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LEPTOSPIROSIS - A REVIEW

 

Clinical courses

ABOUT AUTHOR:
Akshay Rajgaria
Kanak Manjari Institute of Pharmaceutical Sciences
akshaykrish2007@gmail.com

ABSTRACT
Leptospirosis is a worldwide zoonotic infection with a much greater incidence in tropical regions and has now been identified as one of the emerging infectious diseases. The epidemiology of leptospirosis has been modified by changes in animal husbandry, climate, and human behavior. Resurgent interest in leptospirosis has resulted from large outbreaks that have received significant publicity.

Reference Id: PHARMATUTOR-ART-1978

INTRODUCTION
Leptospirosis is a fairly uncommon bacterial infection caused by a strain of Leptospira. It is most commonly transmitted from animals to humans when people with unhealed breaks in the skin, come into contact with water or soil that has been contaminated with animal urine - the bacterium can also enter the body through the eyes or mucous membranes. Typically, the animals that transmit the infection to humans include rats, skunks, opossums, foxes, raccoons and other vermin.


Although more common in tropical areas, non-tropical urban conglomerations with low levels of sanitation are seeing more cases, especially during the summer and autumn months. Most of the urban areas affected involve large cities in the developing world.

TYPES OF LEPTOSPIROSIS


  • Mild Leptospirosis - the patient experiences muscle pains, chills and possibly a headache. 90% of cases are of this type.
  • Severe Leptospirosis - can be life-threatening. There is a risk of organ failure and internal hemorrhaging. This occurs when the bacterium infects the kidneys, liver and other major organs. Experts are not sure why some patients develop the severe form - people who are already very ill, such as those with pneumonia, young children under five, and elderly individuals are more likely to suffer from severe Leptospirosis.

OCCURENCE
As mentioned above, leptospirosis is more common in the tropics, but may also occur in the poor parts of large cities in developing nations that are not in tropical areas. When cases do occur, they tend to be sporadic.

Leptospirosis exists globally, but is more common in tropical and subtropical parts of the world. The bacterium thrives in hot and humid environments.

The following areas and/or countries/continents are known to have the highest incidences of leptospirosis: Africa, India, China, Central America, Brazil, Caribbean, South East Asia, and Southern Russia.

Cases of infection are also reported in the following tourist hotspots: New Zealand, Australia, Hawaii, and Barbados.

After flooding, large outbreaks of leptospirosis may occur.

According to WHO (World Health Organization), approximately 10 million people are thought to come down with leptospirosis annually. Death rates are hard to calculate, because they tend to occur in parts of the world with very basic public health services which do not routinely report many causes of deaths.

Climate change, including more cases of flooding around the world, probably means that leptospirosis incidence globally will increase. WHO believes the leptospirosis death rate may be between 5%  to 25% of infected patients. This does not mean that an infected person with access to proper healthcare has a similar risk of dying.

In 1995, leptospirosis ceased being a modifiable disease in the USA, so nobody really knows what the true incidence numbers there might be.

In 2009, in England, according to health authorities, there were 33 reported cases, of which 14 were acquired while the patients were abroad.

In 2009 in France there were 209 cases. Experts believe the numbers in the USA could well be over 1,000 each year. Australia reported 141 cases in 2006.

In the majority of cases, infection occurred in people who either worked in or were involved in:

  • Sewage works
  • Farms, and were regularly in contact with animals or infected water or soil
  • Death rates in developed nations are much lower than in poorer countries.

PATHOLOGY
Leptospirosis is characterized by the development of vasculitis, endothelial damage, and inflammatory 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. The overall structure of the liver is not significantly disrupted, but there may be intrahepatic cholestasis Hypertrophy and hyperplasia of Kupffer cells is evident , and erythrophagocytosis has been reported. In the kidneys, interstitial nephritis is the major finding, accompanied by an intense cellular infiltration composed of neutrophils and moncytes . Leptospires can be seen within the renal tubules. By electron microscopy, the tubular cell brush borders are denuded, the tubular basement membrane is thickened, and tubular cells exhibit mitochondrial depletion on addition, minor changes are seen in the glomeruli, suggesting an anatomical basis for proteinuria in leptospirosis.

