University of Alabama at Birmingham 2004 Case #9 Universidad Peruana Cayetano Heredia
Last week the Gorgas participants were in Iquitos, located on the banks of the Amazon River, which is the largest city in the world (over 500,000 inhabitants) that is not reachable by road.  The nearest road ends over 800 km away and all goods and people must come in by air or river.  The following patient was seen by the Gorgas participants on the Pediatrics ward of the Hospital Apoyo de Iquitos.  We are grateful to Dr. Joe Vinetz (Gorgas Expert ?01) of the University of California San Diego and his team in Iquitos (Eddy Segura, MD and Christian Ganoza, MD) for advice and assistance with laboratory confirmation of this case.
Image for 04/05/04History: 7 yo male with daily high spiking fevers for 3 weeks before admission.  Vomiting and diarrhea for the first 5 days.  Noted to be jaundiced by the second week of the illness with dark urine and a question of pale stools.  No sore throat, rash, flank pain, arthralgias or myalgias.  No cough or sputum production.  No history of TB, malaria, dengue.  The patient had received 5 days of co-trimoxazole and 5 days of ciprofloxacin in the period up to hospital admission.

Epidemiology: Born and lives in a rural area on an Amazonian tributary near Iquitos.  No running water, sewage, or electricity in the house.  Some malaria in the community but in the household only a grandfather ever had malaria (3 years ago).  Fully vaccinated, including yellow fever and hepatitis B.

Physical Examination: When seen by the Gorgas participants on the 3rd hospital day, a consistent pattern of temperature spikes to 39°C on each day was noted.  Mildly lethargic but not toxic appearing and with clear sensorium.  Mildly icteric sclera without injection [see image A].  Neck supple with no lymphadenopathy. Chest clear.  Liver markedly enlarged 6 cm below the costal margin [see image B; fingertip shows liver edge].  No splenomegaly or ascites.  Skin and CNS normal.  No CVA tenderness.

Laboratory Examination: Hct 27, WBC 7.6 with 62 segs, no bands, 8 monos and 30 lymphs.   Platelets 296,000.   Bilirubin on admission (3 weeks into illness) was 1.7 (1.1 direct, 0.6 indirect).  SGOT 76 (N=45), SGPT 108 (N=45), Alkaline phosphatase 4,986 (N=400).  BUN 17, Cr 0.7.  CXR normal.  U/S abdomen with moderate hepatomegaly, no space occupying lesions and a pattern consistent with fatty infiltration.  3 thick films for malaria performed over 2 weeks were negative.

Diagnosis: Leptospirosis.

Image for 04/05/04 DiscussionDiscussion: Real-time PCR of both urine and blood were performed in the Iquitos laboratories of the Peru-United States Leptospirosis Consortium.  A TaqMan® assay targeting the 16S ribosomal DNA [BMC Infect Dis 2002;2(1):13], using an Opticon 2 DNA Engine (MJ Research), was positive for pathogenic Leptospira (serum, 220 Leptospira/ml; urine, 36,000 Leptospira/ml) [see image C].  Cultures of blood and urine samples in Ellinghausen McCullough Johnson Harris (EMJH) semi-solid media are pending and may take up to 12 weeks to become positive.  Serological testing (IgM ELISA and Microagglutination Test [MAT]) is pending.

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, viral hepatitis.  The classically described textbook manifestations of leptospirosis represent only a small portion of a much wider spectrum of disease.  Typically, leptospirosis is described as having an initial septicemic phase which may be mild, with fever, myalgia, headache, conjunctival suffusion, and abdominal wall pain.  The illness may be 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 2 distinct stages may be obscured and run together in severe disease (Weil?s Disease) manifested by jaundice, hemorrhage, and renal failure.  In Iquitos as in many other areas of the tropics, data indicates a seroprevalance of up to 40% of the general population (J. Vinetz, unpublished) with most individuals not having a discernible history of a prolonged febrile illness consistent with typical descriptions of leptospirosis.  This is consistent with the feeling that most cases in the tropics are not diagnosed due to the non-specificity of the illness and the unavailablity of diagnostic tests in resource poor environments.

Our patient did not have the conjunctival suffusion and the muscle tenderness in calves and lumber areas often mentioned as distinguishing features of leptospirosis.  A recent review of large case series of leptospirosis found these to be only variably present (40-100%) [Lancet Infect Dis 2003;3(12):757-71].  Typhoid should have responded to the pre-admission ciprofloxacin, there is no brucellosis in the Iquitos area, and the patient was vaccinated against yellow fever and hepatitis.  Clinically, patients with viral hepatitis become afebrile with the onset of jaundice.  The clinical course here is too long for dengue.

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.  The WBC is usually normal to low with no left shift and thrombocytopenia may be present but is not a usual finding.  In severe or prolonged disease, renal damage will occur and the sediment is usually active.  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 (as in our patient).  Cultured leptospires are only visible and confirmed using dark-field microscopy.  Diagnosis is most often serological and retrospective (the microscopic agglutination test [MAT], IgM ELISA, or a commercially available dipstick test).  PCR-based diagnosis holds great promise due to the rapidity with which results can be available compared to other techniques.

Leptospirosis is endemic in almost every country but more so in the tropics.  Traditionally an occupational disease and a disease of poverty, it has also emerged as a disease of adventure travelers (hikers, bikers, boaters, swimmers) who 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.

Whether or not to treat leptospirosis remains controversial [Clin Infect Dis 2003;36(12):1514-5].  Insufficient numbers of cases from properly controlled trials a