RATIONAL DIAGNOSIS AND TREATMENT OF LEPTOSPIROSIS
Dr. Sarala Rajajee*
Consultant Pediatrician and Hematologist, Chennai.*
The genus Leptospira consists of two species, L. Interrogans and L. biflexia, only the former of which is known to cause human disease. More than 200 serovars of L. Interrogans have been identified. Leptospira are spiral-shaped aerobic spirochetes with 18 or more coils per cell. They tend to stain poorly with common laboratory stains and are best visualized by dark field microscopy, silver strain or fluorescent microscopy.

Humans most often become infected after exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue. Portals of entry include cuts or abraded skin, mucous membranes or conjunctiva. The infection is rarely acquired by ingestion of food contaminated with urine or via aerosols. Controversy exists as to whether Leptospira can penetrate the intact skin.

Leptospirosis is associated with a variable clinical course. The disease may manifest as a subclinical illness followed by seroconversion, a self-limited systemic infection, or a severe, potentially fatal illness accompanied by multiorgan failure.

Leptospirosis presents with the abrupt onset of fever, rigors, myalgia and headache in 75 to 100 percent of patients, after an incubation period of two to 26 days (average 10 days). From 25 to 35 percent of cases have an associated non-productive cough and approximately 50 percent experience nausea, vomiting and diarrhea. Other less common symptoms include arthralgia, bone pain, sore throat, and abdominal pain; acalculous cholecystitis can occur in children. While leptospirosis has classically been described as a biphasic illness, fewer than 50 percent of cases exhibit a biphasic course.
Physical Examination
Physical examination is often unrevealing. An important, but frequently overlooked sign, is conjunctival suffusion. This is not a common finding in other infectious diseases, and its presence in a patient with a non-specific febrile illness should raise the diagnosis of leptospirosis. From 7 to 40% patients can have muscle tenderness, splenomegaly, lymphadenopathy, pharyngitis, hepatomegaly, muscle rigidity, abnormal respiratory auscultation, or skin rash. Aseptic meningitis can be documented in 50 to 85 percent of patients if cerebrospinal fluid (CSF) is examined after seven days of illness. The meningitis is thought to be secondary to a host immune response to the organism rather than to direct infection.

During an outbreak of leptospirosis in India, 90 children with suspected leptospirosis were screened with serologic studies. 15 (17 percent) had leptospirosis. Clinical features that were significantly associated with leptospirosis included: (a) Conjunctival suffusion, (b) Hemorrhage, (c) Abdominal pain, (d) Hepatosplenomegaly and (e) Edema

In a study by S. Rajajee et al., one hundred and thirty nine cases were diagnosed during a 4-year period. The commonest symptoms were fever 133 (96%), headache and myalgia 34 (24%). Jaundice was present in only 25 (18%) of cases renal failure in 2 cases. The frequently encountered clinical signs were hepatomegaly in 100 (72%), myalgia in 34 (24%) with icterus in 25 (18%), 12 (9%) children presented with shock and 10 (7%) had meningitis, CPK estimated was a useful index of myositis. The diagnosis was confirmed by Dark field microscopy and paired or single high serological tests (MAT, ELISA IgM). Overlapping infections such as culture positive Salmonella typhi with leptospirosis (Serology positive) or Dengue Hemorrhagic fever with Leptospirosis presented with complications such as a myocarditis, shock and ARDS. Presentation of non-icteric forms of Leptospirosis are often non-specific and may be missed unless there is a high index of suspicion. This study emphasizes the myositis and meningitis forms of leptospirosis. Delayed diagnosis leads to increased mortality and morbidity.

While most cases of leptospirosis are mild to moderate, the course may be complicated by renal failure, uveitis, hemorrhage, acute respiratory distress syndrome, myocarditis and rhabdomyolysis. Liver failure is generally reversible and not a cause of death in leptospirosis. Dyspnea, oliguria, WBC counts above 12,900/mm3, repolarization abnormalities on electrocardiograms, and alveolar infiltrates on chest radiography have been associated with adverse outcome. Vasculitis with necrosis of extremities may be seen in severe cases.

The potential severity of leptospirosis was illustrated in a retrospective study of 60 patients with leptospirosis requiring ICU admission in India. Multiorgan failure developed in 46 patients (77 percent); the mortality for patients with leptospirosis requiring ICU admission was 52 percent.

Severe pulmonary disease may be under diagnosed in regions of high endemicity. Among 321 patients with serologic and clinical evidence of leptospirosis in Peru, seven (3.7%) had severe pulmonary manifestations, including Hemoptysis in six. Five of the seven patients died, four from pulmonary hemorrhage and one from acute respiratory distress syndrome and multiorgan failure
Laboratory Findings
Leptospirosis is a nonspecific clinical illness, and routine laboratory tests are similarly non diagnostic. White blood cell (WBC) counts are generally less than 10,000/mm3 but may range between 3,000 and 26,000/mm3; a shift to the left is seen in about two-thirds of patients. Urinalysis frequently shows proteinuria, pyuria, granular casts and occasionally microscopic hematuria. Elevated creatine kinase is found in approximately 50% of patients and may be a useful clue for the diagnosis. Approximately 40% of patients have minimal to moderate elevations of hepatic transaminases (usually <200 IU/L). Hyponatremia is common in severe leptospirosis.

