endemic cases in tropical climates. The spirochete infects via contact with mucous membranes or breaks in skin. Domestic and sylvatic animals, from cattle to fowl, may carry the disease, including rodent populations in urban areas. Infected animals are often asymptomatic but can develop clinical symptoms. In ungulates, it may cause spontaneous abortion.
Leptospirosis has traditionally been considered an occupational disease, seen in patients with close contact with livestock or unsanitary water; however, the past decade has seen several outbreaks in urban slums of endemic areas. Additionally, cases may appear in developed countries following travel, particularly involving water focused activities in which patients could have close contact with local animals and fresh water. Affluent travelers participating in adventure sports, such as white water rafting, hiking, and swimming, represent a growing at risk population for infection.

Which individuals are at greater risk of developing Leptospirosis?

Individuals with recreational or occupational risk factors for exposure are at risk. Occupations involving irrigation, sewage, farming, or animal husbandry are potential sources of exposure. Recreational activities involving close contact with animals, exposure to nonsanitary water, including natural rivers or lakes, or travel to endemic regions place patients at risk. The incubation period for Leptospira ranges from 2 to 20 days. If the disease is infected, the history interview should thoroughly cover at least the potential incubation period
Although traditionally associated with occupational exposure, recreational exposure and poor sanitary conditions represent a rapidly growing number of cases. Cases may appear in developed countries following travel, particularly adventure travel, in which patients could be exposed to contaminated water. Individuals who work closely with animals, those who live without basic sanitation, and individuals who travel to edemic areas and participate in recreational activities with exposure to animals or water are at risk populations.

Beware: there are other diseases that can mimic Leptospirosis:

The major diseases that can mimic the presentation of leptospirosis are Dengue fever, Malaria, Typhoid, typhus, influenza, q-fever, brucella, and ehrlichiosis

What laboratory studies should you order and what should you expect to find?

Results consistent with the diagnosis

The complete blood count (CBC) with differential is helpful in the diagnosis of Leptospirosis. In the majority of patients, the white blood cell (WBC) count will be within normal limits. Leukocytosis occurs in a significant minority, approximately 35-40%, of patients. Leukopenia occurs less frequently, less than 10% or patients. A left shift is present in approximately two-thirds of patients. Thrombocytopenia is a common finding. Pancytopenia is uncommon but is a harbinger of severe disease and poor prognosis when present.
The basic metabolic panel may reveal an elevated creatinine level, as well as abnormal electrolytes. Hypokalemia and hyperkalemia have both been reported in leptospirosis. When there is a disturbance in potassium level, this should raise concern for progression to severe disease.
Urinalysis will often be abnormal. Sterile pyuria, Hematuria, and protenuria are common abnormalities. In one case series, 72% of confirmed cases (171/239) had hematuria and 54% (124/229) had proteinuria. These findings are present during the early stage of the illness.
Elevations in transaminases are also common, but usually less than four times the upper limit of normal. More marked elevations may be seen but should raise concerns for more severe disease. Bilirubin is commonly elevated and gives the characteristic jaundiced appearance.
Cerebral spinal fluid may show pleocytosis with elevation in protein and normal glucose.

Results that confirm the diagnosis

Leptospira may be grown from blood, urine, and cerebral spinal fluid (CSF) specimens, but it requires special medium (such as Fletcher’s, Ellinghausen McCullough Johson and Harris (EMJH), or polysorbate 80) and can take between 1 week and 3 months to grow. Leptospira species stain poorly with typical cell stains and are best visualized by Dark field microscopy, fluorescent microscopy, or silver stain.
For these reasons, diagnosis of Leptospirosis requires a high index of suspicion. A sensitive and specific point of care test is effectively nonexistent for clinical practice, but efforts are being made to develop more reliable, rapid point of care tests for this disease.
IgM and IgG antibodies may be useful for diagnosis. IgM antibodies appear as early as 2 days after infection, and IgG may appear by the seventh day. Bajani and colleagues studied four commercially available diagnostic tests and microscopic agglutination testing (MAT) and found that, in the first 14 days of illness, sensitivity ranged from 38.5 to 52.7%. In the first 7 days of illness, the highest sensitivity was 40% by IgM dipstick assay (LDS). However, LDS also had the highest frequency of false positives, 21.8% in healthy volunteers.
Current preferred reference test is MAT. However, MAT is limited by logistic and clinical factors. Performance of the MAT test requires serovar-specific antigens and maintenance of live-cell comparisons. MAT may significantly under report disease because of poor quality control measures. In monitored laboratories with adequate quality control measures, the false-negative rate was 5% in one study and much greater in less monitored settings. Additionally, antibodies detectable by MAT usually only occur after day 6 of symptoms. Thus, samples from initial presentation could be falsely negative.
Conversely, in previously exposed patients, detectable titers may persist for years. Confirmation requires greater than four-fold titer increase between acute and convalescent-phase serum samples in an appropriate clinical setting. Often, collection of convalescent phase serum samples is problematic because of patient follow-up. In acute phase of illness, IgM by ELISA is more sensitive than MAT. This relationship continues up to 28 days after onset of symptoms.
Polymerase chain reaction (PCR) test depends on presence of organism DNA rather than immunoglobulins. This gives a theoretical advantage in that it would be able to detect infection prior to detectable immune response. Additionally, the test would be negative if the organism were absent, whereas immunoglobulin dependent tests can remain positive for a prolonged period of time after resolution of illness. PCR has a specificity of 96% and specificity of 99%. PCR is most accurate when taken during the acute phase of illness, as these samples are more likely to contain organisms.

