Visceral leishmaniasis in a patient with Wegener's granulomatosis

S. Sollima, M. Corbellino, R. Piolini, S. Calattini, S. Imparato and S. Antinori

Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Milan, Italy

Correspondence to: S. Sollima, Institute of Infectious and Tropical Diseases, University of Milan, L. Sacco Hospital, Via GB Grassi, 74, 20157 Milan, Italy. E-mail: salvatore.sollima{at}unimi.it

SIR, In this report we present the unusual case of a patient with Wegener's granulomatosis who developed visceral leishmaniasis (VL). Although the clinical picture could suggest a reactivation of the underlying disease, other diagnoses were also considered. By means of polymerase chain reaction (PCR), Leishmania DNA was detected early in peripheral blood. Treatment with liposomal amphotericin B was effective. VL should be taken into account in differential diagnosis when patients receiving chronic immunosuppressive therapy develop fever and pancytopenia. Furthermore, PCR on peripheral blood is a useful tool in the rapid, non-invasive diagnosis of VL.

A 76-yr-old man from Sicily was admitted to our hospital because of intermittent fever, chills and fatigue. Symptoms had arisen 1 month earlier and had not responded to a 1-week course of antibiotic therapy with piperacillin-tazobactam. Three years earlier the patient had been diagnosed with Wegener's granulomatosis and placed on maintenance treatment with prednisone, cyclophosphamide and trimethoprim-sulphamethoxazole. The latter two drugs had been interrupted at the onset of symptoms.

Physical examination revealed paleness of the skin and mucous membranes, herpetic vesicular lesions localized to the right periorbital region (in consequence of which a course of acyclovir was started intravenously) and mild splenomegaly. No lymphadenopathy or hepatomegaly was found. The temperature was 39°C. Laboratory assessments showed a haemoglobin level of 75 g/l, a white blood cell (WBC) count of 1.06 x 109/l, a platelet count of 45 x 109/l, an erythrocyte sedimentation rate of 47 mm/h, hypoalbuminaemia (27 g/l), mild hypergammaglobulinaemia, proteinuria (0.735 g/day), and a c-ANCA titre of 1:710 U/ml. Absolute CD4+ and CD8+ T lymphocyte counts were 0.047 x 109 cells/l and 0.137 x 109 cells/l respectively. The chest radiograph was negative, as well as blood and urine cultures. Based on the clinical history and geographical origin of the patient, VL was suspected. PCR for Leishmania DNA in peripheral blood turned out positive, while the search for antileishmanial antibodies was negative. The diagnosis was confirmed by direct microscopic demonstration of rare amastigotes of Leishmania spp. in a bone marrow aspirate, in which PCR for Leishmania DNA was also positive. Furthermore, using PCR-restriction fragment length polymorphism (RFLP) analysis, the protozoa were identified as Leishmania infantum species. Liposomal amphotericin B (AmBisome) 3 mg/kg/day was administered for 5 consecutive days plus another single infusion 1 week later, leading to rapid defervescence, prompt haematological recovery and disappearance of Leishmania parasites in peripheral blood (Fig. 1). During the 24 months of follow-up the patient remained in good health and received no drugs except for low-dose prednisone; PCR for Leishmania DNA in peripheral blood remained negative.



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FIG. 1. Leishmania DNA burden estimated by semi-quantitative PCR in bone marrow aspirate (BM) and peripheral blood (WB) before (day 0) and following therapy (from day 4 to day 15). Seven serial 10-fold dilutions of the extracted DNA underwent separate PCR amplification with human ß-globin and Leishmania-specific primers. Lane M, 100 base pair (bp) molecular-weight marker; lanes 2–7, serial 10-fold dilutions from 1 µg to 1 pg of target DNA; lane 8, negative control; lane 9, positive control.

 
VL or kala-azar is a severe disorder caused by protozoa of the Leishmania donovani complex, intracellular parasites infecting numerous mammalian species, including humans, and usually transmitted through the bite of haematophagous sandflies. The disease is endemic in 62 countries worldwide, affecting many areas of the tropics, subtropics and southern Europe, with an estimated yearly incidence of 500,000 cases [1]. Since the mid-1980s, VL has been increasingly recognized as an opportunistic infection associated with various immunodeficiency conditions, such as neoplasms, organ transplantation, HIV infection or long-term treatment with immunosuppressive agents [25]. In fact, after acute or subclinical infection, the parasite survives in a latent form in macrophages without causing any clinical manifestations of disease, unless the person becomes immunocompromised.

The typical clinical and laboratory features of VL include fever, hepatosplenomegaly, pancytopenia and hypergammaglobulinaemia, although involvement of virtually any organ is possible and unusual manifestations may be seen [6]. Therefore, VL may be confused with many other infectious and non-infectious diseases. On the other hand, WG may present with a range of features [79], some of which overlap with those of VL.

However, as in the case described here, a suggestive clinical presentation coupled with geographical origin or travel history of the patient should lead to early consideration of VL, although laboratory assessments are usually required to confirm the diagnosis [1]. In recent years, PCR for Leishmania DNA in peripheral blood has emerged as a highly sensitive and specific method for the diagnosis of VL when compared with more traditional and invasive tools, such as microscopic demonstration or in vitro isolation of parasites in bone marrow or splenic aspirates. Molecular amplification is also more reliable than serology, the latter often being negative in immunocompromised hosts. In addition, PCR allows rapid monitoring of response to therapy [10].

This report suggests two important considerations. First, patients treated for WG living or travelling in endemic areas are at increased risk of developing VL through reactivation of a latent infection or a newly acquired infection. Clinicians should consider this when they approach patients with WG who develop fever and pancytopenia while on treatment with immunosuppressive agents. Second, PCR for Leishmania DNA in peripheral blood may be the test of choice both for early, non-invasive diagnosis of VL and for monitoring therapeutic response.

The patient has given consent for this material to appear in Rheumatology.

This work was supported in part by Fondo Interno Ricerca Scientifica e Tecnologica (first) 2003—Università di Milano.

The authors have declared no conflicts of interest.

References

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Accepted 31 March 2004





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