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    Patient’s hematologic parameters and blood transfusion rate during a period lasting 15 months before and after VL diagnosis (WBC, white blood cells; PLT, platelets).

  • 1

    Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, Wasunna MK, Bryceson AD, 2002. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2 :494–501.

    • Search Google Scholar
    • Export Citation
  • 2

    Pagliano P, Rossi M, Rescigno C, Altieri S, Coppola MG, Gramiccia M, Scalone A, Gradoni L, Faella F, 2003. Mediterranean visceral leishmaniasis in HIV-negative adults: a retrospective analysis of 64 consecutive cases (1995–2001). J Antimicrob Chemother 52 :264–268.

    • Search Google Scholar
    • Export Citation
  • 3

    Vento S, Cainelli F, Cesario F, 2006. Infections and thalassaemia. Lancet Infect Dis 6 :226–233.

  • 4

    Davidson RN, di Martino L, Gradoni L, Giacchino R, Gaeta GB, Pempinello R, Scotti S, Cascio A, Castagnola E, Maisto A, Gramiccia M, di Caprio D, Wilkinson RJ, Bryceson AD, 1996. Short-Course treatment of visceral leishmaniasis with liposomal Amphotericin B (Ambisome). Clin Infect Dis 22 :938–942.

    • Search Google Scholar
    • Export Citation
  • 5

    Garcia-Tsao G, 2005. Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 42 (Suppl 1):S85–S92.

  • 6

    Pagliano P, Carannante N, Gramiccia M, Ascione T, Stornaiuolo G, Gradoni L, Faella FS, Gaeta GB, 2007. Visceral leishmaniasis causes fever and decompensation in patients with cirrhosis. Gut 56 :893–894.

    • Search Google Scholar
    • Export Citation
  • 7

    Fichoux Y, Quaranta JF, Aufeuvre JP, Lelievre A, Marty P, Suffia I, Rousseau D, Kubar J, 1999. Occurrence of Leishmania infantum parasitemia in asymptomatic blood donors living in an area of endemicity in southern France. J Clin Microbiol 37 :1953–1957.

    • Search Google Scholar
    • Export Citation
  • 8

    Ossandon A, Bompane D, Alessandri C, Marocchi E, Conti F, Valesini G, 2006. Leishmania in SLE mimicking an exacerbation. Clin Exp Rheumatol 24 :186–190.

    • Search Google Scholar
    • Export Citation
  • 9

    Basset D, Faraut F, Marty P, Dereure J, Rosenthal E, Mary C, Pratlong F, Lachaud L, Bastien P, Dedet JP, 2005. Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature. Microbes Infect 7 :1370–1375.

    • Search Google Scholar
    • Export Citation
  • 10

    Bassetti M, Pizzorni C, Gradoni L, Del Bono V, Cutolo M, Viscoli C, 2006. Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with adalimumab. Rheumatology (Oxford) 45 :1446–1448.

    • Search Google Scholar
    • Export Citation
  • 11

    Weisser M, Khanlari B, Terracciano L, Arber C, Gratwohl A, Bassetti S, Hatz C, Battegay M, Flückiger U, 2007. Visceral leishmaniasis: a threat to immunocompromised patients in non-endemic areas? Clin Microbiol Infect 13 :751–753.

    • Search Google Scholar
    • Export Citation
  • 12

    Bouchonnet F, Boechat N, Bonay M, Hance AJ, 2002. Alpha/ beta interferon impairs the ability of human macrophages to control growth of Mycobacterium bovis BCG. Infect Immun 70 :3020–3025.

    • Search Google Scholar
    • Export Citation
  • 13

    Puoti M, Babudieri S, Rezza G, Viale P, Antonini MG, Maida I, Rossi S, Zanini B, Putzolu V, Fenu L, Baiguera C, Sassu S, Carosi G, Mura MS, 2004. Use of pegylated interferons is associated with an increased incidence of infections during combination treatment of chronic hepatitis C: a side effect of pegylation? Antivir Ther 9 :627–630.

    • Search Google Scholar
    • Export Citation
  • 14

    Sabbatani S, Manfredi R, Marinacci G, Pavoni G, Crostoni L, Chiodo F, 2006. Reactivation of severe acute pulmonary tuberculosis during treatment with pegylated interferon-alpha and ribavirin for chronic HCV hepatitis. Scand J Infect Dis 38 :205–208.