What imaging studies will be helpful in making or excluding the diagnosis of Leptospirosis?

Imaging studies may be helpful in the clinical evaluation of leptospirosis but are not necessary for diagnosis. Chest X-ray (CXR) is low cost and often rapidly available. CXR may show disseminated small nodular opacities or ill-defined ground-glass opacities, which may progress to confluent areas of consolidation. The abnormalities are generally bilateral, non-lobar, and more predominant peripherally. The pathophysiology of these findings is not fully understood but is consistent with alveolar hemorrhage.

Respiratory symptoms or abnormal findings on CXR are not uncommon in patients with leptospirosis. Leptospirosis should be seriously considered in patients with pulmonary symptoms and fever, especially in subtropical and tropical areas. In addition to hepatic or renal dysfunction, respiratory symptoms could be potential presentations of leptospirosis. Im and colleagues found that rapidly evolving, nonlobar, bilateral, predominantly peripheral diffuse nodular or confluent ground-glass lesions on CXR are suggestive of leptospirosis in the appropriate clinical context. These findings may present in the first 72 hours of illness.

Ultrasound may reveal splenomegaly, hepatomegaly, or renal enlargement. A case-control study found that the kidneys of patients with confirmed leptospirosis were approximately 1.5 cm larger than control patients.

What consult service or services would be helpful for making the diagnosis and assisting with treatment?

If you decide the patient has Leptospirosis, what therapies should you initiate immediately?

Infectious Disease consultation is helpful for assistance in confirming the diagnosis and guiding management. If the patient has hemoptysis, abnormal potassium levels (hypokalemia or hyperkalemia), altered mental status, or significant comorbid medical conditions, critical care consultation should be sought early.

Oral Doxycycline 100mg oral twice a day for 7 days is the recommended treatment for mild to moderate leptospirosis. Doxycycline has been shown to reduced length of illness and decrease shedding in the urine. For severe disease, intravenous penicillin G (6 million units daily), ceftriaxone (1 gram daily), cefotaxime (1 g every 6 hours), or doxycycline (100mg every 12 hours) have been shown to be effective and therapeutically equivalent.

1. Anti-infective agents

If I am not sure what pathogen is causing the infection, what anti-infective should I order?

In areas where rickettsial infections are also endemic, treatment with doxycycline for severe disease is prudent because of coverage for both organisms. If the diagnosis is in doubt, using intravenous (IV) doxycycline and cefotaxime has been recommended (Table IV).

Table IV.

Organism	Antibiotic	Dose	Alternative
S. Pneumoniae(Pcn MIC< 0.1 ug/ml)	PenicillinCeftriaxoneCefotaxime	20-24 mil. units/d (divided Q4H)2-4 g/d (divided Q12H)12 g/d (divided Q6H)	Chloramphenicol 4-6 g/d (divided Q6H)
S. Pneumoniae(MIC > 0.1 ug/ml	Vancomycin +- rifampin	2 g/d (divided Q12H)1200 mg daily (divided Q12H)	Chloramphenicol
N. meningitidis	Penicillin	20-24 mil. units/d (divided Q4H)	CeftriaxoneCefotaxime
L. monocytogenes	Ampicillin	12 g/d (divided Q4H)4-8 mg intrathecal5 mg/kg/d systemic	Trimethoprim-sulfa15-20 mg/d (trimethroprim)(divided Q6H)
H. influenzae	CeftriaxoneCefotaxime	2-4 g/d (divided Q12H)12 g/d (divided Q6H)	Chloramphenicol

Supportive care, including IV fluid resuscitation and potassium supplementation in hypokalemia may be helpful. However, the backbone of treatment is antibiotic treatment. Leptospirosis responds well to antibiotics if correctly identified.

What complications could arise as a consequence of Leptospirosis?

What should you tell the family about the patient's prognosis?

In severe disease, chronic kidney damage is a risk. Diffuse alveolar hemorrhage can lead to respiratory failure. In most cases, these symptoms resolve with antibiotic treatment.

Most leptospirosis infections (routinely estimated as 90% of cases) result in subclinical or mild illness. However, 5-10% of infections result in multiple organ damage, clinically important manifestations in kidney, liver, and lung. Risk factors for poor outcome include altered mental status at presentation, older than 40 years of age, oliguria, and respiratory insufficiency. Mortality is usually due to respiratory, renal, or cardiac failure. Additionally, disruptions in potassium level can be a predictor of poor outcome.

