Leptospirosis: Minimum Essential Information

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Key messages:

Introduction

Leptospirosis is a bacterial infection caused by bacteria of the genus Leptospira that affects both humans and animals.

It occurs worldwide, but is endemic in tropical and sub-tropical regions (most countries in the South-East Asia; China; Africa; South and Central America). Outbreaks have been reported from Nicaragua, Salvador, Brazil. In India, only four states report more than 500 cases per year– Kerala, Gujarat, Tamil Nadu and Maharashtra. The disease has been reported from all districts of Kerala, and is the leading infectious cause of death in the state. Tamil Nadu and Andamans are also endemic for Leptospirosis.

Risk factors and Transmission pathways

Animals (domestic and feral) are the reservoir of infection. Disease transmission occurs through contact of mucous membranes (or broken skin) with water (immersion or swimming), moist soil or vegetation contaminated with the urine of infected animals. Sometimes infection occurs through inhalation/ingestion of droplet aerosols of fluids/food contaminated by urine.

Epidemiological Risk Factors

Incubation period:

Range: 2 to 30 days

Usual: 10 days

Pathophysiology

The pathophysiology of Leptospirosis is not well understood. Nevertheless, the following mechanisms are suggested:

Penetration of tissue barriers and entry into body–> Hematogenous dissemination (very high levels of leptospiremia noticed)–> Inability of Human TLR4 to recognize leptospiral lipopolysaccharide (LPS)–> tissue and systemic responses to infection–> Cytokine storm (in patients with severe disease), with raised levels of IL-6, IL-10, TNF-alpha–>

Inhibition of protective Th 1 immune response (due to overproduction of IL-10)–>

Hepatocellular damage and disruption of hepatocyte intercellular junctions–> leakage of bile into sinusoidal blood vessels (rise in direct bilirubin)
Leptospirosis-induced hemolysis
Pulmonary hemorrhage
Renal involvement: mild nonoliguric renal dysfunction (due to decreased expression of sodium-hydrogen exchanger 3–> decreased absorption of sodium and fluid by proximal tubule) to complete renal failure (Weil’s syndrome)

Clinical Features and classification of disease:

Leptospirosis has many non-specific signs and symptoms, making clinical diagnosis difficult. Severe disease is also known as ‘Weil’s Disease’, and can be fatal.

Approximately 90% of clinical illnesses present as a nonspecific acute febrile illness, while approximately 10% progress to severe, potentially fatal illness with multi-organ dysfunction.

Illness may be biphasic, with the patient briefly recovering from mild illness, but then developing more severe illness.

Severe calf tenderness and conjunctival suffusion though pathognomonic, are not present in all patients.

Leptospirosis during pregnancy can cause fetal
complications including fetal death or abortion.

The case fatality rate for leptospirosis is approximately 5%–15% among patients with severe illness. Among patients with severe pulmonary hemorrhagic syndrome, the case fatality rate can exceed 50%.

Note: All the clinical features either decrease or disappear within two to three days and then they reappear and may progress to severe disease.

Diagnosis:

There are several approaches to diagnosis.

I. World Health Organization recommended approach for resource-poor settings (Modified Faine’s criteria):

The Modified Faine’s criteria (2012) includes clinical data (Part A), Epidemiological factors (Part B), and Laboratory findings (Part C). Each criterion is assigned a score (Any one of the laboratory tests is scored, not multiple tests), and a total score of more than 25 is required to make a presumptive diagnosis of Leptospirosis.

The performance of the Modified Faine’s Criteria (2012) has been evaluated by Bandara et al, and is as under:

II. Diagnostic guidelines of the WHO South East Asia Regional Office and India’s National Guidelines for Leptospirosis:

Note: the two Guidelines are similar, not identical.

