LEPTOSPIROSIS

an update
Dr.T.V.Rao MD

11/27/2010

Dr.T.V.Rao MD

Leptospirosis
Leptospirosis [lep-to-spy-RO-sis].
What is Leptospirosis?
Leptospirosis is a potentially serious illness that can effect many parts of the Body. Leptospirosis is commonly caused by Leptospira interrogans, a corkscrew-shaped bacterium (spirochete).
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What is Leptospirosis?
Leptospirosis, also known as canicola fever, hemorrhagic jaundice, infectious jaundice, mud fever, spirochetal jaundice, swamp fever, swineherd's disease, caver's flu or sewerman's flu, is a bacterial infection resulting from exposure to the Leptospira interrogans bacterium. There is an acute form of human infection known as Weil's disease, where the patient suffers from jaundice, though this term is often (incorrectly) used to describe any case of infection..
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CDC Definition of Leptospirosis Clinical description

An illness characterized by fever, headache, chills, myalgia, conjunctival suffusion, and less frequently by meningitis, rash, jaundice, or renal insufficiency. Symptoms may be biphasic.

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Leptospirosis is still less understood Disease

Leptospirosis is a zoonotic disease that has emerged as an important cause of morbidity and mortality among impoverished populations. One hundred years after the discovery of the causative spirochaetal agent, little is understood about Leptospira spp. pathogenesis, which in turn has hampered the development of new intervention strategies to address this neglected disease
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Epidemiology
In 1886, Weil, a German doctor observed 4 cases of Leptospirosis with jaundice, than this disease is called as Weil disease In China: in 1937, Professor Tang zeguang discovered Leptospirosis in Guangzhou

Early History
The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice and nephritis". Leptospira was first observed in 1907 from a post mortem renal tissue slice. In 1908, Inada and Ito first identified it as the causative organism and in 1916 noted its presence in rats.

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Dr.T.V.Rao MD

Leptospirosis - Zoonosis
Leptospirosis is an acute anthropo-zoonotic infection of worldwide significance caused by spirochete Leptospira interrogans which has 23 serogroups and >200 serovars. Various factors influencing the animal activity, suitability of the environment for the survival of the organism and behavioural and occupational habits of human beings can be the determinants of incidence and prevalence of the disease.
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Leptospirosis A Major Zoonotic Infection

Weil's disease is comparatively rare, though 'mild' cases of Leptospirosis happen everywhere there are carriers, and it is believed that Leptospirosis is one of the most common zoonotic infections in the world. Millions of people are infected each year, but information and treatment can be limited, especially in the developed world where cases are considered 'rare' by the medical community.
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Leptospirosis can be a Serious Health Problem

Leptospirosis, an infectious disease with a wide global distribution, has been by and large neglected as a serious health problem till recently. The increasing reports of outbreaks and clusters of cases, particularly from Southeast Asia and North and Central American countries, has brought attention to the public health problem posed by this spirocheatal infection
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INDIA
The first of its kind in India was reported in the 1920s from Andaman and Nicobar Islands. In 1993, a serosurvey of conservancy workers in Madras (using MAT) revealed a prevalence rate of 32.9%. In 1994, an increase in the number of individuals with uveitis was noted at Aravind Eye hospital, Madurai, India after an epidemic of leptospirosis in South India; the epidemic followed severe flooding of the Tamil Nadu District in the autumn of 1993 In 1995, a seroprevalence rate of 12% leptospirosis was found among febrile and jaundice patients in Pondicherry

Major reports on Leptospirosis India

The first of its kind in India was reported in the 1920s from Andaman and Nicobar Islands. In 1993, a serosurvey of conservancy workers in Madras (using MAT) revealed a prevalence rate of 32.9%. In 1994, an increase in the number of individuals with uveitis was noted at Aravind Eye hospital, Madurai, India after an epidemic of leptospirosis in South India; the epidemic followed severe flooding of the Tamil Nadu District in the autumn of 1993 In 1995, a seroprevalence rate of 12% leptospirosis was found among febrile and jaundice patients in Pondicherry

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Animals spread Leptospirosis

Rats, Mice, Wild Rodents, Dogs, Swine, Cattle are principle source of infection The above animals excrete Leptospira both in active infection and Asymptomatic stage The Leptospira survive and remain viable for several weeks in stagnant water.