    • Search Google Scholar
    • Export Citation
  • 15

    Telesca C, Angelico M, Piccolo P, Nosotti L, Morrone A, Longhi C, Carbone M, Baiocchi L, 2007. Interferon-alpha treatment of hepatitis D induces tuberculosis exacerbation in an immigrant. J Infect 54 :e223–e226.

    • Search Google Scholar
    • Export Citation
  • 16

    Stanley AC, Engwerda CR, 2007. Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol 85 :138–147.

  • 17

    Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL, 2002. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420 :502–507.

    • Search Google Scholar
    • Export Citation
  • 18

    Murray HW, Flanders KC, Donaldson DD, Sypek JP, Gotwals PJ, Liu J, Ma X, 2005. Antagonizing deactivating cytokine to enhance host defence and chemotherapy in experimental visceral leishmaniasis. Infect Immun 73 :3903–3911.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Distinguishing Visceral Leishmaniasis from Intolerance to Pegylated Interferon-α in a Thalassemic Splenectomized Patient Treated for Chronic Hepatitis C

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  • 1 ‘D. Cotugno’ Hospital, Department of Emergency, 1st Division of Infectious Diseases, Naples, Italy; ‘A. Cardarelli’ Hospital, Hematology Unit, Naples, Italy; Istituto Superiore di Sanità, Department of Infectious, Parasitic and Immunomediated Diseases, Rome, Italy

A 37-year-old splenectomized man affected by β-thalassemia and chronic hepatitis, recently treated with pegylated interferon-α (Peg-IFN), was admitted because of elevated fever lasting 3 months and unresponsiveness to broad-spectrum antibiotics. Laboratory studies showed white blood cell and platelet counts within the normal range but lower than observed before Peg-IFN treatment and an elevated erythrocyte sedimentation rate. The blood transfusion rate was reported to be increased compared with the period preceding Peg-IFN treatment. A diagnosis of visceral leishmaniasis (VL) was made after Leishmania amastigotes were identified from Giemsa-stained smears of bone marrow aspirates. Cure occurred after liposomal amphotericin B was administered. Symptoms of VL may be difficult to distinguish from the manifestations of Peg-IFN intolerance. We suggest that VL must be suspected in any immunodepressed patient with an unexplained fever and a history of exposure in an endemic area.

INTRODUCTION

Visceral leishmaniasis (VL), a disseminated intracellular protozoan infection transmitted by the bite of phlebotomine sandflies, is endemic in the areas bordering the Mediterranean basin. The spectrum of infection ranges from asymptomatic, subclinical, and self-resolving disease to the overt VL characterized by fever, splenomegaly, and pancytopenia. VL has a higher incidence in children and in immunocompromised patients and results in the death if left untreated.1,2

Thalassemia is frequently observed in the Mediterranean area. Patients with major thalassemia are frequently splenectomized and must receive regularly blood transfusions to control anemia and its sequelae. A high incidence of post-transfusion chronic hepatitis sustained by hepatitis C virus (HCV) is reported in patients with major thalassemia. Pegy-lated interferon-α (Peg-IFN) is the treatment recommended for such cases. Fever, weight loss, asthenia, and increase in blood transfusion rate are commonly reported in patients with major thalassemia undergoing IFN treatment.3

Here, we describe the first case of VL occurring during treatment with Peg-IFN of chronic HCV hepatitis in a splenectomized patient with major thalassemia.

CASE REPORT

A 37-year-old man was admitted because of fever unresponsive to broad-spectrum antibiotics. The patient had been diagnosed as affected by thalassemia major (IVS-I6/IVS-I1) when he was 2 years old. His medical history was remarkable for a splenectomy and a diagnosis of chronic HCV hepatitis. Three months before admission, the patient had started Peg-IFN-α2b for treatment of chronic hepatitis (Peg-Intron, 80 μg/wk; Schering Corp., Kenilworth, NJ). After 4 weeks of therapy, high fever and weight loss began, and the blood transfusion rate had to be increased because of worsening anemia (Figure 1). Peg-IFN was discontinued after 10 weeks of therapy because of a suspicion of intolerance, with no improvement in symptoms and hematologic findings.

