Gorgas Case 2018-09

Discussion: Positive IgM for leptospirosis; the test used has a reported sensitivity of 84% and specificity of 91% for the diagnosis of acute leptospirosis [Cien Saude Colet 2017;22:4001]. Negative malaria smear. Negative HIV and Hepatitis B serology. Positive IgM for dengue with negative NS1 antigen, both taken the day of admission. The positive IgM for dengue with a negative NS1 antigen taken before seven days of illness makes the diagnosis of acute dengue less likely in this case. In addition, liver compromise with transaminitis in dengue is common, but the constellation of symptoms and signs, in particular the presence of muscle pain, the development of significant jaundice with relatively normal liver transaminases, acute renal failure and pulmonary involvement is most highly suggestive of leptospirosis. Serology by the Microagglutination technique (MAT) for leptospirosis, which is considered the gold standard for diagnosis was not available at the Hospital.

Leptospirosis needs to be considered in the differential diagnosis of any undifferentiated tropical fever.  It has protean clinical manifestations and at differing stages of the illness may be impossible to distinguish clinically from yellow fever, dengue, rickettsial disease, typhoid, malaria, brucellosis, tuberculosis, or viral hepatitis.

Typically, leptospirosis is described as having an initial septicemic phase, which may be mild, with fever, myalgia, headache, conjunctival suffusion (see Gorgas Case 2008-04 and Gorgas Case 2009-04), and abdominal wall pain.  Our patient had the typical muscle tenderness in calves often described as distinguishing features of leptospirosis and marked jaundice, but did not present with conjunctival suffusion.  The illness is often self-limited but in some cases, after an apparent recovery, may present a biphasic illness and progress to an immune stage manifest by fever, meningitis, and uveitis.  The two distinct stages may be obscured and run together in severe disease (Weil’s Disease) manifested by the classic defining triad of jaundice, hemorrhage, and renal failure.  Weil´s disease has a mortality of 10%.

The true incidence of pulmonary involvement is unclear, appears to have increased in recent years, and may be as high as 70%.  Patients may present with symptoms ranging from cough, dyspnea and hemoptysis to ARDS [Respirology 2018;23:28 and Clin Infect Dis. 2005 Feb 1;40(3):343-51].  The present case shows a typical radiographic evolution that is thought to represent intra-alveolar and interstitial hemorrhage [Braz J Infect Dis. 2007 Feb;11(1):142-8].  Pulmonary involvement has emerged as the main cause of death due to leptospirosis in some countries.

Jaundice and bilirubinemia out of proportion with hepatocellular damage is the usual finding in leptospirosis.  This is manifest as significant jaundice in the face of an SGOT and SGPT that is no more than 3-4X normal with an alkaline phosphatase that may be as high as 10X normal.  The mechanism of the cholestasis in leptospirosis is not entirely clear.  In severe or prolonged disease, renal damage will occur and the sediment is usually active.  Non-oliguric hypokalemic renal failure is characteristic.  Progression to oliguric renal failure would be predictive of higher mortality. More recently, neutrophil and platelet counts have been identified as predictors of mortality [Trans R Soc Trop Med Hyg 2017;111:531].

Isolation of Leptospira in culture is difficult and insensitive. Culture in special media in tubes held at 28-30°C for prolonged periods is necessary.  Blood is only positive in the first week of illness after which urine becomes progressively more positive.  Cultured leptospires are only visible and confirmed using dark-field microscopy.  Diagnosis is most often serological and retrospective [MAT], IgM ELISA, or a commercially available rapid dipstick test.

Leptospirosis is endemic in almost every country but more so in the tropics. The incidence of leptospirosis in the Americas is difficult to determine. A survey of 24 countries performed between 1996-2005 showed that Brazil (3165 annual cases) and Cuba (558 annual cases) had the highest burden of disease [Rev Panam Salud Publica 2012;32:169]. Peru reported approximately 100 cases annually during that study period. Traditionally an occupational disease and a disease of poverty in peri-urban slums, it has also emerged as a disease of adventure travelers (hikers, bikers, boaters, swimmers) that have contact with standing or moving water. Leptospires may penetrate conjunctiva, macerated skin, or possibly the oropharynx.  Leptospirosis is maintained in the environment by long-term carriage and excretion of the organism from the urinary system of asymptomatic animal carriers.  Rodents are most frequently implicated with swine, cattle, and dogs next most frequent, but the full spectrum of mammals forming the reservoir is unclear. Our patient told us that he has seen rodents inside his house and that he uses to swim in a pond near his house.

Classification of leptospires is complex and obscure to most clinicians.  While most human isolates are L. interrogans, further division into a number of species using DNA relatedness is hampered by a traditional naming system that uses serologically defined antigenic determinants (serovars and serogroups) that may be shared by two or more species.

Clinical trials support the use of intravenous antibiotics for severe disease.  Cefotaxime or ceftriaxone are equivalent to penicillin and much more convenient due to once daily dosing [Clin Infect Dis. 2003;36(12):1507-13.; Clin Infect Dis. 2004;39(10):1417-24.].  Milder disease may be treated with oral doxycycline.  Efficacy appears best when treatment is begun within 4 days of illness onset.

The patient deteriorated over the first day in the hospital after several episodes of hemoptysis progressing to marked respiratory distress for which he required intubation and mechanical ventilation in the ICU. Renal function normalized by day 5 after three sessions of hemodialysis. He was treated with IV ceftriaxone 1g/d for 10 days with full recovery but some residual jaundice at discharge. He will be followed by our colleagues at the Regional Hospital.