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Leptospirosis Reservoir (Maintenance Host)

Cattle Cats (rare) Dogs Horses Pigs Rodents Wildlife (opossum, raccoons, skunks and many other species)
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What causes Leptospirosis

Leptospirosis is a bacterial disease that affects humans and animals. Leptospira bacteria are found worldwide and there are many different types or serovars capable of causing disease. Disease caused by Leptospira bacteria is most common in temperate or tropical climates and appears to be rare in North America.

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Pathogenic strains x Non pathogenic Leptospirosis

There are several species of Leptospira only few are pathogenic to Humans, rest to some Animals and Many in Nature as saprophytes Leptospira Interrogans is Pathogenic there are 200 serovars. Leptospira biflexa Non Pathogenic there are 60 serovars Further classifications are made on shared antigens

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Morphology
The Leptospira appear tightly coiled thin flexible Spirochetes 5 15 microns long. Fine spiral of 0.1 0.2 microns One end appears bent forms a hook. Actively motile Can be Seen with dark field Microscopy.

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Important species in Leptospirosis

The genera Leptospira contains three species,

namely L interrogans, L biflexa and L parva. The first includes 23 serogroups and more than 250 serovars and is the principal cause of leptospirosis in humans and animals. most common being L. canicola, L. hardjo and L. hebdomadis.

Two types of leptospirosis: 1. Anicteric leptospirosis or self-limited illness (85% to 90% of the cases) 2. Icteric leptospirosisor weils syndrome (5% to 10)

Antigenic structure
All isolates of L.inttterogans from different parts of the world are serologically related and exhibit cross reactions in serologic tests. Overlapping of Antigens do occur in different species. Outer envelop contains large amount of Lipopolysaccharides ( LPS ) Antigenic structure varies from one strain to other This variation forms the basis of serologic classification

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Genome of Leptospira
L. interrogans serogroup Icterhaemorrhagiae consists of a 4.33 megabase large chromosome and a 359 kilo base small chromosome, totalling 4,768 predicted genes. A series of genes have been discovered that could potentially be related to adhesion. This genome differs from the two other pathogenic spirochete (Treponema palladium and Borrelia burgdorferi), though some similar genes are visible (CHGC, 2004).

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Epidemiology - Occupation
Certain occupational groups such as agriculture workers in rice and cane fields, miners and sever cleaners are potential victims

Pathogenesis
Skin,mucous membranes leptospira Type of Influenzatyphoid fever Pulmonary Hemorrhage ieterohemorrhage Renal failure Meningoencephalitis

Blood stream

leptospiramia Hemorrhagic pneumonitis Hepatitis

Organs

Interstitial nephritis Meningitis and Encephalitis

Leptospirosis
Pathogenesis
Leptospires penetrate mucous membranes or abraded skin and multiply rapidly upon entering the blood stream. They spread to the kidney, liver, spleen, central nervous system, eyes and genital tract. Initial antibody response clears most organs except the kidneys where the infection can remain and be shed for weeks to months. Leptospirosis causes a severe vasculitis with endothelial damage. Kidney damage, shock, heart damage with arrhythmias. Liver damage with icterus and low vit k levels Eye disease-Uveitis*

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Pathogenesis
Leptospira are present in the water bodies Enter through breaks in the skin ( cuts and abrasions) and mucous membranes Enters through Mouth Nose Conjunctive Rarely enters though ingestion. Incubation period 1 2 weeks When multiples blood stream produces fever. May establish organ involvement in Kidney and Liver, May produce hemorrhage and necrosis in the tissues and initiates dysfunction of these organs
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Pathology
The basic pathological finding is infectiousinfectious-toxic lesion of the systemic capillary In some cases severe damage can be seen in the organs and tissues

Liver: cellular infiltration around the portal area Kidney: Interstitial nephritis Lung: pulmonary congestion and hemorrhage Brain: perivascular cuffing

