Scandinavian Journal of Infectious Diseases

ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19

Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia Aurélia Henn, Guillaume Mellon, Benoît Henry, Damien Roos-Weil, Stéphane Jauréguiberry, Pierre Mordant, Arnaud Fekkar & Eric Caumes To cite this article: Aurélia Henn, Guillaume Mellon, Benoît Henry, Damien Roos-Weil, Stéphane Jauréguiberry, Pierre Mordant, Arnaud Fekkar & Eric Caumes (2014) Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia, Scandinavian Journal of Infectious Diseases, 46:3, 231-234 To link to this article: http://dx.doi.org/10.3109/00365548.2013.866269

Published online: 23 Jan 2014.

Submit your article to this journal

Article views: 102

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [University of California Santa Barbara]

Date: 12 September 2015, At: 22:38

Scandinavian Journal of Infectious Diseases, 2014; 46: 231–234

CASE REPORT

Downloaded by [University of California Santa Barbara] at 22:38 12 September 2015

Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia

AURÉLIA HENN1, GUILLAUME MELLON1, BENOÎT HENRY1, DAMIEN ROOS-WEIL2, STÉPHANE JAURÉGUIBERRY1, PIERRE MORDANT3, ARNAUD FEKKAR4 & ERIC CAUMES1 From the 1Infectious and Tropical Diseases Department, 2Hematology Department, Groupe Hospitalier Universitaire Pitié Salpêtrière, Université Pierre et Marie Curie–Paris 6, 3Thoracic Surgery Department, Hôpital Européen Georges Pompidou, Université René Descartes–Paris 5, and 4Mycology and Parasitology Laboratory, Groupe Hospitalier Universitaire Pitié Salpêtrière, Université Pierre et Marie Curie–Paris 6, Paris, France

Abstract We report the case of a 42-y-old man treated with alemtuzumab for chronic lymphocytic leukaemia, who developed 3 successive deep fungal infections. Despite being treated with liposomal amphotericin B and 5-flucytosine for disseminated cryptococcosis, he developed pulmonary invasive aspergillosis, followed by pulmonary mucormycosis. Several deep fungal infections may occur in association in an immunocompromised host after treatment with alemtuzumab.

Keywords: Alemtuzumab, invasive aspergillosis, cryptococcosis, mucormycosis, chronic lymphocytic leukaemia

Introduction Alemtuzumab is a recombinant, fully humanized, monoclonal antibody directed against the CD52 antigen and is mainly used in the treatment of chronic lymphocytic leukaemia (CLL) [1]. It may cause serious side effects such as long-term lymphocytopenia and neutropenia [2]. We describe a patient with the association of disseminated cryptococcosis, invasive pulmonary aspergillosis, and pulmonary mucormycosis occurring after 4 courses of alemtuzumab. Case report A 42-y-old man had been treated since 2000 for CLL. From 2000 to 2012, he received 3 lines of treatment comprising polychemotherapy with anthracyclines, purine analogues (fludarabine), alkylating agents (cyclophosphamide), autologous

stem cell transplantation, high-dose corticosteroids, and immunotherapy (rituximab), alternatively or in combination. Due to a partial response, a fourth line of treatment with alemtuzumab was started on 11 July 2012. On 28 September, 4 days after the fourth course of alemtuzumab, he was diagnosed with pancytopenia (haemoglobin 70 g/l, lymphocytes 0.16 ⫻ 109/l, neutrophils 0.03 ⫻ 109/l, and platelets 25 ⫻ 109/l). Two weeks later the patient became febrile, prompting transfer to an infectious diseases department. Sepsis was diagnosed and linked to an extended-spectrum beta-lactamase producing Escherichia coli urinary tract infection and disseminated cryptococcosis. Cryptococcus neoformans was found in the cerebrospinal fluid, blood, bone marrow, and urine. He received imipenem, amikacin, liposomal amphotericin B (3 mg/kg/day), and 5-flucytosine (100 mg/kg/day).

Correspondence: A. Henn, Hôpital Pitié Salpêtrière, Service de Maladies Infectieuses, 47/83 boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Tel: ⫹ 33 1 42 16 03 95. Fax: ⫹ 33 1 42 16 04 45. E-mail: [email protected] (Received 26 October 2013 ; accepted 29 October 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.866269

Downloaded by [University of California Santa Barbara] at 22:38 12 September 2015