The case definition has three categories

A. Suspect (Only clinical features):

Acute febrile illness (≥ 38.5°C) and/or severe headache with:
– Myalgia
– Prostration and/or
– Conjunctival suffusion
– History of exposure to leptospira-contaminated environment

B. Probable (Clinical features + Rapid diagnostic tests):

At Primary Health Care level

Suspect case with any two (*one according to India’s National Guidelines) of the following:
– Calf tenderness
– Cough with or without hemoptysis
– Jaundice
– Hemorrhagic manifestations
– Meningeal irritation
– Anuria/oliguria and/or proteinuria
– Breathlessness
– Cardiac arrhythmias
– Skin rashes

At Secondary and Tertiary Health Care levels

Suspect case with a positive rapid IgM test And/Or

Supportive serologic findings (i.e. a MAT titer equal to 200 in a single sample) And/Or

Any three of the following:
– Urinary findings: Proteinuria, pus cells, blood
– Relative neutrophilia (> 80%) with lymphopenia
– Platelets less than 100,000/cu mm
– Elevated serum bilirubin more than 2 mg%; liver enzymes moderately raised (Serum alkaline phosphatase, S amylase, CPK).

C. Confirmed (Clinical features + positive MAT/PCR/Culture)

Suspect/ Probable case with any of the following

• Isolation of leptospires from clinical specimens
• Positive PCR result
• Seroconversion from a negative to positive or fourfold rise in titer by MAT
• Titer by MAT of 400 and greater in a single sample.

Where laboratory capacity not well established:
Positive by two different rapid diagnostic tests could be considered as laboratory confirmed case.

Note: Case definitions do not indicate or reflect severity of disease.

Laboratory diagnosis

Approaches

Laboratory diagnosis based on duration of illness

Differential diagnosis

Differential diagnoses of leptospirosis include

influenza
pneumonia
arboviral infections (ie dengue, chikungunya, Zika virus, Ross River virus)
malaria
typhoid
rickettsia
Q fever
acute viral hepatitis
pyelonephritis and
meningitis.

Haemorrhagic complications can also mimic meningococcaemia or severe dengue.

Co-infections have also been reported, particularly in post-flooding settings, when outbreaks of multiple diseases (eg leptospirosis, dengue, typhoid) can occur at the same time.

Case Management

Primary Health Care level (Leptospirosis endemic areas)

Clinically suspected Leptospirosis/ Mild disease and rapid immunodiagnostic test positive cases/ Clinically stable patients with negative ELISA and negative rapid immunodiagnostic test:

Adults: Doxycycline 100 mg twice a day x 7 days
Pregnant and lactating mothers: Cap. Ampicillin 500 mg every 6th hourly

Children <8 years: Amoxycillin/ Ampicillin 30-50 mg/kg/day in divided doses x 7 days

Screen all cases of suspected Leptospirosis by rapid immunodiagnostic test (will require confirmation by ELISA)

Referral

All suspected leptospirosis cases whether positive or negative with rapid immunodiagnostic test having feature of organ dysfunction as follows should be IMMEDIATELY shifted to higher centre.

Hypotension
Decreased urine output (<400ml per day)
Jaundice (serum bilirubin >3.0 mg%)
Haemoptysis or breathlessness
Bleeding tendency
Irregular pulse
Altered level of consciousness

While shifting patients to higher centre, individual patient’s record should be furnished in the following order

Age,
Sex
Occupation
Clinical symptoms
Date of onset of clinical symptoms
Serological result
Hospitalization details-treatment given and outcome

Secondary Health Care level

Case management same as at Primary Health Care level.

Referral

All suspected leptospirosis cases whether positive or negative with rapid immunodiagnostic test having feature of organ dysfunction as follows should be
IMMEDIATELY shifted to higher centre.

Renal :

Decreased urine output (< 400 ml per day)
High blood urea (> 60 mg. % )
High S. Creatinine (> 2.5 mg% )
Clinical features of uremia, breathlessness, convulsion, delirium, and / or
altered level of consciousness

Hepatic :

Jaundice
High S. Bilirubin(>3.0m.g. %)

Pulmonary :

Breathlessness
Haemoptysis
Increased respiratory rate
X- ray chest showing opacities

Blood :

Bleeding tendency
Low platelet count

Neurological :

Altered level of consciousness

Tertiary Health Care level/ Medical College

Any case of fever in leptospira endemic areas during monsoon and post-monsoon season should be
administered antibiotics as follows

Adults:

Doxycycline 100 mg twice a day for seven days

Inj. Crystalline penicillin 20 lacs IU IV every 6 hourly after sensitivity test.