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LEPTOSPIROSIS
Clinical features incubation period: 7-14 days biphasic commonly involves CNS, kidneys, and liver often misdiagnosed as hepatitis or meningitis petechial rash, morbilliform or urticarial in appearance - in 10-30%of cases within first 2 days, sometimes pruritic

LEPTOSPIROSIS
Clinical features acute leptospiremia phase abrupt onset of fever severe headache muscle pain nausea jaundice in more severe cases symptoms persist for up to 7 days

Incubation period: Biphasic illness. 2 to 20 days (~ 10).

Fever, chills and rigors. Myalgia (calf & lumbar0 Conjunctival suffusion. GI symptoms. Lymphadenitis, hepatosplenomegaly. Leptospires isolated in blood/CSF. Aseptic meningitis retro-orbital headache and photophobia. CSF neutrophilic pleocytosis
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Coincides with appearance of antibodies. Aseptic meningitis. Rash and uveitis.. Haemorrhagic pneumonitis. Hepato renal damage. Death due to MOF / pulm hge. Leptospires isolated in urine/aqueous humor/kidney. Aseptic meningitis headache/vomiting. CSF lymphocytic pleocytosis Lepto PCR negative.

Lepto PCR positive.

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Clinical Manifestations
Type of Influenza-typhoid fever 3 Symptoms:
Chills and Fever Myalgia Fatigue

3 signs:
Conjunctival suffusion Calf muscle tenderness Enlargement of lymph nodes

May present with

Jaundice Hemorrhage Nitrogen retention The Illness is Biphasic with initial temperature when the second phase comes with raise of IgM titers raise Aseptic meningitis initial headache, stiffness of neck, pleocytosis of Cerebro spinal fluid

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Clinical Manifestations
Complicated clinical manifestations One serotype can result in many kinds of clinical manifestations One clinical type can be caused by many serotypes Clinical manifestations vary greatly in different patients Incubation period: 7-13 days(2-28d)

Weils syndrome is said to be present when the following clinical feature are present:
Altered sensorium Acute renal failure Myocarditis and hypotension Pulmonary hemorrhage Features of acute hepatic failure

Weils Syndrome
Weil's syndrome is a severe form of Leptospirosis that causes a continuous fever, stupor, and a reduction in the blood's ability to clot, which leads to bleeding within tissues. Blood tests reveal anaemia. By the third to sixth day, signs of kidney damage and liver injury appear. Kidney abnormalities may cause blood in the urine and painful urination. Liver injury tends to be mild and usually heals completely.

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Hepatitis - Leptospirosis
Hepatitis is the frequent complication Elevation of serum creatine phosphilipae enzyme raise differentiates from Viral hepatitis where the enzyme is not raised

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Renal manifestations
Some form of renal involvement is invariable in Leptospirosis. It usually occurs as asymptomatic urinary abnormality in the form of mild proteinuria with few casts & cells in the urine. Severe renal involvement in the form of acute renal failure, (which occurs in icteric Leptospirosis) is rare.

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Nephritis - Leptospirosis
Kidney involvement in animals produce chronic disease of the kidney and the infected animal starts shedding large number of Leptospira and main source of environmental contamination of bacteria and results I human infections Human urine also contain Spirochetes in the second and third week of infection

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Presenting with Jaundice is significant and Important, Serious Manifestation

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May present with Major Complications

Nephritis Hepatitis. Manifestations in eye Muscular lesions Many infections are mild and subclinical

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Ocular manifestations
Conjunctival suffusion / hemorrhage Late complication Anterior uveal tract inflammation Iritis / Iridocyclitis / chorioretinitis occurs 2 weeks 1 yr (6 months)
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Pulmonary manifestations
Manifested in most cases through cough & chest pain and in few cases by hemoptysis. Severe involvement leading to respiratory failure does not occur in anicteric leptospirosis
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Clinical Manifestations
Type of pulmonary hemorrhage
1 Type of mild hemorrhage

