CASE REPORT

Cryptococcal fungemia in a neutropenic patientwith AIDS while receiving caspofungin

Prashant Malhotraa, Sanjiv S. Shaha, Mark Kaplana,b,Joseph P. McGowana,c,*

aNorth Shore University Hospital, Manhasset, NY, USAbNew York University School of Medicine, New York, USAcAlbert Einstein College of Medicine, New York, USA

Accepted 4 January 2005

01do

eaMa1

KEYWORDSHIV/AIDS;Cryptococcus;Caspofungin;Neutropenia

63-4453/$30.00 Q 2005 The Britishi:10.1016/j.jinf.2005.01.002

* Corresponding author. Address: Dses, North Shore University Hospitanhasset, New York 11030, USA. Tel.

516 562 2626.E-mail address: jmcgowan@nshs.ed

Abstract Empiric choice of anti-fungal therapy in febrile neutropenia should bebased upon a host’s susceptibility to specific fungal pathogens. We present a case of apatient with multiple risk factors for fungemia including HIV infection, Hodgkin’sdisease, corticosteroid use and chemotherapy-induced neutropenia who developeddisseminated cryptococcal infection while receiving caspofungin.Q 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction

Fungal infections are an important cause of morbidityand mortality in patients with impaired immunity.1

Host immune status should be an important consider-ationwhenplanning interventions for prophylaxis andtreatment of fungal infections. Amphotericin B hasbeen the anti-fungal agent most extensively used inthe setting offebrile neutropenia.2 The availability ofcaspofungin may provide an effective and possiblyless toxic alternative to amphotericin B; however,the anti-fungal spectrum of these two agents isdifferent.3 Caspofungin, like other echinocandins, isnot active against basidiomycetous yeasts, such as

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Cryptococcus neoformans, Trichosporon species andRhodotorula.4 In the era of potent anti-retroviraltherapy accompanied by immune reconstitution,HIV-infected patients are receiving aggressive che-motherapy for both HIV-associated and other malig-nancies.5,6 Following anti-cancer chemotherapy,patients with febrile neutropenia and HIV infectionmay differ from uninfected individuals in theirsusceptibility to certain fungal infections, whichmay affect the choice of empiric anti-fungal therapy.We report a case of an HIV-infected patient withneutropenic fever after receiving chemotherapy forHodgkin’s disease who developed cryptococcemia onempiric caspofungin.

Case review

A 50-year-old male presented to our institution witha 1 day history of high-grade fever associated with

Journal of Infection (2005) 51, e181–e183

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Elsevier Ltd. All rights reserved.

P. Malhotra et al.e182

fatigue but no other localizing signs. The patienthad been diagnosed with stage IV mixed cellularitytype Hodgkin’s disease (with bone marrow involve-ment) 3 months prior to admission. One week beforehis admission, he had received his third cycle ofdoxorubicin/bleomycin/vinblastine/dacarbazine.

He was diagnosed with HIV infection in 1994 andwas coinfected with hepatitis C. He had no historyof opportunistic infections. His anti-retroviral regi-men at the time of hospital admission consisted oftenofovir, lamivudine and ritonavir-boosted ataza-navir. Prior to the initiation of chemotherapy hisCD4 count was 270 cells/mm3 and an HIV-1 viralload was !50 copies/ml. His lowest CD4 count was20 cells/mm3 (CD4 percentage was 17) during hishospital admission.

His initial physical examination was remarkableonly for a temperature of 102.5 F. On admission, hehad a total white cell count of 0.4!109 cells/l. Anextended metabolic panel was normal except formildly elevated transaminases. Chest roentogramrevealed minimal bibasilar linear atelectasis but noacute infiltrate. He was initiated on intravenouspiperacillin/tazobactam and gentamicin but hisfever persisted. On the fifth hospital day, hedeveloped dyspnoea and basal crackles wereheard bilaterally on chest auscultation. Concurrentchest radiography demonstrated indistinct biapicalinfiltrates with associated nodularity; findings thatwere confirmed on a thoracic CT scan. He wasempirically started on primaquine and clindamycinto cover Pneumocystis pneumonia (he was allergicto trimethoprim-sulfamethoxazole) and underwentbronchoscopy. Special stains for Pneumocystis, andstains and cultures for acid-fast organisms, fungiand bacteria from a broncheoalveolar lavage werenegative. A serum cryptococcal antigen was nega-tive. Blood cultures from admission were negativefor growth. The patient continued with febrileneutropenia and intravenous caspofungin (70 mgloading dose followed by 50 mg daily) was added onthe eighth day of hospitalisation. The lung infil-trates were felt to be secondary to bleomycin-induced lung toxicity and he was empirically startedon intravenous steroids on the tenth hospital day.The patient became afebrile 1 day later. Pentoxifyl-line was added to taper his steroid dosage. Repeatblood cultures continued to show no growth. Hisoxygen requirements steadily decreased and heimproved clinically over the next 2 weeks whileremaining hospitalised.

