LEPTOSPIROSIS

Leptospirosis-synonyms Mud fever Japanese seven day fever Leptospiral Jaundice Spirochete Jaundice Autumn fever Elippani (mal)

Introduction Leptospirosis is a most widespread zoonotic disease in the world caused by the pathogenic bacteria called leptospires. Generally it is transmitted by the infected urine of rodents. Case fatality may vary from 0.3 – 8 %. Severe form of leptospirosis is called Weil’s Syndrome Also included as water borne disease

Distribution Worldwide disease. Most common in tropical & subtropical areas with high rainfall. In India with frequent outbreaks in Maharashtra ,Gujarat, Karnataka, Kerala & Andaman islands especially during the monsoon.

Leptospirosis: (A re-emerging disease) Endemic in South East Asia Region 12 out of 18 areas with the highest incidence are located in SEAR (Pappas, 2008) Major outbreaks reported more notably in India, Indonesia, Sri Lanka and Thailand. Outbreaks in SEAR as well as in South and North America Leptospirosis as a re-emerging infectious disease

Incidence No: of cases worldwide is not known precisely. 0.1 – 1 /100,000 per year in temperate climates. 10 – 100 /100,000 per year in humid tropics. During outbreaks & in high exposure risk groups it may reach >100 per 100,000.

History of Leptospirosis Adolf Weil described leptospirosis as a disease entity in 1886.

Leptospirosis in India 1931 – An outbreak in Andaman islands. 1960 – Serological evidence 1983 – An outbreak in cattles Now endemic in all parts of India. All cases of fever with jaundice are now screened for leptospirosis as a mandatory laboratory test.

Leptospirosis in Kerala Reported in Kerala from 1997 onwards . Increasing trend of incidence is clearly seen. Case fatality rate in 2005 -10.62% 2006 -13.78% up to June 2007 -10.53% Majority of cases occurred in late Monsoon.

Epidemiological determinants

Causative agent - Leptospira Corkscrew -shaped delicate flexible spirochetes. About 6 – 20 micrometer long & 0.1 micrometer thick. Posses a large number of closely wound spirals & characteristic end hooks. Actively motile.

Causative agent - Leptospira

Leptospira Too thin to visible under ordinary microscope. dark field micros copy is using. Order-Spirochaetals. Family- Leptospiraceae. Genus- Leptospira

1.Taxonomy and Classification Bacteriology 1.Taxonomy and Classification A. Serological classification (prior to 1989) – Divided into two speies • L. interrogans, comprising all pathogenic strains • L. biflexa, containing the saprophytic strains – Divided into numerous serovars • defined by agglutination after cross-absorption with homologous antigen • Serovars that are antigenically related have traditionally been grouped into serogroups

Icterrohaemorrhagiae,copenhageni,smithi etc LEPTOSPIRA L.INTERRGANS L.BIFLEX ICTERROHAEMORRHAGIAE-SERO.GP Icterrohaemorrhagiae,copenhageni,smithi etc Serovar OVER 200 SEROVARS HAVE BEEN IDENTIFIED & ASSEMBLED IN 23 SEROGROUPs. A new serovar Barathy strain Kolenchery belonging to the Austarlis group has been identified from Kerala.

Epidemiology Animals can be divided into maintenance hosts accidental (incidental) hosts. The most important maintenance hosts are small mammals

Reservoir of infection Rodents –(Rattus rattus ,Rattus norvegicus, Mus musculus ) Dogs Wild animals Domesticated animals Caged game animals

Epidemiology Different animals may be reservoirs of distinct serovars, rats are generally maintenance hosts for serovars lcterohaemorrhagiae and Ballum dairy cattle may harbor serovars hardjo, pomona pigs may harbor pomona,tarassovi,

Epidemiology Human infections may be acquired through occupational exposures recreational exposures avocational exposures • Direct or Indirect contact with infected animals