Cough and hemoptysis A little bit of moist rale can be heard Dot Dot-like or small nodular densities in chest X X-ray Prognosis is fine if treatment is given in time

COMPLICATIONS can be Life Threat

Azotemia Oliguria Hemorrhage Purpura Hemolysis Gastrointestinal bleeding Hypoprothrombinemia and Thrombocytopenia

Differential Diagnosis
Influenza Meningitis (encephalitis) Viral hepatitis Rickettsiosis Typhoid fever Septicemia Toxoplasmosis Legionnaires disease If with jaundice during or after an acute febrile illness, Malaria,septicemia, alcoholic hepatitis and typhoid fever

Leptospirosis High Risk Situations.

High Risk Situations. Swimming and scuba diving. Kayaking and canoeing. Sailing, windsurfing, fishing and skiing. Caving and underground exploration. Cleaning and jetting operations. Animal handling, control and management.
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Medical professionals Guidance Leptospirosis

The infection is extremely easy to miss in initial stages; often the symptoms are misdiagnosed as influenza, viral illness or Pyrexia of unknown origin. Patients often ignore the significance of their symptoms unless prior education. To allow for correct diagnosis the patient must inform of having any potential or prior contact with affected areas.

Other Facts on
Leptospirosis
An infection from one strain will provide immunity but only to that strain. Exposure to other strains will still cause infection. It is usual for more than one strain to exist within a specific population of infected animals. Immunity to one type is no great advantage to reducing your risk

Laboratory Diagnosis
Specimens
1 Blood to be collected in

a heparin tube 2 CSF, Tissues Microscopic examination 3 Urine to be collected with great care to avoid contamination 4 Serum for agglutination tests
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Laboratory Diagnosis
Laboratory diagnostic tests are broadly divided into two categories via, direct evidences (isolation of organism or demonstration of leptospires or amplification of specific fragment of leptospiral DNA) and indirect evidences (detection of antibodies to leptospires).

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Laboratory Diagnosis
Alternatively, the different methods used in the laboratory can be categorized into bacteriological, microscopic,
immunological/serological and molecular techniques.
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Diagnosis
Direct visualization of leptospires in blood (early phase) or urine (late phase) by dark field microscopic examination
Low sensitivity (40.2%) and specificity (61.5%) Need special media (Fletcher's, Ellinghausen's, polysorbate 80) Takes 2-3 weeks to be positive

IgM antibodies appear in late phase (5-7 days)

Microscopic agglutination test (MAT), ELISA Titer >1:100 helps, but fourfold rise in titer is diagnostic (need convalescent sample)

Microscopic Agglutination test

Serial dilutions of patients sera are reacted with live suspensions of leptospiral serovars The MAT is ready by dark- field microscopy Tightly agglutinated clumps of leptospires are seen in cases of positive sera The end point is the highest dilution of serum at which 50% agglutination occurs The end point is determined by presence of approximately 50% free, unagglutinated leptospires compared to the control suspension Considerable effort is required to reduce the subjective effect of observer variation, even within laboratories.

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Microscopic Agglutination Test MAT

The MAT is a complex test to control, perform and interpret. Live cultures of all serovars required to be tested have to be maintained The range of antigens used should include all locally common serovars Cut-off depends on prevalence of antibodies in the population Paired sera (at 2 weeks interval) are required to confirm a diagnosis with certainty
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Serological tests MAT

Microscopic agglutination test (MAT) is the benchmark test for serodiagnosis of leptospirosis. It is complex and time consuming. But it is an invaluable tool not only for diagnosis, but for epidemiology and serological characterization of leptospiral isolates.

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Culturing of Leptospira
Leptospira grows best under aerobic conditions at 280 to 300c best demonstrated in Semisolid agar media Optimal Media Fletchers Media Stuarts Media Optimal growth after 1 2 weeks
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IgM ELISA
Use broadly reacting antigen Serogroup cannot be identified Positive earlier than MAT Ready made reagents with long shelf-life Need ELISA reader and washer. Many commercial kits are now available to detect IgM antibodies by plate ELISA e,g. Serion classic, Panbio

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Early and Prompt Diagnosis is Highly Essential

The development of simpler, rapid assays for diagnosis has been based largely on the recognition that early initiation of antibiotic therapy is important in acute disease but also on the need for assays which can be used more widely.

