zoonosis presenting as an acute and febrile illness with a variable clinical course and AKI in up to two-thirds of patients [7,8]. Although most cases are reported in tropical zones, leptospirosis is an infrequent disease in the United States and Western Europe, although endemic cases previously have been reported [9]. Here, we report 3 patients presenting with fever and AKI due to acute TIN, initially thought to harbor Hantavirus infection but finally shown to have an infection with Leptospira interrogans.

Case 1: An 18-year-old male student was admitted to the emergency department of the university hospital for fever and AKI. The patient reported ftu-like symptoms and abdominal pain (Table 1) that started 5 days ago, with worsening nausea and recurrent vomiting. In addition, the patient noted oliguria as well as hemoptysis. His medical history was inconspicuous except for an allergic asthma. On admission, blood pressure was 130/80 mm Hg; heart rate, 88 beats per minute; and body temperature, 38.1?C. Physical examination revealed renal tenderness upon percussion, a macular rash, and subconjuncival hemorrhage of the right eye. A chest x-ray showed Pulmonary infiltrates, and Abdominal ultrasound demonstrated enlarged kidneys and hepatosplenomegaly. Blood tests revealed elevated levels for serum creatinine, Liver enzymes, Lactate dehydrogenase , and C-reactive protein (CRP) as well as thrombo- cytopenia and anemia (Table 2). Because of Progressive respiratory failure, the patient was transferred to the intensive care unit. Empiric antibiotic treatment with piperacillin, tazobactam, and clarithromycin was started, and the patient’s condition and laboratory values improved subsequently. Urinalysis suggested predominantly tubular damage; a diagnostic kidney biopsy was performed, revealing ATN and acute nongranulomatous TIN. Hantavirus serology was negative, whereas immunoglobin M for leptospirosis was positive. A follow-up demonstrated seroconversion with a positive immunoglobin G titer, confirming leptospirosis.

Case 2: A 41-year-old male patient with a history of

extensive alcohol consumption presented with progressive nausea, vomiting, and Loss of appetite. In addition, the patient reported fever, diarrhea, and impaired urinary output for the recent days (Table 1). On admission, the vital signs were 130/70 mm Hg, 120 beats per minute, and 38.6?C. Physical examination showed an enlarged liver but was otherwise unremarkable. Further imaging demonstrated pulmonary infiltrates, intraperitoneal ftuid, hepatosplenomegaly, and

signs of acalculous cholecystitis. Initial blood tests showed thrombocytopenia, elevated levels for serum creatinine, LDH, and CRP (Table 2). Urinalysis suggested tubular damage but also demonstrated hematuria and transient albuminuria; Hantavirus infection was suspected, and symptomatic Therapeutic measures were initiated. The patient’s status improved spontaneously, and blood values normalized. Surprisingly, Serologic testing was negative for Hantavirus but revealed an acute leptospiral infection.

Table 1 clinical signs and symptoms on presentation, prior medication, and test results

Case 3: A 20-year-old woman presented at another hospital with abdominal pain, fever, and chills for 5 days. The patient reported previous recurrent urinary tract in- fections but did not have dysuric complaints. One week ago, the patient underwent surgery on a toenail, followed by a medication with a cephalosporin and a nonsteroidal anti- inftammatory drug (NSAID) (ibuprofen). Laboratory tests upon admission revealed significantly impaired renal function, and the patient was immediately transferred to the university hospital for further treatment. Physical examination showed ftank pain upon percussion and fever up to 38.5?C (Table 1) but was otherwise unsuspicious with normal vital signs (120/80 mm Hg, 68 beats per minute). Laboratory testing confirmed AKI associated with anemia, lymphocytopenia, and monocytosis as well as elevated CRP and LDH values (Table 2). Because the clinical presentation pointed to Hantavirus infection but urinalysis suggested acute glomerular dysfunction, a kidney biopsy was per-

formed, revealing acute TIN and ATN. The histologic changes were consistent with both prior NSAID medication and Hantavirus infection. Serologic testing, however, eliminated Hantavirus infection but pointed to leptospirosis. Clinical symptoms resolved within 5 days, and the patient was discharged without specific treatment.

Leptospirosis is a worldwide zoonosis caused by the spirochete L interrogans that primarily adheres to renal epithelial cells and hepatocytes in a variety of wild and domestic animals. Small rodents are considered carrier animals that–once infected–may shed the pathogens in their urine throughout life, thereby contaminating the environment [10]. Leptospirosis is more common in tropical climates, with endemic areas in Latin America and Asia. However, the disease may also play a role in the United States and Western Europe. Traveling activities to endemic areas, occupational exposure, and recreational activities such as fresh-water swimming are increasing risk factors for infection [11]. Estimations report an incidence of leptospirosis of about 10 to 100 per 100 000 in

tropical settings and 0.1 to 1.0 in 100 000 per year in temperate regions [10]. Leptospirosis has an incubation period of an average of 10 days and may have a variable clinical course, presenting either as a subclinical illness with seroconversion or as a self-limited Systemic Infection. In 5% to 10% of cases, however, the disease is severe, requiring hospitalization [12,13]. Severe forms of leptospirosis are characterized by multiorgan failure, including AKI, Liver failure, severe pulmonary hemorrhagic syndrome, rhabdomyolysis, or bleeding compli- cations. Although liver failure is generally reversible, oliguria, thrombocytopenia, and pulmonary involvement have been associated with adverse outcomes and a mortality rate more than 10% [14].