Laboratory studies showed platelet and white blood cell counts within the normal range but lower than those recorded before Peg-IFN treatment (Figure 1), elevated IgG (52.5 g/L), and high liver enzymes. Erythrocyte sedimentation rate was 118 mm/h. The T-cell profile showed a CD4/CD8 ratio of 0.8 and was unremarkable for the other findings. Blood, urine, and stool cultures were sterile. HCV-RNA dosage was positive. Serology for HIV, Brucella, and Salmonella was negative. A tuberculin skin test (Mantoux method) was not reactive. Antipyretic agents (Paracetamol) and broad-spectrum antibiotics were administered with no effect during a 10-day period.

Based on the above evidence, a bone marrow aspirate was performed, and 1–10 amastigotes of Leishmania/100 oil immersion fields (2+) were found in Giemsa staining. An immunofluorescent antibody test (IFAT), performed after bone marrow study, showed high titers (1/5120) of anti-Leishmania–specific antibodies. The patient was diagnosed as having VL.

At VL diagnosis, the patient appeared severely ill, and fever was 39.2°C. Physical examination showed an enlarged liver exceeding 10 cm from the right costal margin but was unremarkable for other findings. Treatment with liposomal amphotericin B (l-AmB, AmBisome; Gilead Sciences, Ltd., Dublin, Ireland) at a dosage proven highly effective in adult Italian patients in a multicenter trial (3 mg/kg at Days 1–5 and 10) was administered.4 Defervescence occurred 2 weeks after the first dose of l-AmB; no increase in mean blood urea nitrogen and serum creatinine levels compared with pre-treatment levels was evident. Leishmania IFAT titer decreased to undetectable after 18 months. Liver enzymes, HCV-RNA, and IgG levels were persistently elevated. No VL relapse occurred after a 24-month follow-up period.

As shown in Figure 1, hematologic findings worsened during Peg-IFN therapy, and no improvement was observed after the therapy was discontinued on suspicion of high-grade intolerance. In fact, the blood transfusion rate (expressed in microliters per day consumption) increased when Peg-IFN therapy was administered and started to improve after l-AmB therapy, returning to baseline values only after 12 months. Similarly, a decrease in white blood cell and platelet counts was evident when Peg-IFN was administered. L-AmB therapy induced a rapid increase in white blood cell and platelet counts, with values returning to baseline after 9 months.

DISCUSSION

Infections have a high incidence in splenectomized patients and frequently complicate the course of liver diseases and major thalassemia.3,5 However, this is the first case of VL reported either in a splenectomized or thalassemic adult, which we assessed by a systematic search of English language literature, performed through MEDLINE database and Co-chrane Library with the search strings “leishmaniasis AND splenectomy” and “leishmaniasis AND thalassemia,” retrieving no case of this type. Furthermore, of 1,495 VL clinical records stored at the Italian Istituto Superiore di Sanità database (~60% of all VL cases occurred in Italy since 1980), only one case of this type was recorded, consisting of an 11-year-old thalassemic child developing VL 2 years after splenectomy (L Gradoni, personal communication).

The patient had an ambiguous presentation of VL and, despite the fact that he lived in a highly endemic area, diagnosis was troublesome because symptoms such as increasing blood transfusion rate, weight loss, and fever first suggested intolerance to Peg-IFN. On the other hand, platelet and white blood cell counts were higher than commonly observed in VL. Furthermore, elevated IgG levels are also seen in patients with liver diseases. Only the lack of improvement after Peg-IFN was withdrawn allowed to exclude drug toxicity, and forced to further extensive investigations. The demonstration of a high Leishmania IFAT titer suggests that if this test had been included among the routine laboratory tests for fever investigation, it would have been sufficient to support VL diagnosis without further invasive investigations.2,6 After diagnosis was established through a bone marrow aspirate, a short course of l-AmB treatment successfully cured the patient, thereby confirming the high efficacy of this drug for treating VL in patients with severe underlying conditions.

