Summary
- Leptospirosis: bacterial zoonosis
- Transmission via contact with contaminated fresh water
- Fever, muscle pain, cough, red eyes,
- Hepatomegaly, icterus, haemorrhagic tendency, meningitis, nephritis
- Difficult clinical diagnosis: water contact, leukocytosis, urine analysis, lumbar puncture
- Serology and direct detection of bacteria are difficult to carry out
- Treatment tetracyclines, penicillin
General
Leptospirosis is a bacterial disease which is distributed world-wide. There are even occasional cases in Belgium and the Netherlands. Leptospires are the only pathogenic spirochaetes which are free-living in the environment. In comparison, Treponema pallidum is only found in humans and Borrelia spirochaetes are only found in arthropods and mammals.
The severe form of leptospirosis was described in 1886 by the German Adolf Weil, Professor of Medicine at the University of Heidelberg. It is therefore still called Weil’s disease. In 1907 Stimson discovered the organism in kidney tissue from a patient who died during a yellow fever epidemic (see Clinical aspects).
Clinically it is indeed very difficult to differentiate between yellow fever and leptospirosis. In regions where scrub typhus and hantavirosis are endemic, differentiation between Orientia tsutsugamushi, hantavirus infection and leptospirosis on clinical criteria alone is not possible.
Taxonomy
The bacteria are very delicate and spiral-shaped. They have a typical terminal hook (Gr. leptos = delicate, slender, speira = spiral, interrogans = question mark). The bacteria are so thin that they cannot be detected with normal light microscopy. They can be detected using phase contrast or dark-field microscopy (urine) and by means of silver staining of tissue sections. Leptospires have a characteristic double membrane architecture with features of both Gram-positive and Gram-negative bacteria. Traditionally, the genus Leptospira contained two species: Leptospira interrogans sensu lato, which was pathogenic and L. biflexa sensu lato which was non-pathogenic for man. These species were differentiated by several phenotypic characteristics. However, new taxonomic work using DNA reassociation data (percentage of DNA: DNA hybridisation), the genus is now classified into 21 species. Within the species different serovars can be differentiated by cross-agglutination absorption testing. There are more than 200 serovars of which L. interrogans serovar icterohaemorrhagiae is the most important. Others include canicola, tarassovi, pyrogenes, bataviae, javanica, ballum, cynopteri, celledoni, panama, shermani, ranarum, bufonis, pomona, hebdomadis, autumnalis and grippotyphosa. There is a poor correlation between clinical severity and the serovar of the bacteria.
Transmission
The pathogenic bacteria can survive in fresh water but die in seawater. Infected animals retain bacteria in their kidneys for a long time and eliminate them in the urine. Transmission follows contact with fresh water contaminated with the urine of infected animals. Rats form the main reservoir, but other animals such as cattle, dogs, cats and pigs may also become infected. It is an important animal disease.
Leptospires are killed by gastric acid and bile salts. They penetrate the body via wounds and via the mucosa of the mouth, nose and eyes (conjunctivae). Water is the most important route of transmission, but direct contact with infected animals may also be significant (slaughterhouse workers, veterinary surgeons). It is a disease associated with certain occupations, e.g. workers in paddy fields or on sugar cane plantations, farmers, workers in sewers and canals, gold prospectors (gold dust obtained from water courses). People who bathe or swim in infected surface water are at increased risk of this zoonosis. Now that rafting, kayaking and adventure sports in tropical regions have become popular there is an increase in leptospirosis in tourists. Ideal conditions for transmission are produced when dirty streets with large rat populations are flooded.
Clinical aspects
In view of the many sub-species of leptospires, a wide spectrum of diseases is possible. Symptoms range from mild fever with a ‘flu’-like syndrome to atypical pneumonia, myocarditis, aseptic meningitis or the severe Weil’s disease with liver and kidney failure, meningitis and haemorrhage. The disease course has three phases: the first septicaemic, the second with leptospiruria (leptospires in the urine) and the third, convalescence phase.
During the first phase the leptospires are present in the blood in low numbers (too low to be detected in a blood smear using phase contrast microscopy). Subsequently the organisms disappear from the blood due to the formation of antibodies. Cellular defence also clears the bacteria from the various tissues. Leptospires persist in the kidney. In the renal tubules the organisms can multiply and cause renal damage. Bacteria are eliminated with the urine, although the concentration is quite low: < 104/ml urine. The bacteria may remain in the kidneys for months, even after clinical recovery. Leptospires might also persist in the choroid plexus of the brain.
