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Diagnosis and reasoning

In this time and age of frequent foreign travel, it is not uncommon for doctors in temperate countries to encounter patients with diseases acquired from the tropics and subtropics. Thus, appreciation of the geographical patterns of illnesses is essential when evaluating such patients; the gentleman featured in this case is an excellent example in this regard. Note the interesting pattern of symptoms he has presented with: - Intermittent fever, a generalized headache, and myalgia for 7 days - Jaundice for 2 days - Dark urine for 2 days The initial cluster of symptoms is most suggestive of a prodrome; the subsequent development of jaundice hints at progressive involvement of the liver or biliary system. The dark color of urine might be due to concentration or the presence of bilirubin; alternate possibilities include hematuria secondary to glomerular or urinary tract pathology, or hemoglobinuria secondary to intravascular hemolysis. When this group of symptoms are considered in isolation, a wide array of differential diagnoses present themselves; these include acute viral hepatitis, leptospirosis, certain rickettsioses, hantavirus infection, dengue, falciparum malaria, and yellow fever. However, a review of the Centers for Disease Control and Prevention (CDC) monograph on diseases endemic to Sri Lanka immediately rules out yellow fever; falciparum malaria has also been eradicated from the island. The CDC also mentions that dengue, leptospirosis and acute viral hepatitis have relatively higher rates of prevalence in Sri Lanka (as compared to the other remaining diagnoses), making these the key differentials to consider in this patient. Another important point in the history is his exposure to unchlorinated water; this makes leptospirosis a key differential. In this context, one could postulate that the darkening of his urine is due to hematuria secondary to icterohemorrhagic leptospirosis. A careful examination brings a few signs to light. Note the presence of conjunctival injection on examination; while this is a classical finding of leptospirosis, it may also occur in viral infections such as dengue. However, icterus is a rather uncommon sign in dengue, and typically indicates severe disease which is often accompanied by features of fluid leakage, manifesting as hypotension, ascites or pleural effusion; the absence of these features makes this diagnosis less likely. Bilateral calf tenderness can also occur in all of the above, as can tender hepatomegaly; thus, while the clinical findings most favor leptospirosis, they are not diagnostic. Targeted investigation starting with a full blood count (FBC), urinalysis, liver profile and creatine phosphokinase (CPK) assay is an essential next step. The FBC reveals the presence of a neutrophil leukocytosis; this is more in favor of leptospirosis. In dengue and viral hepatitis a lymphocytosis or lymphopenia would be typical. Unfortunately thrombocytopenia may occur in all of these conditions, and is not diagnostically helpful here. The urinalysis shows turbidity with significant amounts of protein, pus cells and red cells. These findings are compatible with leptospirosis, with dengue and viral hepatitis being unlikely to give rise to such a picture. Note also the presence of hyaline and granular casts; these are also a common finding in leptospirosis. His liver profile is also profoundly illuminating. The elevated direct and total bilirubin levels and alkaline phosphatase (ALP) levels suggest a cholestatic picture; this can occur in any form of hepatic inflammation. However, note the mildly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In acute viral hepatitis, one typically sees marked elevation of AST/ALT levels (often in thousands of units). Note also that CPK is significantly elevated, indicating that myositis is present. While both viral infections and leptospirosis can give rise to this picture, CPK levels in dengue myositis are often far higher, ranging from thousands to hundreds of thousands of units. Thus, leptospirosis is indeed the probable diagnosis; confirmatory testing via a leptospira dipstick assay is a good next step, as this has a specificity and sensitivity comparable to that of enzyme-linked immunosorbent assay (ELISA) for leptospira IgM. This turns out to be positive, clinching the diagnosis. Treatment with intravenous (IV) penicillin or a 3rd generation cephalosporin should be commenced immediately; this will very likely result in rapid resolution of symptoms. Acetaminophen should also be administered, given its antipyretic as well as analgesic properties. Oral doxycycline is useful only in milder forms of the illness. Lamivudine, an antiviral agent used in acute hepatitis, has no place in the management of this patient. Considering the patient in this case, an MAT was performed and came back several days later with a titre of 1:6400, confirming the presence of leptospirosis.