Pathological findings in the heart include interstitial myocarditis with infiltration of predominantly lymphocytes and plasma cells, petechial hemorrhages (particularly in the epicardium), mononuclear infiltration in the epicardium, pericardial effusions, and coronary arteritis In the lungs, pulmonary congestion and hemorrhage are common and infiltration of alveolar spaces by monocytes and neutrophils occurs .Hyaline membrane formation may occur .Leptospires may be seen within endothelial cells in interalveolar septa, and attached to capillary endothelial cells.In skeletal muscles, particularly of the leg, focal necrosis of isolated muscle fibers occurs, with infiltration of histiocytes, neutrophils, and plasma cells. This evidence of myositis correlates with the intense myalgia reported by some patients .In brain, perivascular cuffing is observed.

SIGN AND SYMPTOMS OF LEPTOSPIROSIS
Leptospirosis signs and symptoms usually appear suddenly, about 7 to 14 days after the person has become infected; in some cases they may appear earlier or later.

Signs and symptoms of mild leptospirosis

  • Chills
  • Coughing
  • Diarrhea
  • Headaches, these can come on suddenly
  • High fever
  • Muscle pain, particularly lower back and calves
  • Nausea
  • Poor appetite
  • Red and irritated eyes
  • Skin pain

The patient usually gets better within one week without any treatment. A small proportion of them will not improve, and will go on to develop severe leptospirosis.

Signs and symptoms of severe leptospirosis - these will appear a few days after mild leptospirosis symptoms have disappeared. Signs and symptoms depend on which vital organs have been affected.

Signs and symptoms when the heart, liver and kidneys are affected

  • Fatigue
  • Irregular heartbeat, often accelerated heartbeat
  • Muscle pains
  • Nausea
  • Nosebleeds
  • Pain in the chest
  • Panting
  • Poor appetite
  • The hands, feet or ankles swell
  • Unexplained weight loss
  • Yellowing of the whites of the eyes, tongue and skin (jaundice)
  • Untreated patients may develop life-threatening kidney failure.

Signs and symptoms when the brain is affected - meningitis refers to infection on the outer layer of the brain, while encephalitis refers to infection of brain tissue. The signs and symptoms for both meningitis and encephalitis are similar, and may include:

  • A blotchy rash appears on the skin. When a glass is pressed against it, it does not change color or fade
  • Confusion or disorientation
  • Drowsiness
  • Fits (seizures)
  • High fever
  • Nausea
  • Photophobia (sensitivity to light)
  • Problems with physical movements
  • Stiff neck
  • The patient is unable to speak
  • Vomiting
  • Aggressiveness, or unusual behavior

Untreated meningitis or encephalitis can result in serious brain damage, and may be life-threatening.

Signs and symptoms when the lungs are affected - this is the most serious and life-threatening of all leptospirosis complications. Loss of lung function, when the patient cannot breathe, is a fatal condition.

Signs and symptoms may include:

  • High fever
  • Panting
  • Coughing up blood - in severe cases there is so much blood that the patient chokes

CAUSES OF LEPTOSPIROSIS
Leptospira
,a bacterium, may exist in raccoons, bats, sheep, dogs, mice, rats, horses, cattle, buffaloes, and pigs. They inhabit the animals' kidneys and are expelled when they urinate, and infect the soil or water supplies. Contamination can persist in soil or water for months.

People can become infected by:
1. Drinking contaminated water
2. Coming into contact with contaminated water or soil if they have unhealed cuts in their skin
3. Their eyes, nose or mouth come into contact with contaminated water or soil
4. Coming into contact with the blood of an infected animal (less common)

Humans are not commonly infected. Outbreaks may occur when there are floods. Humans rarely infect other humans, but might do so during sexual intercourse or breastfeeding.

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DIAGNOSIS FOR LEPTOSPYROSIS
In its early stages, mild leptospirosis is hard to diagnose, because many of the symptoms are similar to flu and other common infections. Diagnostic procedures for flu are not good at identifying leptospirosis.

It is only when severe leptospirosis is considered, that targeted diagnostic tests are ordered. If the patient is in an industrialized nation, the doctor will ask about any recent travel abroad, especially to areas where leptospirosis is common.

The doctor may also ask whether the patient swam in a lake, pond, canal or river. The patient should inform the doctor about any activities that occurred in a slaughterhouse, farm, animal care, or anything that might have involved contact with animal urine or blood.

If the doctor wants to confirm or rule out leptospirosis, a series of blood and urine tests will be ordered.

TREATMENT

Acute leptospirosis - the doctor may prescribe a 5 to 7 day course of some tetracycline antibiotic.