Resistance- leptospira Very susceptible to heat 10 mnts at 50 degree centigrade 10 seconds in 60 degree centi: Sensitive to acid Readily destroyed by chlorine

Epidemiology Under laboratory conditions, leptospires in water at room temperature remain viable for several months at pH 7.2 to 8.0, but in river water survival is shorter and is prolonged at lower temperatures The presence of domestic sewage decreases the survival time to a matter of hours, but in an oxidation ditch filled with cattle slurry, viable leptospires were detected for several weeks

Epidemiology When soil was contaminated with urine from infected rats or voles, leptospires survived for approximately 2 weeks in rain-water-flooded soil it survived for at least 3 weeks

Epidemiology Portal of entry – usually • abrasions or cuts in the skin or via the conjunctiva • infection may take place via intact skin after prolonged immersion in water

Environmental factors Endemic in many countries. Has a seasonal distribution. Associated with Poor housing Limited water supply Rodent intensity.

Leptospirosis as Epidemic Associated with 1. Changes in human behavior 2. Contamination of water by animal / sewage 3. Changes in animal reservoir density 4. Follow natural disasters like cyclones & floods

Source of infection Leptospires are excreted in the urine of infected animals ,rodents etc.

Host factor Age –most affected age group is 20-40 yrs Children acquire infection from domestic dogs Sex - males are more prone to get infection Occupation – agricultural & live stock farmers Immunity – Asolid serovar specific immunity follows an infection

Risk groups Agricultural & Live stock farmers Workers in rice fields & sugar cane fields Underground sewers Meat & animal handlers Swimmers

Leptospirosis: an emerging zoonose amplified by seasonal flooding Occupational vulnerability: about 75% of leptospirosis cases are farmers Vectors of leptospirosis: Rice field rodents (Bandicota sp. And Rattus sp.) Leptospira interrogans, transported by water in the environment Recreational vulnerability affecting a wider range of rural populations

Mode of transmission 1. Direct contact with urine or tissue of infected animal a.through skin abrasions b.intact mucus mem: 2. Indirect contact- a.broken skin with infected soil,water or vegetation b.through ingestion of food & water contaminated with leptospira 3. Droplet infection- inhalation of droplets of infected urine

Leptospires in the body TISSUES BLOOD ORGANS LEPTOSPIRA CONVOLUTED TUBULES OF KIDNEY URINE

f. Pathology Leptospirosis is characterized by the development of vasculitis, endothelial damage, and inflamma-tory infiltrates composed of moncytic cells, plasma cells, histiocytes, and neutrophils. On gross examination, petechial hemorrhages are common and may be extensive, and organs are often discolored due to the degree of icterus The histopathology is most marked in the liver, kidneys, heart, and lungs, but other organs may also be affected according to the severity of the individual infection.

Pathogenesis of severe disease vasculitis Damage to small blood vessels Leptospira Direct cytotoxic injury Immunological injury Massive migration of fluid from Intravesicular to interstitial compartment Renal dysfunction,vascular injury To internal organs

Spectrum of illness

Clinical patterns-as per WHO 1. Mild –influenza like illness 2. Weil’s syndrome characterised by jaundice,renal failure,haemorrhage, &myocarditis with arrhythimias 3. Meningitis/ Meningo encephalitis 4. Pulmonary haemorrhage with respiratory failure

Incubation period Usually 10 days Range- 4-20 days

Clinical Features Of Leptospirosis The spectrum of symptoms is extremely broad; the classical syndrome of Weil’s disease represents only the most severe presentation The clinical presentation of leptospirosis is biphasic acute or septicemic phase-1w immune phase-antibody production and excretion of leptospires in the urine

Clinical Features Of Leptospirosis Most of the complications of leptospirosis are associated with localization of leptospires within the tissues during the immune phase and thus occur during the second week of the illness.