Leptospirosis exhibits a wide spectrum of symptoms. Mild forms are often atypical and are generally missed unless they are specifically sought for. Severe forms exhibit a more dramatic symptomatology and course. In severe leptospirosis, after an incubation of 2 to 20 days there is sudden high fever. This is accompanied by pronounced headache (95%) and general malaise. Patients can sometimes pinpoint to within the hour when the illness began. The fever lasts approximately 7 days. The fever may then subside for a few days and then increase once more (biphasic fever). Absence of this fever pattern does not rule out the disease. Significant muscle pain is almost always present. If it is absent the diagnosis is improbable. The eyes are bloodshot (25%), but there is no pus, unlike in purulent conjunctivitis. The bacteria may be present for months in the aqueous humour of the anterior chamber of the eye and in 2% of patients chronic inflammation (uveitis) may occur. There are two patterns: (1) self-limiting anterior uveitis with photophobia, blurred vision and pain, and (2) posterior or panuveitis with cotton-wool spots, choroiditis, retinal haemorrhage, vitreous humour membranes and papillitis. There is sometimes a sore throat and a dry cough, later possibly haemoptysis. In 10 to 30% of patients there is a spotty skin rash of the lower legs. [This was initially described as “Fort Bragg Fever”, caused by L. interrogans autumnalis]. After a few days there are organ symptoms. Meningism may occur early, but is more frequent in the second phase. Neck stiffness is not always present. Two thirds of patients suffer nausea and/or vomiting. Swollen lymph nodes are only present in a minority of patients. The spleen is swollen in 20% of cases.
Involvement of the liver is characterised by hepatomegaly, jaundice and a haemorrhagic tendency. Icteric as well as anicteric cases do occur. Conjunctival suffusion is an important orienting sign. Typically the icterus is described as more orange compared to that of viral hepatitis but in practice this is not a very reliable sign. The gall bladder may become inflamed (acute cholecystitis). Transaminases in mild cases increase up to 3x normal but in severe cases up to 50 times. Haptoglobin is usually normal. Patients with Weil’s syndrome have a poorly understood haemorrhagic diathesis, although demonstrable coagulation defects or severe thrombocytopenia might be absent.
Marked elevation of CK levels indicates muscle damage and occurs only in severe cases. Muscle pain occurs especially in the calves, can lead to local swelling which can be so severe that patients cannot walk anymore. Pectoral, back and abdominal muscles may also be involved. Palpation of the calves tends to be painful. The injured muscles heal without scarring. CK levels and muscle symptoms usually diminish in the second week of illness. Rhabdomyolysis seems to be secondary to direct muscle cell invasion with cell necrosis and small intramuscular haemorrhages, but the role of a hypothetical exotoxin has not been excluded. Myocarditis occurs and often leads to congestive heart failure and cardiogenic shock. Electrocardiographic abnormalities are common.
Atypical pneumonia with possible blood-tinged sputum can be expected in severe cases. Pulmonary lesions are primarily haemorrhagic rather than inflammatory. Patients are at risk for secondary bacterial pneumonia.
Kidney damage leads to proteinuria, haematuria and uraemia. Hypovolaemia and poor renal circulation may further exacerbate the renal damage. Hypovolaemia is characterised by oliguria, low blood pressure, diminished skin turgor, flat neck veins. If it is not corrected by giving fluids tubular necrosis will follow. Temporarily haemodialysis is needed in severe renal failure. Sterile pyuria, proteinuria, granular casts, myoglobinuria and enlarged kidneys occur in some patients. The haem part of myoglobin separates form the globin moiety in an acid environment (pH < 5,4). Renal tubular obstruction due to precipitation of myoglobin is important. Myoglobin is less toxic if there is no dehydration or acidosis. Therefore alkalinisation of the urine is important.
During the second phase there is sometimes meningeal irritation with neck stiffness and a picture of lymphocytic meningitis. However this usually only lasts for a few days. Organ complications such as kidney failure and haemorrhages also occur in this phase. The total period of illness is approximately 3 weeks to one month. The mortality is between 5 and 30 %; severe icterus having a poor prognosis. If the patient survives there is usually no residual damage. A long convalescent period is typical.