Because liver tissue preparations performed before Peg-IFN therapy were not available for Leishmania re-evaluation, either coincidental primary infection or re-activation of VL could not be ruled out. Furthermore, we could not determine whether Leishmania was acquired by natural vectorial transmission or by frequent blood transfusions, because the patient lived in a highly endemic area for VL.7

Use of immunosuppressive drugs, such as steroids in patients with systemic lupus erythematous, cyclosporine in transplanted patients, or tumor necrosis factor-α inhibitors in patients with immunologic disorders, are known risk factors for VL.811 A higher susceptibility to infections, including intracellular agents, was reported in patients receiving IFN on the basis of both experimental and clinical evidence, but no study investigated the relationships between VL and IFN administration.1215

The occurrence of VL in our splenectomized patient may be an argument to sustain the increased susceptibility to VL after IFN treatment. The spleen is the main site of Leishmania persistence. Here, during the chronic phase of VL, extensive changes of the lymphoid microenvironment and T-cell apoptosis result in a reduced response to leishmanial antigens and in amastigote overgrowth.16 For this reason, splenectomy may protect from overt VL, as suggested by epidemiologic evidence, and indeed, splenectomy can be used with success in those cases not responding to antileishmanial treatment. Kupfer cells control Leishmania overgrowth in the liver during a self-resolving infection. In our patient, parasites possibly confined within hepatic granulomas by Kupfer cells could have overcome the immune surveillance because of the IFN-induced hepatic macrophage impairment. Consequently, the liver may have represented the site of both Leishmania persistence and overgrowth, and a severe and life-threatening VL developed thereafter.17,18 The in vitro demonstration of macrophage inability to control intracellular Mycobacterium bovis growth after IFN exposure confirms the relationship between drug administration and reduced response to intra-cellular agents and supports our hypothesis.12

In conclusion, distinguishing VL manifestations from those of Peg-IFN intolerance may be difficult. On suspicion of VL, IFAT serology can be an excellent tool to avoid further studies. VL should always be suspected when an explained fever, unresponsive to broad-spectrum antibiotics, is reported in any immunosuppressed patient with a history of exposure in an endemic area.

Figure 1.
Figure 1.

Patient’s hematologic parameters and blood transfusion rate during a period lasting 15 months before and after VL diagnosis (WBC, white blood cells; PLT, platelets).

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 79, 1; 10.4269/ajtmh.2008.79.9

*

Address correspondence to Pasquale Pagliano, c/o Ospedale D. Cotugno, I divisione, Via G. Quagliariello 54, 80131 Naples, Italy. E-mail: ppagliano@libero.it

Authors’ addresses: Pasquale Pagliano, Francesco S. Faella, Giuseppe Mascarella, and Ugo Fusco, Ospedale D. Cotugno, I divisione, via G. Quagliariello 54, 80131, Naples, Italy. Silvia Costantini, Anna Spasiano, Luciano Prossomariti, and Paolo Ricchi, Ospedale Cardarelli, Thalassemic Unit, via A. Cardarelli 9, 80131, Naples, Italy. Luigi Gradoni, Istituto Superiore di Sanità, Department of Infectious, Parasitic and Immunomediated Diseases, Viale Regina Elena 299, 00161, Rome, Italy.

REFERENCES

  • 1

    Guerin PJ, Olliaro P, Sundar S, Boelaert M, Croft SL, Desjeux P, Wasunna MK, Bryceson AD, 2002. Visceral leishmaniasis: current status of control, diagnosis, and treatment, and a proposed research and development agenda. Lancet Infect Dis 2 :494–501.

    • Search Google Scholar
    • Export Citation
  • 2

    Pagliano P, Rossi M, Rescigno C, Altieri S, Coppola MG, Gramiccia M, Scalone A, Gradoni L, Faella F, 2003. Mediterranean visceral leishmaniasis in HIV-negative adults: a retrospective analysis of 64 consecutive cases (1995–2001). J Antimicrob Chemother 52 :264–268.

    • Search Google Scholar
    • Export Citation
  • 3

    Vento S, Cainelli F, Cesario F, 2006. Infections and thalassaemia. Lancet Infect Dis 6 :226–233.

  • 4

    Davidson RN, di Martino L, Gradoni L, Giacchino R, Gaeta GB, Pempinello R, Scotti S, Cascio A, Castagnola E, Maisto A, Gramiccia M, di Caprio D, Wilkinson RJ, Bryceson AD, 1996. Short-Course treatment of visceral leishmaniasis with liposomal Amphotericin B (Ambisome). Clin Infect Dis 22 :938–942.

    • Search Google Scholar
    • Export Citation
  • 5

    Garcia-Tsao G, 2005. Bacterial infections in cirrhosis: treatment and prophylaxis. J Hepatol 42 (Suppl 1):S85–S92.