Severe leptospirosis - the patient will need to be hospitalized and given antibiotics intravenously. Depending on which organs are affected a ventilator to assist in breathing may be required, as might dialysis if the kidneys are affected. Intravenous fluids may be needed to hydrate the patient and provide essential nutrients.

Hospital stays may range from just a few weeks to several months. Duration of stay mostly depends on how the patient responds to antibiotic treatment, and how severely their organs are affected or damaged.

Leptospirosis is treated primarily with antimicrobial therapy. In uncomplicated infections that do not require hospitalization, oral doxycycline has been shown to decrease duration of fever and most symptoms. Hospitalized patients should be treated with intravenous penicillin G therapy, the treatment of choice. A recent clinical trial showed that third-generation cephalosporins are as effective as doxycycline and penicillin in the treatment of acute disease. A review of 7 randomized clinical trials comparing penicillin to no treatment or placebo, as well as penicillin to other agents, yielded inconclusive support for or against antibiotic therapy, especially in severe leptospirosis. A suggestion of shortened duration of illness with IV penicillin did not achieve statistical significance, nor was a difference demonstrated by any intervention in mortality or fever duration.

Severe cases of leptospirosis can affect any organ system and can lead to multi organ failure. In addition to antimicrobials, therapy is supportive. Patients should be managed in a monitored setting because their condition can rapidly progress to cardiovascular collapse and shock. Renal function should be evaluated carefully and dialysis considered in cases of renal failure. In most cases, the renal damage is reversible if the patient survives the acute illness. Access to mechanical ventilation and airway protection should be available in the event of respiratory compromise. Continuous cardiac monitoring should be attained; arrhythmias, including ventricular tachycardia and premature ventricular contractions, as well as atrial fibrillation, flutter, and tachycardia, can occur.

A few cases in the literature have reported that plasma exchange, corticosteroids, and intravenous immunoglobulin may be beneficial in selected patients in whom conventional therapy does not elicit a response.

In general, antibiotic therapy should be effective against leptospirosis and against the other pathogens considered in the differential diagnoses. However, what follows is a description of therapy specific to leptospirosis only.

Treatment approach
Leptospirosis presents with an extensive spectrum of clinical manifestations. Disease presents in 2 phases: an acute/initial phase followed 5 to 7 days later by the immune phase. Approximately 90% of affected patients will have a self-limited, subclinical illness with an uneventful recovery. The remaining patients may present with severe illness associated with the immune phase presenting with multi-organ failure that can result in death. Management of renal failure,  hepatic failure, pulmonary hemorrhages, and myocarditis need to be considered along with antibiotic treatment. Other presentations during this phase include aseptic meningitis and pancreatitis. Death may occur secondary to cardiac arrhythmias, cardiac failure, or adrenal hemorrhage.

Effective management of leptospirosis involves a combination of antibiotic therapy and aggressive supportive therapy for patients with organ damage. Antibiotic therapy must be initiated as soon as possible. The efficacy of antibiotics administered after the fifth day of symptom onset is questionable. In clinical practice, antibiotic therapy is most effective if it is started during the first 5 days of the appearance of symptoms.

Antibiotic therapy
Antibiotic recommendations for the management of leptospirosis are provided according to disease presentation. Preferred antibiotic agents include oral doxycycline for mild disease and intravenous benzyl penicillin for the management of severe cases.

Mild disease
The recommended oral antibiotics for adults and children with mild leptospirosis include doxycycline (not recommended in children 8 years of age or less) or azithromycin as first-line treatment, with ampicillin or amoxicillin as alternative first-line agents. Azithromycin is non-inferior when compared with doxycycline in the treatment of leptospirosis.  The treatment course is 7 to 10 days (except azithromycin), for which the treatment course is 3 days in adults and is not yet established in children).

Moderate to severe disease
Moderate to severe leptospirosis in adults and children is treated with intravenous antibiotic therapy. Benzyl penicillin is recommended as the first-line treatment, with ceftriaxone, cefotaxime, or ampicillin as alternative first-line agents. Ceftriaxone and cefotaxime have shown equivalent clinical efficacy when compared with benzyl penicillin for the management of severe leptospirosis. Adults with penicillin and/or cephalosporin allergy should be treated with azithromycin (not recommended below the age of 16 years) or doxycycline. Children with such an allergy should be treated with doxycycline. Doxycycline and other tetracycline antibiotics may cause permanent tooth discoloration or enamel hyperplasia and are not recommended in children 8 years of age or less. However, their use in this patient group may be considered on a case-by-case basis in severe leptospirosis, where the clinician should evaluate the benefits and risks of such treatment. Erythromycin is a possible alternative and can be given to children below the age of 8 years. Intravenous therapy is recommended for 7 days.