a. Anicteric Leptospirosis The great majority of infections caused by lepto-spires are either subclinical or of very mild severity, and patients will probably not seek medical attention. A smaller proportion of infections, but the overwhelming majority of the recognized cases, present with a febrile illness of sudden onset. Aseptic meningitis may be found in < 25% of all leptospirosis cases, 62% of children < 14 years old

Leptospirosis: (Symptoms)

Leptospirosis - Challenge

Anicteric Leptospirosis: The patients present with : Fever - Patients have remittent fever with chills. It may be moderate to severe. Myalgia - It is a very characteristic fi nding in leptospiro-sis. Calf, abdominal & lumbosacral muscles are very painful & severely tender. This symptom is very useful in differen-tiating leptospirosis from other diseases causing fever. There is associated increase in serum Creatinine Phospho-kinase (C.P.K.) which helps in differentiating leptospirosis from other illnesses.

Anicteric Leptospirosis: The patients present with : Conjunctival Suffusion - There is reddish colouration of conjunctiva. Very useful sign in leptospirosis. Usually bilateral, most marked on palpebral conjunctiva, it may be associated with unilateral or bilateral conjunctival haemorrhage. • Headache - Usually intense, sometimes throbbing, commonly in frontal region. It is often not relieved by analgesics.

Anicteric Leptospirosis: The patients present with : Renal manifestations - Some form of renal involvement is invariable in leptospirosis. It usually occurs as asymp-tomatic urinary abnormality in the form of mild proteinuria with few casts & cells in the urine. Severe renal involve-ment in the form of acute renal failure, (which occurs in icteric leptospirosis) is rare. Pulmonary manifestations - Manifested in most cases through cough & chest pain and in few cases by haemop-tysis. Severe involvement leading to respiratory failure does not occur in anicteric leptospirosis.

Anicteric Leptospirosis: The patients present with : Hemorrhage - Hemorrhagic tendencies are also present in some cases. Note: All the clinical features either decrease or disappear within two to three days and then they reappear. Differential diagnosis - The patients of anicteric leptospirosis are likely to be misdiagnosed as malaria, dengue hemorrhagic fever, viral hepatitis etc. Note: In endemic area all cases of fever with myalgia and conjuncti-val suffusion should be considered as suspected cases of leptospirosis.

Icteric Leptospirosis: This is the more severe form of leptospirosis. As the name suggests all patients have jaundice. Patients present with: Fever Same as in anicteric leptospirosis but may be more severe. Myalgia Headache Conjuctival suffusion Oliguria/Anuria and/or proteinuria Nausea, vomiting Abdominal pain

Icteric Leptospirosis: ( Weil’s syndrome ) In addition, they have features of organ invol-vement. An individual patient may have featu-res of one or more organ involvement. The more severe form of disease with severe liver and kidney involvement is known as Weil’s syndrome.

Icteric Leptospirosis: (Renal) Renal involvement is almost invariably present in leptospi-rosis. In severe cases patients have acute renal failure and present with: Decreased urine output (oliguria or even anuria) Oedema may be present on face and feet. Features of uremia like breathlessness, convulsion, delirium and altered level of consciousness may be present in very severe cases. The renal dysfunction worsens during the fi rst week to the end of 2nd week, after which it starts improving and complete recovery occurs by the end of the 4th week. There is usually no residual renal dysfunction.

Icteric Leptospirosis: (Hepatic) Jaundice is the most important clinical feature. It may be mild to severe. It starts after 4 to 7 days of illness. Hepatic encepha-lopathy or death due to hepatic failure is rare. Hepatomegaly & tenderness in right hypochondrium are usually detected. Laboratory investigations show raised level of serum bilirubin (direct) and alkaline phosphatase. SGOT & SGPT are either nor-mal or mildly elevated. This helps to differentiate leptospirosis from viral hepatitis where SGPT is markedly elevated and also from alcoholic hepatitis where SGOT is markedly elevated. High level of Creatinine Phosphokinase (CPK) is suggestive of Leptos-pirosis. It is normal in viral hepatitis and alcoholic hepatitis helps in differential diagnosis.

Hepatic changes in leptospirosis In severe cases even where hepatic dysfunction and jaundice are present hepatocellular necrosis is unusual but large amounts of bilirubin can be seen in the hepatocytes. After specific chemotherapy, the liver function usually returns to normal.

Icteric Leptospirosis: (Pulmonary involvement) High mortality due to pulmonary involvement is becoming a feature in Leptospirosis. There are wide variations in pulmonary presentation. It is the commonest cause of death due to leptospirosis. Symptoms: In mild cases patient will show only cough, chest pain and blood tinged sputum. In severe cases patients have cough, haemoptysis, rapidly increasing breathlessness which may lead to respiratory failure and death.

Icteric Leptospirosis: (Pulmonary involvement) On examination, these patients have increased respiratory rate with basal creptations, which rapidly spread upwards to middle and upper lobes. X-ray shows basal and mid zone opacity in severe cases. It may be normal in mild cases. The under lying pathology is intra-alveolar haemorrhage. More than ninety percent (90%) of deaths due to leptospirosis occur due to pulmonary alveolar haemorrhage.

Icteric Leptospirosis: (Cardiovascular system involvement) Patients can have any one or more of the following features: Haemorrhage They occur because of Thrombocytopenia, Disseminated Intra-vascular Coagulation (DIC), Secondary to liver involvement leading to coagulation factor defi ciency. Patients may have spontaneous superfi cial bleeding i.e. petechial, purpura, epistaxis or GIT bleeding. In severe cases ecchymosis or intra-cranialhaemorrhage can occur.

Icteric Leptospirosis: (Cardiovascular system involvement) Hypotension Shock: Patient will have hypotension, cold clammy extremities, tachycardia, thready pulse. JVP is either normal or decreased. Echocardiography reveals normal systolic function of left ventricle hence hypotension is due to either dehydration or peripheral vasodilatation. Arrhythmias: Patient presents with palpitation and syncope & irregular pulse. Common arrhythmias seen are supraventricular tachyarrythmias and various degrees of A.V. blocks. Ventricular tachyarrhythmias are infrequent. ST Segment depression and T wave inversion may be present in some patients. All patients with severe , multiple organ involvement should be referred to tertiary care centres.

b. Ocular Involvement Conjunctival suffusion in the presence of scleral icterus is said to be pathognomonic of Weil’s disease Anterior Uveitis may present weeks, months, or occasionally years after the acute stage. Chronic visual disturbance, persisting 20 years or more after the acute illness, has been reported

Subconjunctival haemorrhages in leptospirosis c. Ocular Involvement Subconjunctival haemorrhages in leptospirosis

Icteric Leptospirosis:

c. Icteric leptospirosis Icteric leptospirosis is a much more severe disease in which the clinical course is often very rapidly progressive. Severe cases often present late in the course of the disease, and this contributes to the high mortality rate, which ranges between 5 and 15%. Between 5 and 10% of all patients with leptospi-rosis have the icteric form of the disease

Diagnosis Suspected clinically by Deep jaundice Sub- conjunctival haemorrhage Muscle tenderness Decreased urine output Possible exposure to rat’s urine

Diagnosis by lab methods Presence of proteinuria, RBC ,cell casts. Polymorphonuclear leucocytosis & high ESR. Thrombocytopenia in peripheral smear. Elevated serum creatinine. Positive Weil’s antibody test.

d. Other Complications Acute infection in pregnancy has been reported to cause abortion and fetal death, but not invariably so. a neonate developed jaundice

e. Chronic or Latent Infection This patient exhibited a negligible antibody response to the infecting strain, suggesting the presence of an immune defect. Retinal pathology Meningitis

Uveitis in leptospirosis Ocular Involvement Uveitis in leptospirosis During the recovery phase of leptospirosis, iridocyclitis or uveitis (as seen here) may be associated with the immunological response, often several weeks or months following the initial infection. This photograph of the fundus was taken 3 months after the patient developed acute systemic leptospirosis.

Laboratory diagnosis Dark field microscopy (MAT) Culture from blood (IgM ELISA) PCR Blood-First week. Urine-Second up to sixth week (intermittently). ELISA- Genus specific. MAT – Serovar / serogroup specific. RAPID Test – Lepto- Tek –Dri –Dot.

Differential diagnosis Influenza; Dengue and dengue haemorrhagic fever; Yellow fever and other viral haemorrhagic fevers; Malaria Pyelo nephritis Aseptic meningitis Viral hepatitis Typhoid & other enteric fevers

Complications Renal failure Acute hepatic failure Acute cardio vascular failure Haemorrhage Meningitis pneumonia

Prognosis Mortality of severe leptospirosis is high . range varies =3.5 to 40 %

Cause of death Renal failure Cardio pulmonary failure Widespread haemorrhage Liver failure rare

Recovery from Leptospirosis Most patient recover completely. Some patients may take months/years. Late sequlae may occur.

General measures Complete bed rest Light easily digestible diet Plenty of oral fluids Anti-pyretic medication as needed Patients with complication shall be admitted Sodium, pottassium & phosphorus may be restrictd Nephrotoxic drugs should be avoided

Treatment Penicillin is the drug of choice when given early -7 days. If penicillin allergic tetracycline /erythromycin.

Hepatic involvement Jaundice- mild to severe starts 4-7 days following illness acute liver failure is rare elevation of serum bilirubin with raised alkaline phosphatase, CPK is very much elevated. Treatment- mainly symptomatic & supportive. Hephatic encephalopathy- proteins restricted. Coagulation failure is corrected with Vit-K.

RENAL INVOLVEMENT Invariably seen in all cases. Urine is abnormal with cells Creatinine levels elevate later Renal failure may be oliguria or anuria. Treatment-severe patients require dialysis support.

Pulmonary complications Cough & hemoptysis ,may progress rapidly to breathlessness & res: failure >9% mortality is due to alveolar hemorrhage Treatment- continuous oxygen therapy & ventilatory support

Cardiovascular complications Hypotension& shock due to intravascular fluid leak Myocarditis with serious arrhythimias & cardiac failure. Hemorrhage- fatal GI hemorrrhage, hemetemsis, alveolar hemorrhage & epistaxis Treatment- fluid replacement ,vasopressors ,arrhythimias should be treated in the ICU setting

Immunization Immunity to leptospirosis is largely humoral and is relatively serovar specific. Thus, im-munization protects against disease caused by the homologous serovar or antigenically similar serovars only.

A case history A 25 year old man is brought to the Out Patient Department with history of fever of 3 days duration with following symptoms & signs. High grade fever of continuous nature. Generalized aches & severe myalgia. Yellowish discoloration of eyes & urine. Non-specific head ache.

Natural maintenance hosts & serovars Rats – icterohaemorrhagiae,copenhageni & smithi, etc Dogs – canicola etc Cattle – pomona ,hardjo ,etc

Epidemiology Leptospirosis is presumed to be the most widespread zoonosis in the world Either direct or indirect contact with the urine of an infected animal The incidence is significantly higher in warm climate countries than in temperate regions

Epidemiology Many animals are seronegative carriers. After infection, leptospires localize in the kidneys and are excreted intermittently in the urine Many of these outbreaks have followed exten-ded periods of hot, dry weather, when patho-genic leptospires presumably have multiplied in freshwater ponds or rivers. Cases of leptospiro-sis also follow extensive flooding

Epidemiology Other excretion of leptospires in human urine months after recovery sexual intercourse during convalescence Water-borne transmission has been documented

Treatment Treatment of leptospirosis differs depending on the severity and duration of symptoms at the time of presentation. Patients with mild, flu-like symptoms require only symptomatic treatment but should cautioned to seek further medical help if they develop jaundice