232

A. Henn et al.

On 8 November, because of unexplained hypoxemia the patient underwent thoracic computed tomography (CT), which revealed ground glass opacities, an abscessed nodule in the middle lobe, and a bilateral pleural effusion (Figure 1). Thoracocentesis showed an exudate with 77% of neutrophils, and a galactomannan test was positive (index ⫽ 3.5; Platelia BioRad). A PCR recognizing the 28S rRNA gene of Aspergillus fumigatus was positive at 220,000 copies/ml in the pleural effusion and at 78,000 copies/ml in the bronchoalveolar lavage. The serum galactomannan test became positive (index at 0.68 for a cut-off at 0.5), whereas PCR of the serum remained negative. Oral voriconazole 200 mg twice a day was introduced to treat this probable invasive pulmonary aspergillosis as well as the disseminated cryptococcosis. Liposomal amphotericin B and 5-flucytosine were interrupted. On 10 December, the patient complained of right-sided latero-thoracic chest pain. A thoracic CT scan revealed increased growth of the abscessed nodule of the middle lobe and osteolysis of the adjacent rib; the other nodules and pleural effusion had decreased (Figure 2). After careful preoperative workup, the patient underwent a right middle lobectomy extended to the adjacent rib, which allowed complete resection of the invasive process. Mycological examination of the surgical specimen showed many Mucor-type mycelian filaments. Liposomal amphotericin B (10 mg/kg/day) was introduced for 6 weeks and posaconazole (400 mg every 8 h, adapted to the plasma level) for 9 months. Six months after the initial diagnosis of disseminated cryptococcosis, ofatumumab was started for CLL. A splenectomy was performed 2 months later

Figure 1. Thoracic CT on 8 November 2012: ground glass opacities, abscessed nodule in the middle lobe, bilateral pleural effusion.

Figure 2. Thoracic CT on 15 December 2012: growth of the abscessed nodule of the middle lobe, osteolysis of the adjacent rib, decrease of the other nodules and of the pleural effusion.

because of multiple splenic infarctions attributed to CLL. Nine days after the splenectomy, the patient developed septic shock due to a probable ulcerative colitis and died of multi-organ failure. Discussion This is a unique succession of 3 deep fungal infections (disseminated cryptococcosis, invasive pleuro-pulmonary aspergillosis, and mucormycosis) in a patient with prolonged neutropenia after receiving alemtuzumab for the treatment of CLL. Alemtuzumab is an anti-CD52 antibody that is used in CLL patients who have failed fludarabine therapy and sometimes in frontline therapy in the case of poor risk cytogenetic abnormalities [3]. It has also been used in other circumstances, such as multiple sclerosis and organ transplant rejection. The CD52 antigen is present on the surface of T, B, and natural killer (NK) lymphocytes, and also on macrophages and dendritic cells. Because of the profound induced lymphopenia, alemtuzumab is associated with a high risk of infections, especially viral and bacterial infections. Although less common, fungal infections have also been reported during the use of this treatment [4–6]. Alemtuzumab triggers a long-lasting lymphocytic depletion, estimated as a median of 61 months for CD4 lymphocytes and 30 months for CD8 lymphocytes [7]. Prolonged pancytopenia may also occur, and neutropenia is seen in 20% of patients treated with alemtuzumab [8], which is a well-known risk factor for invasive fungal infections (IFI). In this patient, the neutropenia lasted 9 weeks, which probably contributed to the occurrence of the 3 IFI. The majority of IFI under treatment with alemtuzumab

Downloaded by [University of California Santa Barbara] at 22:38 12 September 2015

Alemtuzumab and three deep fungal infections occur in the first 3 months of treatment, which was also the case with this patient. Cryptococcosis, aspergillosis, and mucormycosis have already been described in alemtuzumab-treated patients. However, multiple fungal infections in the same patient seem less common in the literature. Among 547 solid organ transplant recipients treated with alemtuzumab, cases of oesophageal candidiasis (n ⫽ 12), cryptococcosis (n ⫽ 2), Scedosporium infection (n ⫽ 2), invasive aspergillosis (n ⫽ 1), and mucormycosis (n ⫽ 1) have been observed [9]. Among 27 alemtuzumab-treated patients with lymphoproliferative disorders, 3 cases of invasive aspergillosis, 1 of cryptococcosis, and 1 of histoplasmosis occurred in a subgroup of infected patients [10]. Interestingly, among 240 solid organ transplant recipients treated with alemtuzumab who developed an infection, the occurrence of IFI was not higher when compared with patients treated with basiliximab, but the IFI were more frequently disseminated in the alemtuzumab group. In that study, some patients had multiple IFI (75 IFI in 72 patients) [11]. However the currently presented case is unique, as 3 successive deep fungal infections occurred. Furthermore, the reported patient developed an invasive aspergillosis while receiving liposomal amphotericin B, which is one of its treatments [12]. Some cases of Aspergillus spp. refractory or resistant to amphotericin B have been reported, in particular Aspergillus terreus [13,14]. Although amphotericin B resistance among Aspergillus spp. is uncommon, A. terreus is the first Aspergillus spp. to have shown reduced intrinsic susceptibility to amphotericin B in vitro, whilst Aspergillus flavus and Aspergillus nidulans have been reported to be frequently less susceptible to amphotericin B [15,16]. Unfortunately, the exact species of Aspergillus could not be identified in the patient, but it has been shown that cancer patients with positive Aspergillus cultures have a high frequency of non-fumigatus Aspergillus infection when pre-exposed to amphotericin B or triazoles. These Aspergillus isolates were found to be amphotericin-resistant by Etest method [17]. However, due to the usual diagnostic difficulties of IFI, we cannot rule out the possibility of a delayed diagnosis of a simultaneous pulmonary aspergillosis. The frequency and severity of infectious complications occurring after alemtuzumab therapy have raised the question of antimicrobial prophylaxis in patients treated with alemtuzumab. While co-trimoxazole and valaciclovir are frequently used to prevent Pneumocystis jirovecii pneumonia and cytomegalovirus disease, there is no consensus on the use of antifungal prophylaxis. Fluconazole (ineffective against Aspergillus and Mucorales) and itraconazole (ineffective against Mucorales) have been proposed by some authors [7].