Jaundice is only observed in patients with Weil's Syndrome, the most severe form of leptospirosis. Patients with this syndrome can develop hepatic and renal dysfunction and hemorrhage. In occasional patients, the serum bilirubin concentration reaches 60 to 80 mg/dL (1026 to 1368 mmol/L).

Thrombocytopenia is uncommon, but a poorly understood hemorrhagic diathesis may occur in the absence of demonstrable coagulation defects or severe thrombocytopenia. Pancytopenia has been reported as the presenting manifestation in case reports with complete resolution following treatment with penicillin. The CSF may show a neutrophilic or lymphocytic pleocytosis with minimal to moderately elevated protein concentrations and normal glucose. A low CSF glucose concentration is rarely seen.

Imaging - Chest radiographs may show small nodular densities, which can progress to confluent consolidation or a ground glass appearance. Pathologically, these infiltrates may represent alveolar hemorrhage, ARDS or pulmonary edema.
Differential Diagnosis
Leptospirosis may be confused with a number of different infectious illnesses. Conjunctival suffusion, when it occurs, is one of the most reliable distinguishing features since it rarely occurs with any infectious illness other than leptospirosis.

Malaria and dengue share some common clinical features and similar endemic patterns with leptospirosis.

Leptospirosis may mimic infection with Salmonella typhi particularly in patients with prominent gastrointestinal complaints.

Acute viral illnesses including influenza may mimic leptospirosis, particularly in patients with prominent respiratory tract symptoms.
Diagnosis
Because the clinical features and routine laboratory findings of leptospirosis are not specific, a high index of suspicion must be maintained for the diagnosis. The organism can be cultured, but the diagnosis is more frequently made by serologic testing.

Leptospirosis can be confirmed by culture of the organism from clinical specimens in appropriate media. Blood and CSF specimens are positive during the first 10 days of the illness. Isolation of the organism from the blood is successful in approximately 50% of cases. Urine cultures become positive during the second week of the illness and remain so for up to 30 days after the resolution of symptoms.

Serology - Because some clinical microbiology laboratories do not offer culture or other sophisticated techniques for the diagnosis of leptospirosis, serological tests are most often used for confirmation. A number of serologic tests are employed or are under development, including the microscopic agglutination test (MAT), macroscopic agglutination test, indirect hemagglutination, and ELISA.

While all of these assays are useful in establishing the diagnosis, the gold standard is considered to be the MAT. Unfortunately, this test requires live organisms, considerable expertise. Like other serologic tests, the MAT is most specific when a fourfold or greater rise in titer is detected between acute and convalescent serum specimens. However, a single titer of > 1 : 800 is strong evidence of current or recent infection with leptospira. Cross reactive antibodies have been associated with syphilis, relapsing fever, Lyme disease, and legionellosis. The level of the antibody titers as found in the MAT cannot be used to predict the serovar that infects the individual patient.

The commercially available rapid tests, the microplate IgM ELISA and an IgM dot-ELISA dipstick test, performed well in studies conducted in the United States and Thailand that used MAT as the comparator.

Newer tests - Molecular techniques, such as polymerase chain reaction (PCR), are being explored to assist in the diagnosis of leptospirosis. While not widely available, these show considerable promise for a quick, accurate diagnosis.
Summary
  • Leptospirosis is a zoonosis with protean manifestations caused by the spirochete, Leptospira interrogans.
  • Humans most often become infected after exposure to environmental sources, such as animal urine, contaminated water or soil, or infected animal tissue through cuts or abraded skin, mucous membranes or conjunctiva.
  • Leptospirosis is associated with a variable clinical course. The disease may manifest as a subclinical illness followed by seroconversion, a self-limited systemic infection, or a severe, potentially fatal illness accompanied by multiorgan failure.
  • Leptospirosis presents with the abrupt onset of fever, rigors, myalgia and headache in 75 to 100 percent of patients. While leptospirosis has classically been described as a biphasic illness, fewer than 50% of cases exhibit a biphasic course. Conjunctival suffusion in a patient with a nonspecific febrile illness should raise suspicion for the diagnosis of leptospirosis.
  • While most cases of leptospirosis are mild to moderate, the course may be complicated by renal failure, uveitis, hemorrhage, acute respiratory distress syndrome, myocarditis and rhabdomyolysis.
  • Because the clinical features and routine laboratory findings of leptospirosis are not specific, a high index of suspicion must be maintained for the diagnosis. The organism can be cultured, but the diagnosis is more frequently made by serologic testing. The microscopic agglutination test (MAT) is considered the gold standard for serologic diagnosis. Rapid serologic tests have been developed that have performed well in clinical studies.
Treatment and Prevention of Leptospirosis Treatment
The vast majority of infections with leptospira are self-limiting. Although penicillin, tetracyclines, chloramphenicol, and erythromycin have anti-leptospiral activity in vitro and in animal models, it remains controversial whether antimicrobials produce a beneficial effect in mild human leptospirosis since the illness has a variable natural history. Nevertheless, if the illness is severe enough to result in a physician visit and the diagnosis is recognized, antibiotic therapy should be given.
Efficacy
Two small, randomized, placebo-controlled trials have shown a benefit from antimicrobial therapy. In one in which doxycycline (100 mg PO twice daily) was compared to placebo, doxycycline shortened the illness by an average of two days and prevented shedding of the organism in the urine. In the second trial, patients with severe leptospirosis who were treated with penicillin (6 million units daily) had fewer days of fever, more rapid resolution of serum creatinine elevations, and a shorter hospital stay; penicillin therapy also prevented urinary shedding.