Pulmonary hemorrhage is a major cause of death in severe leptospirosis. This has resulted in the recognition of severe pulmonary form of leptosipirosis (SPFL). In SPFL, respiratory symptoms, such as dyspnea and hemoptysis, develop between the fourth and sixth day of illness and may rapidly progress to death within 72 hours. The pathophysiology of the pulmonary hemorrhage effect of leptospirosis is unclear. It is currently believed that this is a manifestation of either toxin-mediated mechanisms or exacerbated host immune responses. General consensus is disseminated intravascular coagulation (DIC) is not the cause of pulmonary hemorrhage.

Reported mortality rates from recreational exposures have been lower than occupational exposures, suggesting recreational exposure portends better outcome than occupational exposure. This is likely multi-factoral with patients’ exposure to leptospirosis by recreational activities being younger and presumably having baseline better fitness and access to health providers.

How do you contract Leptospirosis and how frequent is this disease?

Leptospirosis is the most widespread bacterial zoonosis in the world. Leptospirosis occurs sporadically in temperate climates and is endemic in tropical countries. It is present in urban and rural areas and affects those in poverty and affluence. Leptospirosis has been traditionally considered an occupational disease; however, there is a growing burden in illness associated with poor sanitary conditions in the slums of tropical developing countries, as well as an increase in cases from recreational exposures. The majority of cases are sub-clinical or self-limiting. Rapid, one sample point of care testing is not currently available, making definitive diagnosis problematic and likely resulting in under reporting of disease burden.

Heavy rainfall or flooding facilitates the spread of leptospirosis. For this reason, incidence increases in wet months. Several outbreaks have been associated with heavy rains or flooding, including typhoons and hurricanes. In the United States, approximately 50-150 case were reported per year until 1995 when the disease was removed from the CDC’s list of reportable diseases.

Leptospira bacteria are spread through direct or indirect contact between urine from infected animals and breaks in human skin or mucous membranes. The most common means of indirect contact is contaminated water, soil, or other contaminated fomite. A wide range of domestic and sylvatic animals, including ungulates, fowl, and rodents, may be hosts.

What other clinical manifestations may help me to diagnose and manage Leptospirosis?

Renal Failure: In animal models, leptospirosis causes impaired proximal tubule sodium reabsorption, resulting in increased sodium delivery to the distal tubule, potassium wasting, and polyuric or non-oliguric renal failure. Although the mechanism has not been confirmed in humans, the clinical presentation can be consistent with this mechanism. This results in volume depletion and can lead to oliguric renal failure by acute tubular necrosis. Leptospira have a unique ability to rapidly penetrate host cells, which is not fully understood.

Respiratory impairment: Mechanism of lung injury in leptospirosis is not fully understood. Current thinking is that it is toxin-mediated and may involve over exuberant immune response. Radiographic findings are consistent with diffuse alveolar hemorrhage, which may progress to acute respiratory distress syndrome or SPFL. DIC is currently not thought to play a role in leptospirosis.

Jaundice: Leptospira establish and reproduce in the liver early in illness. This is facilitated by leptospira ability to rapidly disseminate and penetrate host cells. Leptospira concentration in liver and kidney tissue has been found to exceed that found in lung tissue. However, hemorrhagic pneumoniae have not been observed in the liver and kidney.

What other additional laboratory findings may be ordered?

Rapid, low cost, point of care PCR testing is a promising potential future test for leptospirosis. PCR testing is currently sensitive and specific but not widely available. The growing global burden of this disease has increased demand for accurate point of care testing.

How can Leptospirosis be prevented?

Doxycycline is the only currently recommended prophylactic medication, although definitive supportive evidence has not been shown. Because of the increasing incidence of recreational acquisition, Doxycycline 200mg PO per week 1-2 days prior to high risk recreational activity and continuing through duration of potential exposure is recommended.

Vaccination is a potential means of prevention. China and Cuba have leptospirosis vaccines available for human use, which have reported moderate efficacy. However, the protection conferred from these vaccines is limited to specific serogroups and is likely short-term. The Leptospira genus has approximately 240 serovars. This diversity causes difficulty developing a durable vaccination. The limitations of vaccination were demonstrated by a national outbreak in Cuba of a serovar not included in the vaccine. These vaccines are licensed only in China and Cuba.

WHAT'S THE EVIDENCE for specific management and treatment recommendations?

In a prospective randomized trial, Penicillin G 1.5 million units IV q6 hours and Ceftriaxone 1g daily were shown to have equivalent efficacy in treating severe, late stage leptospirosis (primary outcome time to effervescence). Median duration of fever from initiation of treatment was 3 days for both groups. No differences were observed for other complications of leptospirosis, including renal failure, respiratory failure, liver impairment, thrombocytopenia, and mortality.

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