233

In conclusion, alemtuzumab-treated patients should be investigated for IFI upon presentation of fever or any other sign of focal infection, particularly in the case of neutropenia. When the evolution of an IFI under alemtuzumab is unexpected, the possibility of another fungal infection must be considered. Thus, fluconazole or itraconazole prophylaxis could be recommended in addition to co-trimoxazole and valaciclovir in these patients. Declaration of interest: No funding; no conflict of interest. References [1] Hallek M. Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol 2013;88:803–16. [2] Skoetz N, Bauer K, Elter T, Monsef I, Roloff V, Hallek M, et al. Alemtuzumab for patients with chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2012;2:CD008078. [3] Gribben JG. How I treat CLL up front. Blood 2010;115: 187–97. [4] Nath DS, Kandaswamy R, Gruessner R, Sutherland DE, Dunn DL, Humar A. Fungal infections in transplant recipients receiving alemtuzumab. Transplant Proc 2005; 37:934–6. [5] Silveira FP, Husain S, Kwak EJ, Linden PK, Marcos A, Shapiro R, et al. Cryptococcosis in liver and kidney transplant recipients receiving anti-thymocyte globulin or alemtuzumab. Transpl Infect Dis 2007;9:22–7. [6] Walsh R, Ortiz J, Foster P, Palma-Vargas J, Rosenblatt S, Wright F. Fungal and mycobacterial infections after Campath (alemtuzumab) induction for renal transplantation. Transpl Infect Dis 2008;10:236–9. [7] Elter T, Vehreschild JJ, Gribben J, Cornely OA, Engert A, Hallek M. Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab. Ann Hematol 2009;88:121–32. [8] Osterborg A, Karlsson C, Lundin J, Kimby E, Mellstedt H. Strategies in the management of alemtuzumabrelated side effects. Semin Oncol 2006;33(2 Suppl 5): S29–35. [9] Peleg AY, Husain S, Kwak EJ, Silveira FP, Ndirangu M, Tran J, et al. Opportunistic infections in 547 organ transplant recipients receiving alemtuzumab, a humanized monoclonal CD-52 antibody. Clin Infect Dis 2007;44:204–12. [10] Martin SI, Marty FM, Fiumara K, Treon SP, Gribben JG, Baden LR. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis 2006;43:16–24. [11] Safdar N, Smith J, Knasinski V, Sherkow C, Herrforth C, Knechtle S, et al. Infections after the use of alemtuzumab in solid organ transplant recipients: a comparative study. Diagn Microbiol Infect Dis 2010;66:7–15. [12] Fortún J, Meije Y, Fresco G, Moreno S. [Aspergillosis. Clinical forms and treatment]. Enferm Infecc Microbiol Clin 2012;30:201–8. [13] Iwen PC, Rupp ME, Langnas AN, Reed EC, Hinrichs SH. Invasive pulmonary aspergillosis due to Aspergillus terreus: 12-year experience and review of the literature. Clin Infect Dis 1998;26:1092–7. [14] Walsh TJ, Petraitis V, Petraitiene R, Field-Ridley A, Sutton D, Ghannoum M, et al. Experimental pulmonary

234

A. Henn et al.

Downloaded by [University of California Santa Barbara] at 22:38 12 September 2015

aspergillosis due to Aspergillus terreus: pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B. J Infect Dis 2003;188:305–19. [15] Kontoyiannis DP, Lewis RE, May GS, Osherov N, Rinaldi MG. Aspergillus nidulans is frequently resistant to amphotericin B. Mycoses 2002;45:406–7. [16] Colozza C, Posteraro B, Santilli S, De Carolis E, Sanguinetti M, Girmenia C. In vitro activities of

amphotericin B and AmBisome against Aspergillus isolates recovered from Italian patients treated for haematological malignancies. Int J Antimicrob Agents 2012;39:440–3. [17] Lionakis MS, Lewis RE, Torres HA, Albert ND, Raad II, Kontoyiannis DP. Increased frequency of nonfumigatus Aspergillus species in amphotericin B- or triazolepre-exposed cancer patients with positive cultures for aspergilli. Diagn Microbiol Infect Dis 2005;52:15–20.

Disseminated cryptococcosis, invasive aspergillosis, and mucormycosis in a patient treated with alemtuzumab for chronic lymphocytic leukaemia.

We report the case of a 42-y-old man treated with alemtuzumab for chronic lymphocytic leukaemia, who developed 3 successive deep fungal infections. De...
453KB Sizes 1 Downloads 0 Views