On the twenty-fifth hospital day, the patientbecame severely dyspnoeic while on steroids andpentoxifylline. A thoracic CT scan showed increasedreticulonodular opacities with a small pneu-mothorax and pneumomediastinum. There was no

evidence for pulmonary embolism. A repeatbronchoscopy was performed which again wasnegative for Pneumocystis, bacterial, mycobacter-ial and fungal pathogens. Concurrent blood culturesgrew C. neoformans and a previously negativeserum cryptococcal antigen became positive at atitre of 1:128. Cerebrospinal fluid cryptococcalantigen and fungal cultures were negative. Thepatient was successfully treated with intravenousfluconazole for 6 weeks. His fever and dyspnoeacompletely resolved 1 week after the initiation ofazole therapy. Repeat blood cultures prior todischarge showed no growth. Maintenance oralfluconazole was continued after completion ofintravenous therapy.

Discussion

HIV-infected patients with neutropenic fever fol-lowing anti-cancer chemotherapy are susceptiblenot only to the usual fungal pathogens identified inthis setting (such as Candida species and Aspergillusspecies) but may also be prone to infection withadditional fungal organisms such as Cryptococcus,Histoplasma and Pneumocystis, among others.Increased susceptibility to these opportunisticpathogens is due to HIV-associated T-helper celldysfunction, which impairs cell-mediated immu-nity. Cellular immunity mediates the activation ofalveolar macrophages that phagocytose inhaledyeast cells of C. neoformans.7 Neutrophils andmonoctye-dervied macrophages are capable of invitro killing of C. neoformans and may controlC. neoformans infection in the bloodstream.7,8

Furthermore, this patient was treated with cortico-steroids, which also increase the risk for crypto-coccosis by impairing neutrophil chemotaxis,inducing lymphopenia and depressing cell-mediated immunity.7 Hodgkin’s disease and otherlymphoproliferative disorders (such as chronicleukaemia) are independently associated with thedevelopment of cryptococcal infections.7,9 Ourpatient was also receiving pentoxifylline, whichmay decrease secretion of the proinflammatorycytokine tumour necrosis factor-a (TNF).10 Whilecryptococcal infections have not been reported inpatients receiving pentoxifylline, there have beencases of pulmonary Cryptococcus in patients receiv-ing the anti-TNF monoclonal antibody infliximab.11

Even though patients receiving anti-cancer chemo-therapy can be both lymphopenic and neutropenic,the absence of disseminated cryptococcosis as acommon fungal pathogen in the febrile neutropenichost is likely due to the inadequate duration of

Cryptococcal fungemia on caspofungin e183

T-cell deficiency. However, purine analogs,although not used in our patient, can causeleucopenia, in particular profound and prolongedlymphopenia, and have been associated with avariety of opportunistic infections includingcryptococcosis.12

Anti-fungal treatment is instituted empirically inchemotherapy-induced neutropenic patients whocontinue to be febrile on broad-spectrum anti-biotics.2 Although amphotericin B is often used insuch patients, recent separate studies in thissetting have favourably compared voriconazoleand caspofungin, respectively, with liposomalamphotericin B.3,13 Encouragingly, the occurrenceof breakthrough invasive fungal pathogens was notcommon in these studies and no cases of C.neoformans were identified. However, neitherstudy described whether patients with HIV infectionwere excluded or, if not specifically excluded, theproportion of patients with HIV infection in eitherarm. Walsh et al. reported that febrile neutropenicpatients who received caspofungin had improvedshort-term survival, similar incidence of break-through fungal infection and a lower rate ofnephrotoxicity compared with those who receivedamphotericin B.3 Caspofungin is an echinocandinthat inhibits the synthesis of 1, 3-beta-D-glucan inthe fungal cell wall of Candida species andAspergillus species. However, caspofungin is notactive against C. neoformans. Echinocandin resist-ance may be due to the presence of a structurallydifferent glucan synthase in C. neoformans, poordrug penetration or calcineurin dependent regu-lation of 1, 3-beta-D-glucan synthase expression.4,14

This case illustrates that C. neoformans funge-mia can occur in the febrile neutropenic patientparticularly if the host’s cell-mediated immunity isalso impaired. Clinicians should be aware that thechoice of an empiric anti-fungal agent in theneutropenic patient with fever should be influencedby the individual’s susceptibility to certain fungalpathogens.15 Caspofungin, which is not activeagainst C. neoformans, should be used withcaution, if at all, in HIV-infected patients withchemotherapy-induced neutropenia. AmphotericinB and its lipid formulations, and possibly voricona-zole, may be more appropriate in these patients.

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