Typical clinical features of leptospirosis are fever as well as gastrointestinal and ftu-like symptoms, which were present in all

3 reported patients. Hepatosplenomegaly, known to be significantly associated with the disease, was also noted in the affected patients. However, clinical features were also consistent with nephropathia epidemica [15]. Because the events occurred in a region endemic for Hantavirus infections, this differential diagnosis was initially suspected. Surprisingly, serologic testing was negative, requiring further evaluation. In patient 1, conjunctival suffusion eventually led to the idea of leptospiral infection. In the other 2 patients, only serologic testing for L interrogans resolved the mystery. Of interest, in patient 2, hepatic involvement with pathologic liver enzymes, ascites, and hepatomegaly was initially attributed to prior extensive alcohol consumption. However, the presence of acalculous cholecystitis in this patient should have raised some suspicion.

Acute kidney injury is the most common complication of leptospirosis, although the mechanisms remain still unclear [10]. Acute tubular necrosis and TIN are the predominant clinicoPathologic findings in affected patients, clinically characterized by polyuria with hypokalemia and hyponatremia [13]. Recent evidence supports the idea that acute epithelial damage results in an inftammatory response; leptospiral membrane proteins stimulate proinftammatory chemokines

secretion by renal tubule epithelial cells, mediated by toll-like receptor 2 and p38 mitogen-activated protein kinase [16]. Although both proximal and distal tubules can be severely damaged, it remains unclear which part of the nephron is primarily affected. Previous pathologic studies demonstrated that patients dying in the first 3 weeks after disease onset had interstitial edema and ATN, whereas those dying after 3 weeks exhibited a diffuse and severe TIN [17]. In addition, secondary Ischemic changes may be superimposed [10]. This has probably been the case in patient 3, with additional intake of NSAIDs; however, the specific effects of NSAID medication or leptospiral infection on renal function are difficult to differentiate. Recent studies suggest that inhibition of the Na⁺-K⁺-Cl^– cotransporter activity in the thick ascending limb by an outer membrane protein of Leptospira is responsible for the increased urinary fractional excretion of potassium and sodium [18], resulting in hyponatremia, as noted in patients 1 and 2. Like in Hantavirus infection, significant albuminuria may be determined in cases of leptospirosis, pointing to some damage of the glomerular basement. How this occurs remains poorly understood; usually, renal biopsy does not show any glomerular abnormalities. In general, renal outcome is excellent, with glomerular function restored within 2 weeks after clinical improvement and reestablished concentration capacity of the nephron within 6 months [19].

Two of the presented patients had several organs affected presenting with Hepatic dysfunction, rhabdomyolysis, AKI, and pulmonary involvement; chest X-rays showed infiltrates, and arterial blood gas analysis revealed impaired oxygenation. Although pulmonary involvement is common in Hantavirus infection of the new world, it is rare in patients with nephropathia epidemica. Similarly, hepatic involvement in Hantavirus infection is possible but less common than in leptospirosis. Altogether, clinical features as well as laboratory results, including thrombocytopenia and elevated LDH and CRP levels, did favor an infectious disease, consistent with both leptospirosis and Hantavirus infection [15].

To establish the diagnosis of leptospirosis, culture, serology, and polymerase chain reaction may be used. Although L interrogans can be grown in vitro from clinical specimen using special media, this approach may take weeks to months. Serologic tests are most often used for confirma- tion, with the microscopic agglutination test as criterion standard, although rapid enzyme-linked immunosorbent assays have shown comparable results [20]. Alternatively, polymerase chain reaction is a fast and accurate but expensive method and, therefore, may be reserved for epidemiological questions or for severely ill patients in whom establishing the diagnosis is time-sensitive. Although it remains controversial, whether antimicrobials have a beneficial effect in human leptospirosis, it is widely accepted to treat the disease. Based on small randomized trials, therapy for mild disease with penicillin or doxycyline shortens the duration of the illness and prevents shedding of the organisms. Because of high mortality of patients with severe leptospirosis, antiinfective therapy is recommended and should include doxycycline or a

third-generation cephalosporin [21]. However, patients 2 and 3 did not receive antibiotics as inpatients because clinical and laboratory signs had already improved when the diagnosis of leptospirosis was established. Given the unclear role of antibiotics in this condition and the fact that damage is already done, antibiotic treatment may not improve outcome. Although prevention primarily consists of avoiding contact with potential sources of infection, doxycycline prophylaxis may be an effective measure in high-risk candidates [22]. Of note, the reported patients were questioned again on potential sources of infection when the diagnosis was established; it turned out that both patients 1 and 2 had swum in the same river 1 week before symptoms started, whereas patient 3 reported to have worked in a garden shed where rats have been spotted a few days ago.

In conclusion, this case series shows that Hantavirus infection can mimic leptospirosis. Because symptoms may be attributed to other diseases, a leptospiral infection may often remain undiagnosed. Because of its global importance, serologic testing for leptospirosis should be considered in any patient with nondistinctive AKI due to acute tubuloin- terstial nephritis and fever.

Acknowledgment

The authors thank Silke Kassner for her help in acquiring clinical data and laboratory values.

Christian S. Haas MD Walter Lehne MD Philip Muck MD Anja Boehm MD

Department of Medicine I University of Luebeck 23538 Luebeck, Germany

E-mail address: [email protected]

Jan Rupp MD Institute of Medical Microbiology and Hygiene University of Luebeck, 23538, Luebeck, Germany

Juergen Steinhoff MD Hendrik Lehnert MD Department of Medicine I University of Luebeck 23538 Luebeck, Germany

http://dx.doi.org/10.1016/j.ajem.2012.04.007

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