Supportive therapy
The type and degree of supportive measures required in patients with leptospirosis are highly variable and are assessed individually according to the organ involvement.

Severe disease is associated with the immune phase and may manifest with renal failure, hepatic failure, and /or pulmonary hemorrhages (Weil's syndrome). Other presentations during this phase include aseptic meningitis and pancreatitis. Death may occur secondary to cardiac arrhythmias, cardiac failure, or adrenal hemorrhage, hence the need for ongoing cardiac monitoring and support if required.

Overall, patients must be monitored for changes consistent with volume depletion and hemorrhage. Physicians should ensure adequate hydration, correct coagulopathy, and correction of electrolyte disturbances. Patients with pulmonary involvement, with or without haemorrhage, may require mechanical ventilation. Intravenous methylprednisolone has been used successfully in patients with pulmonary leptospirosis. Patients with acute renal failure may require acute dialysis in severe disease, taking into consideration the symptoms of fluid overload, acidosis, and hyperkalaemia. The decision must be made on a case by case basis. Intravenous corticosteroids have been used successfully in a patient with delayed diagnosis

Cardiac monitoring is recommended to timely identify arrhythmias secondary to cardiac irritability. Cardiac arrhythmias should be managed according to recognised guidelines such as those from the American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC).

Scarce data in the literature recommend plasma exchange. In addition, intravenous immunoglobulin (IVIG) has been used successfully in some cases

Patients at high risk of exposure
Doxycycline chemoprophylaxis has demonstrated protective efficacy in military personnel without known previous exposure.  It has also reduced illness severity in endemic areas but not serological evidence of infection. A once-weekly dose of doxycycline is recommended for persons at risk of unavoidable exposure. Other people at risk of exposure include those travelling to high-risk areas after natural disasters, such as flooding or cyclone, or during high-risk season The highest incidence of infection has been documented in tropical regions during the rainy season and late summer in temperate regions. Countries such as China vaccinate high-risk workers. An observational study has concluded that oral penicillin may be effective chemoprophylaxis against leptospirosis, however further research is needed.

PREVENTION: In non-tropical developed nations the risk of leptospirosis is negligible and most people do not need to avoid doing water sports. According to the National Health Service, UK, the chances of developing the infection in the UK is 1 in 10 million.

Experts say that those who regularly swim in freshwater should make sure that any skin cuts are covered with a waterproof dressing (also to protect against other infections, such as hepatitis A or giardiasis). After swimming in fresh water areas, you should shower thoroughly.

Prevention at work - those who are in contact with animals, or potentially contaminated water or soil should make sure they wear protective clothing and comply with local or national rules and regulations; this may involve wearing gloves, masks, boots and/or goggles.

Travelling to other countries - in areas where leptospirosis is common, do not swim in freshwater, and only come into contact with fresh water areas if you are wearing protecting clothing. Drink sealed bottled water, or boiled fresh water. Make sure any skin lesions are covered in a waterproof dressing. If you cut yourself, clean it and bandage it immediately.

CONCLUSION:
In developed countries, leptospirosis continues to be a disease of considerable economic significance in animal husbandry, but the major burden of human disease remains in tropical and subtropical developing countries. Several recent outbreaks of leptospirosis have drawn attention to the potential effects of climate change and human activity on the incidence of the disease and the broad spectrum of clinical manifestations. The development of several promising approaches to rapid 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 simpler assays which can be used more widely. However, many of these diagnostic advances will be unavailable to those populations for which they would be most useful. At a more fundamental level, understanding of the mechanisms of pathogenesis remains incomplete, but recent advances in the molecular biology of leptospires offer the prospect of more rapid progress in the future.

REFERENCES:
Martinez, R., et al. "Efficacy and Safety of a Vaccine Against Human Leptospirosis in Cuba." Rev Panam Salud Publica. 15.4 Apr. 2004: 249-255.
"Treatment of Acute Human Leptospirosis - Professional Guide." The Leptospirosis Information Center.
United States. Centers for Disease Control and Prevention. "Leptospirosis." Oct. 12, 2005.
"Vets Report Outbreak of Pet Infection." ClickonDetroit.com. Aug. 23, 2010.

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