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Monitoring of the following laboratory parameters is essential:

WBC and platelet counts Blood urea and serum creatinine Serum electrolytes Electrocardiogram for Myocarditis Serum Amylase for pancreatitis

Emerging Trends in Molecular Diagnostic Methods

Several PCR-based DNA fingerprinting methods have become popular and are being used routinely for characterization of leptospires. Random amplified polymorphic DNA (RAPD) fingerprinting, arbitrarily primed PCR (APPCR), single nucleotide polymorphism of specific PCR products are some of the examples. REP-PCR (repetitive extragenic PCR) and FAFLP (fluorescent amplified fragment length polymorphism) are recent methods in the characterization of leptospires.

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Epidemiology
Leptospirosis causes several animal infections Most wide spread zoonotic infection in Nature Human infections are accidental associated with contamination of water, other materials contaminated with excreta and animal flesh. Animal carriers often excrete up to 100million Leptospirosis per ml of urine

Leptospirosis Epidemiology
Leptospires are transmitted to incidental hosts by direct and indirect contact. Direct contact (host to host) is via urine, body secretions, Tran placental and thru the milk. Indirect contact (via urine) in water, on bedding or environmental contaminated products

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How Man gets Infected

Water the great source Drinking Swimming Bathing, as the urine of Rodents chronically infected contaminate water sources Children get infected when in contact with infected Dogs

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Control of Leptospirosis
Rodent control is most important. Humans should avoid contact with water contaminated with animal contact.

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Injection Crystalline penicillin is the drug of choice in treating weils disease because
A. B. C. D. E. It is a leptospiral disease Organism is uniformly sensitive to penicillin No resistance against penicillin is reported so far It is mostly without any undesirable side effects Earlier the treatment started, better is the outcome

Medications that may be routinely prescribed in uncomplicated weils :

Acetaminophen 650 mg orally SOS Doxycycline 100mg twice daily orally for seven days OR Tetracycline 500mg 6 hourly OR Ciprofloxacin 500mg BID Frusemide 40mg IV q 12hrly in case of impending renal failure

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Chemoprophylaxis

Doxycycline 200 mg orally once a week is simple effective measure. When heavy exposure is anticipated

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Leptospirosis Prevention
Elimination of carrier Vaccination for dogs Protection is serovar-specific
Current vaccination is for 3 sero types and is considered very effective Past vaccination was for 2 sero types which are no longer as important. The past vaccine was not as pure as current vaccines and was commonly associated with vaccine allergic reactions.

Prevention
Rodent control measures Immunization of animals with killed vaccines short-lived, requires boosters Protective clothing, footwear Burning canefield prior to harvest (young shoots can cut hands) Doxycycline prophylaxis for high-risk workers (Takafugi ET, NEJM 1984)

The following statements regarding prognosis of Weils disease are true:

Temperature falls by lysis within 3-4 days of treatment Temperature may rise again in the anicteric form
Admission to MICU and close observation are mandatory
If untreated mortality in weils syndrome is 15-20%

Those who recover do so with residual complications

Medical professionals should be cautious Leptospirosis

The infection may progress rapidly to fatal septicemic multisystemic failure or remain as a barely detectable subclinical illness. There is no reliable method to identify the final route of the infection from the initial stage of the disease, and all cases must be treated as potentially lifethreatening.

New Vaccine trails - Leptospira

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ICMR contributes to Knowledge on Leptospirosis

The Regional Medical Research Centre (ICMR), Port Blair is the National Leptospirosis Reference Centre of India and WHO Collaborating Centre for Diagnosis, Research, Reference and Training in Leptospirosis. It maintains one of the largest Leptospira repositories in the world and is the only facility in India for serological and genetic typing of Leptospira.
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Programme created by Dr.T.V.Rao MD for benefit of Medical and Paramedical Professionals , and Students Email doctortvrao@gmail.com

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