Download Correspondence Visceral leishmaniasis during pegylated interferon

Antiviral Therapy 10:695–696
Correspondence
Visceral leishmaniasis during pegylated interferon
therapy for chronic hepatitis C: first report
Antonio Cascio1*, Spinello Antinori 2, Filippo Ricciardi1, Giuseppa Costantino1 and Chiara Iaria 3
1
Scuola di Specializzazione in Malattie Infettive – Dipartimento di Patologia Umana, Università di Messina, Italy
Istituto di Malattie Infettive e Tropicali – Università di Milano, Milano, Italy
3
AILMI (Associazione Italiana per la Lotta contro le Malattie Infettive), Messina, Italy
2
*Corresponding author: Tel: +39 090 221 2033; Fax: +39 090 2939512; E-mail: [email protected]
See: Puoti et al. Use of pegylated interferons is associated with an increased incidence of infections during combination treatment of chronic hepatitis C: a side effect of pegylation? Antiviral Therapy 2004; 9:627–630.
In their recent article, Puoti et al. [1] offer an accurate
analysis of the possible causes and risks of infections in
patients with chronic hepatitis C undergoing treatment
with pegylated interferons (PEG-IFNs). However,
among the causes of infections reported, the authors
did not mention visceral leishmaniasis (VL) nor has VL
has been previously reported in any other patient
treated with IFN or PEG-IFN.
We describe here a case of VL that occurred in a
patient with chronic hepatitis C treated with PEG-IFN.
A 36-year-old white Italian male born and living in
Sicily, Italy, came to our attention complaining of irregular fever (maximum temperature: 41°C), fatigue and
weight loss over 4 weeks. There was a history of intravenous drug abuse. HCV positivity had been documented about a year beforehand and 3 months earlier he
had started treatment with PEG-IFN α-2a (180 µg/wk).
On admission, he was febrile (temperature: 39.0°C)
and pale with hepatosplenomegaly and oropharingeal
thrush; laboratory examinations showed pancytopenia
(haemoglobin 9.4 g/dl, white blood cell count
2.6×103/µl and CD4+ lymphocytopenia (25%, 174/µl).
A culture from a pharyngeal swab yielded Candida
albicans. Cultures of blood and urine tested negative.
However, although several clinical and epidemiological ‘stigmata’ for HIV infection were present, HIV
serology and PCR for HIV-RNA were negative. Based
on positive results of serology and peripheral blood
PCR for Leishmania, a diagnosis of VL was made and
liposomal amphotericin B (3 mg/kg on days 1–5 and
10) was administered. The patient became afebrile
48 h after the beginning of specific therapy.
Subsequently, red blood cell, white blood cell, platelet,
© 2005 International Medical Press 1359-6535
and CD4+ lymphocyte counts gradually came back to
normal. PCR for Leishmania performed on day 10 was
negative.
IFNs are associated with complex antiviral,
immunomodulatory and antiproliferative actions [2].
Neutropenia is a common side effect of IFN therapy.
Puoti et al. demonstrated that HCV patients treated
with IFN are at a higher risk of developing lower respiratory infections due to IFN-related neutropenia. The
use of PEG-IFNs appeared to increase the risk of nonrespiratory infections (cellulitis, dental abscesses, parapharingeal abscess or infections involving other sites
independently from neutropenia) [1].
Polyethylene glycol, the molecule covalently
attached to α-IFN, accumulates in vitro in focal infections and decreases phagocytic activity of tissue
macrophages [3].
Leishmania infection develops in a wide spectrum of
clinical findings, ranging from asymptomatic, subclinical and self-resolving infection to progressive VL characterized by fever, splenomegaly and pancytopenia.
T-cell-dependent immune response and macrophage
activation play a major role during primary infection
or reactivation of latent infection [4]. It could be
hypothesized that the polyethylene glycol-induced
reduction of phagocytic activity may have increased
the risk of progression to VL or, alternatively, that the
reduction of the T helper cells (described among HIVinfected individuals under treatment with IFN) [5]
might be responsible for the disease. It is estimated that
in Sicily there is a burden of at least 150 000 HCVinfected patients, one tenth of whom (approximately
1000–1500) are treated annually with IFN. Since VL is
695
Cascio et al.
endemic in Sicily as well as in other countries of the
Mediterranean basin, physicians should be aware of
the possible unmasking of cryptic Leishmania infection
by IFN.
hepatitis C: a side effect of pegylation? Antiviral Therapy
2004; 9:627–630.
