University of Alabama at Birmingham 2009 Case #2 Universidad Peruana Cayetano Heredia
The following patient was seen in the inpatient department of the 36-bed Tropical Disease Unit at Cayetano Heredia National Hospital.

Image ABC for 02/09/09History:  31 yo male admitted with a 3-day history of fever, chills, diffuse myalgia, progressive dyspnea and jaundice.  There is no present history of rash, retro-ocular pain, cervical or lumbar pain.  15 days earlier a 1-day febrile episode, which included self-limited watery diarrhea, had occurred.  A non-pruritic macular rash that lasted 1 day had occurred within a few hours of receiving an injection of an unknown medication during this initial episode.

Epidemiology:  Born and lives in Lima, but travels every 3-6 months to Pucallpa in the high jungle to cut wood.  Recent visits were 5 and 2 months earlier, and then for 2 days immediately prior to the episode of diarrhea described above.  No history of routine vaccines or against yellow fever, or hepatitis B.  No history of malaria or TB.  In the jungle there is frequent exposure to rivers and ponds and non-potable water is consumed.  Heavy rains had occurred just prior to his illness.

Physical Examination:  T 37.8°C, pulse 79, respiration 30, BP 120/80.  Marked jaundice as well as scleral icterus [Image A].  Rales were present in both lungs; greater on the right side.  No lymphadenopathy or hepatosplenomegaly.

Laboratory Examination:  Hb 12.5 g/dl; WBC 15,400 with 78% neutrophils, 10% lymphs, 4% bands; 16,000 platelets; INR: 1.26; creatinine 4.4 mg/dl (N=<1.0); urea: 117 mg/dl (N=<20); total proteins 6.7 g/dl (normal), albumin 3.7 g/dl (normal); potassium (2.9 mEq/l).  Total bilirubin: 7.7 mg/dl, 5.8 mg/dl direct.  ALT 71 IU/l (N=< 40); alk phosphatase 123 mg/dl (normal), LDH 694.  O2 saturation 98% with FiO2 0.25.  Chest x-ray: progressive appearance of diffuse alveolar and interstitial infiltrates, more pronounced on the right [Images B, C].  Brucella and Salmonella agglutination tests were negative.  Negative malaria smear.  Hepatitis B core IgM was negative.





Diagnosis:  Leptospirosis.
Discussion:  Serology by the Microagglutination technique (MAT) for leptospira:  1:800 for L. icterohemorrhagiae Copenhageni (M20), 1/200 for L. i. iceterohemorrhagiae RGA and L. i. Mankarso (these titers are considered weakly positive).  An IgM ELISA for dengue taken of day 3 of illness was positive.  In acute dengue IgM does not usually turn positive until day 5-7 and then remains positive for several months.  As the clinical picture (jaundice, renal, and pulmonary involvement) and pattern of hepatic function abnormalities here is not consistent with dengue, the positive IgM was felt to reflect an earlier episode of dengue likely from the visit to Pucallpa 2 months earlier.

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 Image A], and abdominal wall pain.  Our patient had the conjunctival suffusion but not the muscle tenderness in calves and lumber areas often described as distinguishing features of leptospirosis.  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 [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 as found in this case is characteristic.  Progression to oliguric renal failure would be predictive of higher mortality.

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.  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.

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.

Recent 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.

There was a marked dissociation between the significant laboratory abnormalities and the patient’s appearance.  He was treated with IV ceftriaxone (1gm/d for 10 days).  The dyspnea and low-grade fever resolved after 4 days and the myalgia for 5 more days.  Jaundice normally takes longer to resolve but the renal function normalized by Day 3.