In 2001 a new bacterium was discovered in Denmark, Leptospira faini serovar Hurstbridge. In two infected patients there was an unusual presentation: chronic infection characterised by subconjunctival bleeding (6 months), intermittent abdominal pain (5 months), severe headache for 2 months accompanied by dizziness and one month of jaundice. Further research needs to be carried out to describe the full pathogenic spectrum of this bacterium.
Differential diagnosis:
This is very broad in view of the variable symptoms. It includes Hantavirus infection, influenza, gastro-enteritis, meningitis, malaria, hepatitis, cholangitis, rickettsiosis (e.g. scrub typhus), borreliosis, typhoid fever, Reye’s syndrome, arboviroses such as yellow fever, Rift valley Fever, Crimean-Congo haemorrhagic fever and West Nile fever as well as arenaviroses. In the case of haemorrhagic tendency; Gram-negative bloodstream infection and the various viral haemorrhagic fevers should be considered.
Diagnosis
Diagnosis is quite difficult. This disease is often missed. The disease may be clinically suspected. Exposure to potentially contaminated water (occupation, accident, swimming, etc.) should be enquired about. In a severe infection there is an influenza-like syndrome with a sudden onset, followed by hepatitis with conjunctivitis and then meningitis, haemorrhages and renal involvement. Milder infections generally exhibit a biphasic fever with muscle pain, red eyes, jaundice and meningism. All the signs are not always present.
There is proteinuria, pyuria and microscopic haematuria. The cerebrospinal fluid initially contains neutrophils. Later lymphocytes predominate, together with elevated protein and normal glucose. In general there is significant leukocytosis, but this is not constant. Thrombocytopenia is common. Early in the course of the disease leptospires can rarely be found in the blood, urine or cerebrospinal fluid (the tests are not very sensitive). Subsequently the bacteria are only found in the urine. Since these are very thin organisms (0.1 µm diameter) a dark-field microscope is needed to detect them. Indirect illumination is used in this method instead of direct illumination, so that fine structures can be detected which are not visible with the traditional microscope. This method is not very sensitive and has been responsible for many errors (many false positives and false negatives).
Serology can be performed. The traditional serology using micro-agglutination test or MAT, requires a well-functioning laboratory this will not be available in practice in low-resources settings. For this reason in 1997 a simple dipstick method (the LEPTO Dipstick®) was developed to detect anti-leptospire IgM in serum. The test is based on a broadly reactive leptospire antigen fixed to a solid strip, together with stabilised monoclonal anti-IgM which has been conjugated with a dye as a signal system. The sensitivity and specificity are quite good (both approximately 90%). The test is not available everywhere and still has to be validated in various geographical regions. Interpretation of MAT serology results to identify the responsible serovars is rather difficult, because the highest titre does not necessarily correlate with the actual serovar which is responsible for the infection.
Culture of the bacteria is the gold standard but is not practical in most settings. Culture of leptospires is difficult and requires non-standard equipment. Special media are required for isolation such as Fletcher’s, Ellinghausen’s, or polysorbate 80 media. Blood and CSF specimens are positive during the first 10 days of the illness. Urine cultures become positive during the second week of the illness and remain so for up to 30 days after resolution of symptoms.
Treatment
The earlier treatment is started, the better the results. Antibiotics such as tetracyclines within the first 4 days are effective in shortening the illness. Sometimes leptospires persist in urine, even with correct treatment. For mild infections, it is preferable to give doxycycline 200 mg per day for 1 week. If there is vomiting IV penicillin is used. For severe infections, ceftriaxone can also be used. This allows for once daily dosing, which is more practical than the multiple dosing schemes using penicillin. Azithromycin and ampicillin are also active against leptospires. Chloramphenicol is not.
Symptomatic and supportive therapy is very important. If there is myoglobinemia, alkalinisation of the urine is important in order to limit the renal damage.
Prevention
Since rats form the main reservoir and contaminate surface water and drains, their control is important for prevention. Nevertheless it should not be forgotten that the animal reservoir is much broader (e.g. dogs etc.) and cannot be eradicated completely. Wearing boots when working in infected water is advisable. Chemoprophylaxis of 200 mg doxycycline per week may be taken as a preventative in high-risk situations. After infection there is protection against the infecting serovar but no cross-immunity.
A vaccine has been developed in Cuba and in France (by the Pasteur Institute). The vaccine is difficult to obtain and is of limited benefit. Many other vaccine candidates have unacceptable side effects and give brief protection without cross-immunity. There are vaccines available for animals.