  • 6

    Pagliano P, Carannante N, Gramiccia M, Ascione T, Stornaiuolo G, Gradoni L, Faella FS, Gaeta GB, 2007. Visceral leishmaniasis causes fever and decompensation in patients with cirrhosis. Gut 56 :893–894.

    • Search Google Scholar
    • Export Citation
  • 7

    Fichoux Y, Quaranta JF, Aufeuvre JP, Lelievre A, Marty P, Suffia I, Rousseau D, Kubar J, 1999. Occurrence of Leishmania infantum parasitemia in asymptomatic blood donors living in an area of endemicity in southern France. J Clin Microbiol 37 :1953–1957.

    • Search Google Scholar
    • Export Citation
  • 8

    Ossandon A, Bompane D, Alessandri C, Marocchi E, Conti F, Valesini G, 2006. Leishmania in SLE mimicking an exacerbation. Clin Exp Rheumatol 24 :186–190.

    • Search Google Scholar
    • Export Citation
  • 9

    Basset D, Faraut F, Marty P, Dereure J, Rosenthal E, Mary C, Pratlong F, Lachaud L, Bastien P, Dedet JP, 2005. Visceral leishmaniasis in organ transplant recipients: 11 new cases and a review of the literature. Microbes Infect 7 :1370–1375.

    • Search Google Scholar
    • Export Citation
  • 10

    Bassetti M, Pizzorni C, Gradoni L, Del Bono V, Cutolo M, Viscoli C, 2006. Visceral leishmaniasis infection in a rheumatoid arthritis patient treated with adalimumab. Rheumatology (Oxford) 45 :1446–1448.

    • Search Google Scholar
    • Export Citation
  • 11

    Weisser M, Khanlari B, Terracciano L, Arber C, Gratwohl A, Bassetti S, Hatz C, Battegay M, Flückiger U, 2007. Visceral leishmaniasis: a threat to immunocompromised patients in non-endemic areas? Clin Microbiol Infect 13 :751–753.

    • Search Google Scholar
    • Export Citation
  • 12

    Bouchonnet F, Boechat N, Bonay M, Hance AJ, 2002. Alpha/ beta interferon impairs the ability of human macrophages to control growth of Mycobacterium bovis BCG. Infect Immun 70 :3020–3025.

    • Search Google Scholar
    • Export Citation
  • 13

    Puoti M, Babudieri S, Rezza G, Viale P, Antonini MG, Maida I, Rossi S, Zanini B, Putzolu V, Fenu L, Baiguera C, Sassu S, Carosi G, Mura MS, 2004. Use of pegylated interferons is associated with an increased incidence of infections during combination treatment of chronic hepatitis C: a side effect of pegylation? Antivir Ther 9 :627–630.

    • Search Google Scholar
    • Export Citation
  • 14

    Sabbatani S, Manfredi R, Marinacci G, Pavoni G, Crostoni L, Chiodo F, 2006. Reactivation of severe acute pulmonary tuberculosis during treatment with pegylated interferon-alpha and ribavirin for chronic HCV hepatitis. Scand J Infect Dis 38 :205–208.

    • Search Google Scholar
    • Export Citation
  • 15

    Telesca C, Angelico M, Piccolo P, Nosotti L, Morrone A, Longhi C, Carbone M, Baiocchi L, 2007. Interferon-alpha treatment of hepatitis D induces tuberculosis exacerbation in an immigrant. J Infect 54 :e223–e226.

    • Search Google Scholar
    • Export Citation
  • 16

    Stanley AC, Engwerda CR, 2007. Balancing immunity and pathology in visceral leishmaniasis. Immunol Cell Biol 85 :138–147.

  • 17

    Belkaid Y, Piccirillo CA, Mendez S, Shevach EM, Sacks DL, 2002. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420 :502–507.

    • Search Google Scholar
    • Export Citation
  • 18

    Murray HW, Flanders KC, Donaldson DD, Sypek JP, Gotwals PJ, Liu J, Ma X, 2005. Antagonizing deactivating cytokine to enhance host defence and chemotherapy in experimental visceral leishmaniasis. Infect Immun 73 :3903–3911.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Pasquale Pagliano, c/o Ospedale D. Cotugno, I Divisione, Via G. Quagliariello 54, 80131 Naples, Italy, E-mail: ppagliano@libero.it.
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