2.
Baron S, Coppenhaver DH & Dianzani F. Introduction to
the interferon system. In Principles and Medical applications.
1992; pp 1–5. Edited by S Baron. Galveston, TX: UTMN.
3.
Laverman P, Dams ET, Storm G, Hafmans TG, Croes HJ,
Oyen WJ, Corstens FH & Boerman OC. Microscopic localization of PEG-liposomes in a rat model of focal infection.
Journal of Controlled Release 2001; 75:347–355.
4.
Herwaldt BL. Leishmaniasis. Lancet 1999; 354:1191–1199.
5.
Vento S, Di Perri G, Cruciani M, garofano T, Concia E &
Bassetti D. Rapid decline of CD4+ cells after interferon
treatment in HIV-1 infection. Lancet 1993; 341:958–959.
References
1.
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. Use of pegylated interferons is associated with an increased incidence of
infections during combination treatment of chronic
Response from Massimo Puoti, Sergio Babudieri,
Giovanni Rezza, Pierluigi Viale, Maria Giulia
Antonini, Ivana Maida, Stefania Rossi, Barbara
Zanini, Valeria Putzolu, Luisa Fenu, Chiara Baiguera,
Salvatore Sassu, Giampiero Carosi and Maria Stella
Mura.
In their letter, Cascio and co-workers report a case of
visceral leishmaniasis (VL) occurring in an individual
with a history of injection drug use taking pegylated
interferon (PEG-IFN) and ribavirin (RBV) as anti-HCV
treatment and living in an area endemic for VL. The
high prevalence of hepatitis C virus in regions where,
not only leishmaniasis, but also tuberculosis (TB) and
other infectious diseases caused by intracellular
microorganism are endemic, supports a careful evaluation of prolonged febrile episodes in patients using
PEG-IFNs. Even if this risk is not considered as a
contraindication for anti-HCV treatment, it should be
taken into consideration when this treatment is started
in such epidemiological settings. Careful environmental
considerations should be part of pre-treatment patient
counselling and screening for latent TB should be
performed in patients at risk of such infections. The
incidence of these infections in patients treated with
PEG-IFNs in regions with these epidemiological issues
should probably be assessed in large Phase IV observational studies and by active Phase IV pharmacovigilance. Lymphocytopenia is not uncommon in patients
696
treated with PEG-IFN and RBV and has been observed
in patients with HIV infection even in the absence of a
significant decrease in the percentage of CD4 cells [1].
However, in the HAART era, CD4 cell decrease has not
been associated with an increased risk of opportunistic
infections
in
HIV-infected
individuals
[1].
Lymphocytopenia has been associated with an
increased risk of infection in an observational study
performed predominantly in African Americans [2];
however, there are no data on the changes in lymphocyte subpopulations in HIV-uninfected patients treated
with PEG-IFNs and RBV. The severe CD4 depletion
observed in this patient could also be the result of leishmaniasis [3], however studies on the change in number
and functions of lymphocytes subpopulations in HIVuninfected patients assuming PEG-IFNs and RBV
should be prompted by this interesting case report.
References
1.
Torriani FJ, Rodriguez-Torres M, Rockstroh JK, Lissen E,
Gonzalez-Garcia J, Lazzarin A, Carosi G, Sasadeusz J,
Katlama C, Montaner J, Sette H Jr, Passe S, De Pamphilis J,
Duff F, Schrenk UM, Dieterich DT; APRICOT Study
Group. Peginterferon alfa-2a plus ribavirin for chronic
hepatitis C virus infection in HIV-infected patients. New
England Journal of Medicine 2004; 351:438–450.
2.
Soza A, Everhart JE, Ghany MG, Doo E, Heller T, Promrat
K, Park Y, Liang TJ & Hoofnagle JH. Neutropenia during
combination therapy of interferon alfa and ribavirin for
chronic hepatitis C. Hepatology 2002; 36:1273–1279.
3.
Herwaldt BL. Leishmaniasis. Lancet 1999; 354:1191–1199.
© 2005 International Medical Press