(For the individuals who are sensitive to penicillin group of drugs following alternative regimes may be used)

Ceftriaxone 1 gm IVx 6 hourly for 7 days
OR
Cefotaxime 1 gm IVx 6 hourly for 7 days
OR
Erythromycin 500 mg IVx 6 hourly for 7 days

Pregnant & lactating mothers should be given capsule ampicillin 500 mg every 6 hourly.

Children< 8 years:

Amoxycillin/ Ampicillin 30-50 mg/kg/day should be given in divided doses for 7 days

Inj. Crystalline penicillin should be given 2–4 lacs IU/kg/ day for 7 days.

(For individuals who are sensitive to penicillin group of drugs following alternative regimes may be used)

Ceftriaxone 50-75 IVmg/kg/day for 7 days
OR
Cefotaxime50-100 IVmg/kg/day for 7 days
OR
Erythromycin 30-50mg/kg/day in divided dose for 7 days

In disease progression multiple organs such as kidney, liver, lungs , CVS and CNS may be involved. The management of organ involvement does not differ from that of non-leptospirosis causes.

Note 1: Jarish–Herxheimer reactions can occur one to 48 hours after starting antibiotics. Common features include sudden onset of shivers or rigors, fever and hypotension. Jarish–Herxheimer is caused by an acute inflammatory response mediated by the release of large amounts of cytokines in response to the sudden and rapid death of Leptospira.

Note 2: A Cochrane Systematic Review concluded that

“Insufficient evidence is available to advocate for or against the use of antibiotics in treatment of leptospirosis
Among survivors who were hospitalized for leptospirosis, use of antibiotics may have decreased duration of clinical illness by two to four days (not statistically significant).
It is possible that penicillin therapy for severely ill patients may increase the risk of death or dialysis compared to those not receiving antibiotics.
There does not seem to be any difference between the appropriate use of IV penicillin, IV cephalosporin, doxycycline or azithromycin.”

The major limitation is the lack of good quality studies investigating the matter. Therefore, a lack of evidence cannot be taken as evidence of no effect (of antibiotics).

Prevention and Control

Personal protection: Avoidance of direct and indirect contact with animal urine is recommended.

Health education: Create awareness about the disease and its prevention.

Rodent control: This should be completed in the pre-monsoon months

Chemoprophylaxis

Doxycycline 200 mg, once a week for 6 weeks, never for more than 8 weeks may be given.

Note: A Cochrane Systematic Review concluded that

“Regular use of weekly doxycycline 200 mg oral therapy has unclear benefit in reducing Leptospira seroconversion or clinical consequences of infection.
It has increased odds for nausea and vomiting, but the medication had to be stopped only in a few (study) participants.
If it is effective in reducing disease, it may be more so in travellers rather than residents of an endemic area.”

Due to this, routine use is not recommended, but may be considered

if short-term intense exposures are anticipated (soldiers, outbreak response personnel, recreational exposure)
or after high-risk exposures (floodwaters).

References and Further Reading:

National Guidelines for Leptospirosis (India) (English) [PDF]:

Click to access File558.pdf

Cochrane Systematic Review on antibiotic use in Leptospirosis:

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD008264.pub2/full

Cochrane Systematic Review on antibiotics to prevent Leptospirosis:

https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD007342.pub2/full

CDC fact sheet on Leptospirosis:

Click to access fs-leptospirosis-clinicians-eng-508.pdf

World Health Organization (WHO) document on Leptospirosis:

Click to access Leptospirosissurveillance.pdf

Article on varied presentations of Leptospirosis: