Sandbox:Leptospirosis

Overview

Leptospirosis is a bacterial zoonotic disorder with ubiquitous distribution,common worldwide, especially in developing countries caused by Leptospira species. Leptospirosis becoming a global public health problem, as evidenced by recent spike in the incidence rates and multiple outbreaks in all continents. The annual estimated incidence of about half a million severe human cases is probably an underestimation, as the disease is severely neglected and its global burden is largely unknown, because of its non-specific symptoms, inadequate surveillance system, and lack of readily available quick and simple diagnostic tests.

Historical Perspective

Association of renal failure with icteric leptospirosis, was first reported over 100 years ago and described by Adolf Weil. Adolf Weil first described the disease leptospirosis as a disease entity in 1886 and the serious form of leptospirosis called Weil's disease is named after Adolf Weil.

Pathophysiology

The disease leptospirosis involves a spectrum of symptoms ranging from subclinical infection to a severe syndrome of multiorgan infection with high mortality and Weil’s disease represents only the most severe presentation. Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup. The presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine.

Reservoirs

The major reservoir for leptospirosis is rat.

Transmission

Pathogenic leptospires live in the renal system and the genital tracts of domestic animals which act as sites of persistence. Bacteria shed from the infected animals such as rodents and domesticat animals through urine. These animals may not show signs of disease, but humans shows signs of illness after contact with infected urine, or through contact with water, soil or food that has been contaminated and the outbreaks are associates with floodwaters. The major route of infection by leptospires is probably by transmission through indirect contact with leptospires secreted into the environment. Humans are considered dead end hosts, but sometimes they also act as carriers. Mammalian species (e.g. rodents, insectivores, dogs, pigs and cattle) act as the main carriers of the disease. Leptospires are excreted in urine into the environment, where they can survive for several months, depending on favourable environmental conditions such as humid and temperate areas. Infection can occurs either by direct contact with the carrier’s urine or through indirect transmission via urine-contaminated environment. The pathogen may also be excreted in the products of abortion in mammalian animal species.

Pathophysiology

Toxin Production
Type of toxin production depends on the serovar Hemolytic toxins: Hemolysins are produced from several serovars such as serovars ballum, hardjo, pomona, and tarassovi which are sphingomyelinases
Immunological Mechanism
Humoral Immunity	Innate Immunity

Acute phase	Immune phase
Also known as Septicemic phase Begins abruptly Characterized by nonspecific signs such as fever, chills, headache and conjunctival suffusion Associate with severe myalgia Other less common findings include: Photophobia, lymphadenopathy, abdominal pain, nausea, vomiting, a transient rash, sore throat, coughing or chest pain Characterestic of this phase also includes: symptoms lasts several days to a week, which is followed by a brief remission, during which the temperature drops and the symptoms disappear	Anicteric leptospirosis	Icteric leptospirosis
	More common but serious illness is uncommon Most of cases present either subclinical or of very mild severity Few cases present with a febrile illness of sudden onset Other symptoms include chills, headache (severe with retro-orbital pain and photophobia), myalgia, abdominal pain, conjunctival suffusion, and skin rash (transient and last <24 hours) May progress to aseptic meningitis in ≤25% of patients and more common in younger age group than the patients with icteric leptospirosis Mortality is very less when compared to icteric leptospirosis	Rapidly progressive and severe form of leptospirosis Less common form of leptospirosis with incidence of 5%-10% Jaundice is not associate with hepatocellular injury, eventually LFT returns to normal after recovery High mortality rate with a range of 5%-15%

Pathology

Pathology
Pathological findings of leptospirosis are due to the development of the following: Vasculitis Endothelial damage Inflammatory infiltrates composed of moncytic cells, plasma cells, histiocytes, and neutrophils
Gross Findings
Gross findings of various organ systems are present as: Extensive petechial hemorrhages are common Discoloration of organs is seen in severe cases of icteric leptospirosis
Histopathological Findings
Liver: No significant structural destruction is seen Intrahepatic cholestasis is seen in few cases Hypertrophy and hyperplasia of Kupffer cells Erythrophagocytosis Kidney: Common histopathological presentation in kidney includes interstitial nephrits with infiltration of neutrophils and moncytes Leptospires are seen in renal tubules Electron microscopy findings include: Thickened tubular basement membrane Denuded tubular brush borders Mitochondrial depletion in tubular cells Glomerular destruction associate with proteinuria is seen in few cases Heart: Leptospirosis is associate with interstitial myocarditis. Cellular infiltration predominantly with lymphocytes and plasma cells Petechial hemorrhages (epicardial hemorrhages are common) Epicardial infilteration of mononuclear cells Pericardial effusion coronary arteritis Lungs: Common pulmonary presentation in leptospirosis are pulmonary congestion and hemorrhage. Alveolar infiltration by monocytes and neutrophils Hyaline membrane formation Leptospires are seen within the endothelial cells in interalveolar septa, and also attached to capillary endothelial cells Skeletal muscle: Focal necrosis of muscle fibers with infiltration of histiocytes, neutrophils, and plasma cells Brain: Perivascular cuffing is seen

Causes

Leptospirosis is caused by various species of Leptospira.

• Phylum = Spirochete
• Family = Leptospiraceae
• Order = Spirochaetales

Not all species of Leptospira are pathogenic, some species are harmless and saprophytes that reside in the environment. Until now there are 50 nonpathogenic serovers and 300 pathogenic serovers are identified. Serovar is the basic unit of Leptospira taxonomy and each serovar consist of closely related isolates based on serological reactions to the bacterial lipopolysaccharide Severe leptospirosis is frequently caused by serovars of the icterohaemorrhagiae serogroup.

Overview

Leptospirosis caused by pathogenic Leptospira species have been found worldwide, except in Antarctica. It is most common in warm, humid environments and in the areas with a high disease incidence in humans include the Caribbean and Latin America, Oceania and parts of Asia. During the past few decades, leptospirosis has become seriously neglected, especially in countries of temperate regions. The main reasons for this situation are probably: 1) a relatively less number of cases noted in the temperate climate zone 2) well established, quite effective methods of therapy and prevention of the disease 3) seemingly well-determined epidemiologic situation concerning the disease.

Prevalence

Leptospirosis, is a zoonotic emerging infectious disease with a worldwide distribution. Tropical climatic conditions are most favourable for survival of leptospires and the morbidity is high due to extreme weather events such as cyclones and floods occurring in recent years. Leptospirosis is particularly prevalent in wet tropical and subtropical regions as the pathogenic leptospires can survive longer in a warm and humid environment.

Incidence

Leptospirosis is an increasing public health problem worldwide, evidenced by markedly increasing incidence rates and multiple outbreaks allover the world. Even though multiple outbreaks has been reported, the true spread and incidence of leptospirosis remains unknown, as the availability of diagnostic tests, testing facilities and surveillance systems are highly variable and frequently absent. Incidence rate in temperate climate is in a range of ~0.1–1 per 100000 per year and it is ~10–100 per 100 000 in the humid tropical regions. In high-exposure risk groups and during outbreaks, the incidence may be >100 per 100000.

Case Fatality Rate

Higher morbidity due to leptospirosis is observed in regions with higher proportion of surface fresh waters such as lakes, rivers, developed canal systems. Case fatality rate due to leptospirosis is > 10%, and > 500,000 cases of severe leptospirosis are reported each year. Worldwide case fatality rates range from 3%-50%.

Developing Countries

Leptospirosis is a neglected disease with a greatest burden on impoverished populations from developing countries and tropical regions. It is a major public health problem in many developing countries, such as Latin America and South-East Asia where the climate is more favorable for leptospires.

Risk Factors

The risk of acquiring leptospirosis is associated with contact with animals, which made leptospirosis as an important occupational disease, especially affecting farmers, slaughterhouse workers, pet traders, veterinarians, rodent catchers and sewer workers who are in contact with mammalian species which acts as a natural carriers of leptospires.

Common Risk Factors

The risk groups include:

• Farmers
• Mine workers
• Sewer workers
• Slaughterhouse workers
• Veterinarians and animal caretakers
• Fish workers
• Dairy farmers
• Military personnel

Natural History, Complications & Prognosis

Leptospirosis is transported by the natural carriers such as feral, semi-domestic and farm and pet animals. The disease leptospirosis is poorly known and unaware of its natural history is mainly due to the wide range of non specific symptoms, subclinical nature of the disease in animals, and non specific laboratory tests making the disease difficult to diagnose.

Natural History

Natural history of leptospirosis varies with each patient. It might be mild or asymptomatic, and go unrecognized or in some patients the illness may progress to kidney or liver failure, aseptic meningitis, life-threatening pulmonary hemorrhage and other syndromes.

Complications

Complications of leptospirosis are associated with localization of pathogen(Leptospires) within the tissues during the immune phase, eventually present during the second week of the illness.

• Aseptic meningitis

Prognosis

The prognosis of leptospirosis depends upon several known and unknown factors, among which the type of pathogenic serovar and the host’s immune status are the important factors which determines the outcome. Most patients recover completely from leptospirosis, but the duration of recovery varies from months to years with or without late sequelae. The late sequelae may include neuropsychiatric problems such as paresis, paralysis, mood swings and depression etc. The major causes of death include renal failure, cardiopulmonary failure, and haemorrhage. Patients with risk factors such as old age and multiple underlying co-morbid conditions are often associated with more severe leptospirosis and increased mortality.

Daignosis

History & Symptoms

The clinical presentation of leptospirosis is biphasic, with the acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production and excretion of leptospires in the urine. Leptospirosis can occur in several forms, which include mild, flu-like symptoms that may not be recognized as leptospirosis, as well as unusual syndrome or fulminant illness without two distinct phases.

The incubation period of leptospirosis in humans is usually 7 to 12 days, with a range of 2 to 29 days.

Common Symptoms

• Fever
• Myalgias
• Headache
• Chills
• Diarrhoea,
• Nausea and vomiting
• Oliguria/anuria
• Jaundice
• Joint pain
• Skin rash
• Cough
• Psychosis
• Delirium

Clinical Manifestations

Clinical manifestations of leptospirosis varies depending upon the serovar and also the host immunity. Typically, leptospirosis presents broadly into 4 clinical catogiries:

1. Mild, influenza-like illness
2. Weil's syndrome characterized by jaundice, renal failure, haemorrhage and myocarditis with arrhythmias
3. Meningitis or Meningoencephalitis
4. Pulmonary haemorrhage with respiratory failure

Laboratory Findings

As the clinical manifestations of the disease are non specific, the clinical diagnosis is difficult. The laboratory investigations for leptospirosis should be considered in patient with an abrupt onset of fever, chills, conjunctival suffusion, headache, myalgia and jaundice with history of occupational exposure to infected animals or contaminated with animal urine. Laboratory investigations useful in the diagnosis of leptospirosis include:

• Identification of leptospires in tissues using antibodies labelled with fluorescent markers
• Antibody detection by serological studies
• Culture the bacteria from blood, urine or tissues
• Other methods such as PCR, Immunostaining etc.

Serological Studies

Most cases of the leptospirosis are diagnosed by serological tests

Treatment

Medical Therapy

For effective treatment of leptospirosis, antibiotics should be used within 5th day after the onset of symptoms and as soon as the diagnosis of leptospirosis is suspected without waiting for the laboratory results. Best initial treatment for severe leptospirosis is Penicillin. For less severe form, drugs such as amoxycillin, ampicillin, doxycycline or erythromycin can be used. Other drugs of choice which are effective, include third-generation cephalosporins, such as ceftriaxone and cefotaxime, and quinolone antibiotics.

Secondary Prevention

For leptospirosis there is no specific vaccines for prevention, but it can be prevented by proper disinfection such as 1% sodium hypochlorite, 70% ethanol, iodine-based disinfectants, quaternary ammonium disinfectants, accelerated hydrogen peroxide, glutaraldehyde, formaldehyde, detergents and acid or by pasturization. These organisms are also sensitive to moist heat (121°C [249.8°F] for a minimum of 15 min).