Laboratory diagnosis (Blood culture) Ideal time: Within 10 days of the onset of the disease. Sample should be collected before antibiotics are started. Media: EMJH, Fletcher’s and Stuart’s (commercially available or obtain from the designated regional/ district laboratory)

Laboratory diagnosis (Blood culture) Procedure: Swab the area with the spirit. Draw the blood using sterile syringe and needle by vein puncture. Take 2 tubes containing 5 ml EMJH medium and inoculate two drops of blood in the fi rst tube and four drops in the second tube. Incubate at 300C for 4-6 weeks. Examine the culture using dark fi eld illumination initially on 1st, 3rd and 5th days followed by at 7-10 days interval upto 6 weeks. Selective culture media containing 5FU 50-1000 μg/ml or a combination of nalidiocic acid 50 μg/ml; vancomycin 10 μg/ml and polymixin B sulphate 5 units/ml or a combination of actidione 100 μg/ml, bacitracin 40 μg/ml, 5-FU 250 mg/ml, neomycin sulphate 2 μg/ml, polymixin B sulphate 0.2 μg/ml and refampicin 10 μg/ml can be used to avoid the contamination.

Management of severe cases Should be treated in higher centre with facilities for organ support. Organ dysfunction may be treated on standard lines. There is nothing specific treatment to leptospirosis. Hypovolemia should be corrected with normal saline. Adequate calories (1000Kcal+100Kcal/year of age) may be given.

Interventions at the level of human host Raising awareness about the disease. Antibiotic prophylaxis- Doxycycline give some degree of protection.It can reduce the severity of disease. Immunization in available countries.Vaccine give protection only against the specific serovar. Health education.

Leptospirosis - Challenges Mimics other diseases; clinical diagnosis is essentially one of exclusion Severe form around 20% with organ failure requiring secondary and tertiary care Definitive diagnosis through laboratory; not widely available Is yet to be considered a priority disease in most SEA countries Generalized underreporting of cases Prevention and control remains difficult to implement

Socio-cultural, economic, environmental and ecological perspectives Common in occupations with frequent exposure to contaminated environment and carrier animals Same group reported to have poor knowledge of the disease, probably related to level of education (Wiwanitkit, 2006) Low socio-economic status independently contribute to the risk of infection (Reis, et al, 2008) Anthropogenic environmental changes (e.g., land use change) documented prior to outbreaks in Peru, Hawaii (Wilcox & Gubler, 2005) and could have played a role in Sri Lanka outbreaks Understanding human behaviour, practices and worldview may prove useful in the success of programmes

Late complications Chronic fatigue Neuro-psychiatric sym : - Headache ,paresis ,paralysis ,mood swings & depression. Uveitis & Iridocyclitis

Management

SYMPTOMS Leptospirosis in humans may show a wide variety of symptoms and signs including: fever; severe headache; myalgias; conjunctival suffusion; jaundice; general malaise; stiff neck; chills; abdominal pain; joint pain; anorexia; nausea; vomiting; – diarrhoea; – oliguria/anuria; – haemorrhages; – skin rash; – photophobia; – cough; – cardiac arrhythmia; – hypotension; – mental confusion; – psychosis; – delirium.

Clinical variety 1.Mild / Anicteric Presents with fever , myalgia conjunctival suffusion & head ache. 2. Severe (Weil’s syndrome ) / Icteric Present with jaundice & renal failure along with all features of mild cases Multiple organ involvement manifest as different complications.

Three epidemiological patterns of leptospirosis were defined by Faine The first occurs in temperate climates where few serovars are involved and human infection almost invariably occurs by direct contact with infected animals though farming of cattle and pigs The second occurs in tropical wet areas, within which there are many more serovars infecting humans and animals and larger numbers of reservoir species, including rodents, farm animals, and dogs The third pattern comprises rodent-borne infection in the urban environment. (slum)

Leptospirosis – Epidemiology