Leptospirosis is a zoonotic disease caused by Leptospira interrogans, a pathogenic spirochete. The annual incidence of clinical disease is estimated to range from 10 to 100 per 100,000 individuals in tropical settings and 0.1 to 1.0 per 100,000 individuals in temperate regions. Overall, it is estimated that between 100 to 200 cases of leptospirosis are identified annually in the United States, with around half of these occurring in Hawaii. Humans usually acquire the disease by direct or indirect contact with the urine of an infected animal - mostly rodents. The usual portal of entry is via abrasions or cuts in the skin or through the conjunctivae; the infection may enter via intact skin following prolonged immersion in water. Note in particular that individuals taking part in recreational water sports such as swimming, canoeing, white water rafting and freshwater fishing are at an increased risk of acquiring the disease. Occupational exposure is common among farmers, sewage workers, slaughterhouse workers, veterinary surgeons, field workers, and military personnel. The spectrum of human disease caused by leptospira is extensive, ranging from subclinical infection to a severe syndrome of multiorgan dysfunction with high mortality. The classical syndrome of Weil's disease represents only the most severe cases. The clinical presentations of leptospirosis include a milder biphasic illness (anicteric form) and fulminant disease (icterohemorrhagic form). The biphasic illness consists of an acute or septicemic phase lasting about a week, followed by the immune phase, characterized by antibody production. It presents as a febrile illness with associated headache, significant myalgia (particularly in the muscles of the back and calves), abdominal pain, conjunctival suffusion, and less often, a skin rash. Icteric leptospirosis is generally more severe, with an often rapidly progressive clinical course; complications such as aseptic meningitis, renal failure, pulmonary haemorrhages, acute respiratory distress syndrome, uveitis, and cardiac involvement may occur. Weil's disease represents the most severe form of the illness. This syndrome can develop after the acute phase as the second phase of a biphasic illness, or simply present as a single, progressive illness. Note also that patients may experience a 'pseudo stage' in which the symptoms as well as the spirochetes disappear from blood cultures and cerebrospinal fluid; this may last for several days. The leukocyte count may range from below normal to moderately elevated in anicteric disease, with neutrophil predominance; liver function tests may reveal a slight elevation in aminotransferases, bilirubin, and alkaline phosphatase. Proteinuria, pyuria, and often microscopic hematuria may be observed upon urinalysis. Hyaline and granular casts may also be present during the first week of illness. In icteric disease, white blood cell counts are often markedly elevated, while marked thrombocytopenia may be present; renal functions may show significant deterioration. Serum creatinine phosphokinase levels may also be markedly increased. Liver function tests generally show a significant rise in bilirubin, with lesser increases in transaminases and a marginal increase in alkaline phosphatase. Note that the increase in bilirubin is generally out of proportion to the other liver function test values. Dark-field microscopic examination of body fluids may detect leptospires, however, this is of poor sensitivity; instead, isolation of the organism by cultures or a microscopic agglutination test (MAT) is most often used for diagnosis. Blood and CSF can be cultured during the first week of symptomatic illness, while urine can be cultured from the start of the second week. In the MAT, a fourfold or greater rise in titers between paired sera is diagnostic of active infection. However, the centers for disease control (CDC) mention that a single titre of ≥1/200 in the presence of a clinically compatible presentation can be used to define 'probable' leptospirosis, while in areas where leptospirosis is endemic, a single titer of ≥1/800 in symptomatic individuals can be considered to be generally indicative of the disease. Note that while MAT may indicate probable serovars, definitive identification can only be performed following isolation techniques; while antigen detection tests using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) methods are also used, they are less sensitive. Other serological tests include IgM antibody detection via ELISA, indirect hemagglutination test (IHA) and molecular diagnostic tests. General treatment measures include bed rest, monitoring of the fluid balance, electrolytes and cardiac functions, analgesics for headaches and muscular pains, and antipyretics for fever. Intravenous (IV) fluids should be used in individuals with oliguria due to dehydration, or in patients with hypotension, in order to maintain appropriate blood pressure and urine output. Following hydration and correction of blood pressure, furosemide may be used to ensure adequate diuresis. Note that dialysis may be required in cases of rapidly worsening renal failure. Definitive treatment with antibiotics should be initiated as soon as the diagnosis is suspected, as this has been shown to reduce the severity of the illness. Doxycycline is standard therapy in patients with early leptospirosis, while either IV penicillin or a 3rd generation cephalosporin may be used in late and severe disease. The prognosis of the disease varies greatly, and depends on both the severity of symptoms as well as the infecting serovar. Note that the serovars icterohaemorrhagiae and copenhageni have a high tendency to cause more severe disease. Most deaths occur between the 10th and 15th days of illness; renal failure is commonly associated with a poor outcome. No vaccine is currently available for prevention of the disease. However, oral doxycycline may be used for chemoprophylaxis of susceptible persons. Avoiding contact with potentially infected animals, and appropriate use of protective equipment is the main mode of deterrence. Proper sanitation and rodent control measures are also important in controlling the incidence of the disease.

Take home messages

  1. Leptospirosis is a zoonotic infection transmitted to humans through rodents.
  2. Early initiation of definitive treatment is critical as this directly impacts on the ultimate outcome.
  3. Doxycycline is used for the treatment of mild disease; IV Penicillin or 3rd generation Cephalosporins are used in patients with more severe disease.

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