Two other trials compared penicillin (6 million units daily) to ceftriaxone (1 g every 4 hours), to cefotaxime (1 g every six hours), and to doxycycline (100 mg IV every 12 hours). All regimens were therapeutically equivalent. The latter study was an open label, randomized trial of 264 patients with severe leptospirosis in northeastern Thailand. Although, all the regimens had similar efficacy for leptospirosis, 25% of patients presenting with a suspicion of severe leptospirosis were diagnosed with rickettsioses with or without leptospirosis. In patients with coinfection or with only rickettsial infection, penicillin was significantly less effective than doxycycline or cefotaxime. The authors recommended doxycycline or cefotaxime (or ceftriaxone) for the treatment of severely ill patients for whom the diagnosis would be in doubt in areas endemic for leptospirosis and rickettsial infection.

In vitro studies show that the newer macrolides, fluoroquinolones, and telithromycin have excellent activity against leptospires, but data are lacking for clinical efficacy.
Adverse reactions
The Jarisch - Herxheimer reaction may occur with penicillin therapy. In a case report, reversible cardiomegaly with a suggestion of pulmonary hypertension by echocardiography occurred within six hours of the administration of cefotaxime and doxycycline for leptospirosis.

Supportive care with dialysis, ventilatory support, and blood products may be necessary in severe cases of leptospirosis.
Antimicrobial treatment
Human leptospirosis is often self-limited and requires no antibiotic treatment. Symptomatic patients presenting for medical care should be treated to shorten the illness and decrease shedding of the organism in the urine.

Oral doxycycline is useful for outpatients because it is also effective for rickettsial disease, which can be confused with leptospirosis (100 mg orally twice daily in adults; 2 mg/kg per day in two equally divided doses in children > 8 years of age to a maximum dose of 200 mg daily). The exceptions are children < 8 years or pregnant women, in whom treatment is with amoxicillin (25 to 50 mg/kg in three equally divided doses.

In children with severe disease, intravenous therapy with penicillin (250,000 to 400,000 units/kg per day in four to six divided doses; maximum dose 6 million units daily), doxycycline (4 mg/kg per day in two equally divided doses; maximum dose 20 mg daily), ceftriaxone (80 to 100 mg/kg once daily; maximum dose 4 g daily), or cefotaxime (150 to 200 mg/kg per day in three to four equally divided doses; maximum dose 12 g daily). Doxycycline should be avoided in children less than eight years of age.

Children less than eight years of age with a severe penicillin allergy should be desensitized to penicillin, ceftriaxone, or cefotaxime. If desensitization is not possible, therapy with azithromycin (10 mg/kg on day one; maximum dose 500 mg/day, followed by 5 mg/kg/day once daily on subsequent days; maximum dose 250 mg/day) or clarithromycin (15 mg/kg/day divided in two equal doses; maximum dose 1 g/day).

The duration of treatment is usually five to seven days.

Treatment of infected pregnant women is similar to that in other patients with the exception of the choice of drugs. Penicillin and ceftriaxone are safe in pregnancy, but doxycycline should not be given. Among patients with severe penicillin allergy, a macrolide may be given, based upon in-vitro susceptibility testing.
Prognosis
Mortality rates in hospitalized patients with leptospirosis have ranged from 4 to 52%. A retrospective review of 282 cases of leptospirosis during a 2002 outbreak in India identified risk factors for mortality. Significant predictors of death in logistic regression analysis included involvement of the lung (e.g., Hemoptysis) and central nervous system.

The major control measure available for humans is to avoid potential sources of infection such as stagnant water, water derived from run-off from animal farms, rodent control, and protection of food from animal contamination.
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