Management of intracranial fungal infections in patients with haematological malignancies

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1 review Management of intracranial fungal infections in patients with haematological malignancies Gloria Mattiuzzi and Francis J. Giles Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA Summary The incidence of, and mortality associated with, invasive fungal infections remains far higher than hoped. As a consequence of the overall increase in the incidence of such infections over time, the incidence of central nervous system (CNS) fungal infections is also increasing and, despite improvements in diagnostic techniques and the introduction of novel antifungal agents, therapy for CNS infections is still associated with discouragingly poor results. In patients with haematological malignancies, opportunistic infections with Candida or Aspergillus remain the most common infections affecting the CNS; however, opportunistic infections with less well-known fungi are becoming more common and must be considered in the differential diagnosis. New techniques for the early diagnosis of invasive fungal infections are emerging. Pharmacologic options for treating invasive fungal infections have also improved during the past few years, with new drugs becoming available that have broader antifungal spectra and better safety profiles. Other novel treatment approaches, such as combination therapy, are also being explored. Early investigations have produced encouraging results; however, large, prospective studies involving many patients are necessary to validate the widespread use of these approaches. This review analyses the existing guidelines for treatment of CNS fungal infections and the literature available on the use of new drugs to generate sets of recommendations for treatment of these life-threatening infections in patients with haematological malignancies. Keywords: central nervous system, fungal infections, haematological malignancies. Correspondence: Gloria Mattiuzzi, Assistant Professor, Leader, Hematologic Malignancies Supportive Care Program, Department of Leukemia, Unit 428, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. gmattiuz@mdanderson.org Overview Despite the introduction of novel agents into the armamentarium of antifungal therapies in the past decade, the incidence of and mortality associated with invasive fungal infections remain far higher than hoped, and these infections continue to pose a challenge for the medical community. Physicians and patients are also facing a new complication: the increasing incidence of infections with what were previously considered to be uncommon opportunistic fungi, bringing with them an expanded clinical spectrum of disease. Several factors account for the increased incidence of invasive fungal infections. The number of immunosuppressed patients continues to rise owing to increasing use of organ transplantation, aggressive chemotherapy regimens for treating cancer, and broad-spectrum antibiotics and corticosteroids, all of which can lead to profound immunosuppression (Groll & Walsh, 2001; Tietz et al, 2001). Also, as patients with cancer or acquired immunodeficiency syndrome (AIDS) survive for longer periods, the risk of developing invasive infections caused by opportunistic pathogens can be expected to increase as well. As a consequence of this overall increase in incidence, the incidence of central nervous system (CNS) fungal infections is also increasing, and despite improvements in diagnostic techniques and the introduction of novel antifungal agents, therapy for CNS infections is still associated with discouragingly poor results (Go et al, 2000; Gottfredsson & Perfect, 2000). The brain and the subarachnoid space are considered immunologically sequestered sites. The subarachnoid space has functional and anatomic barriers against infections, fungal or otherwise, but under certain circumstances (trauma, surgery, or existing immune system abnormalities), fungal pathogens from areas outside the brain are able to breach these barriers. The therapeutic approach for CNS fungal infections in patients with haematological malignancies is predominantly pharmacological, although some groups have attempted surgical treatment. Unfortunately, few of the drugs available for treating fungal infections have good CNS penetration (Table I) and therefore the pharmacologic options are still limited. In this review, we summarise the most common clinical manifestations, diagnostic methods, and treatment strategies ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131, doi: /j x

2 for fungal infections that affect the CNS. Emphasis is placed on those infections that are considered the most common in patients with haematological malignancies, followed by those considered to be emerging fungal infections (Table II). However, several caveats regarding this topic should be noted. Firstly, it is the extremely limited literature on patients with haematological malignancies as distinct from patients with solid tumours or patients undergoing stem cell transplantation, for whom the risks associated with developing fungal CNS disease are quite different. Secondly, historically the outcome of patients with CNS fungal infection has been extremely poor. Although some studies of new agents, used alone or in combination with other drugs, have produced encouraging results, the small numbers of patients in these studies preclude use of their results as a basis for a rule, although they can be used as the basis for suggested best approach guidelines. Ideally, the best approach would consider each patient on an individual basis, taking into consideration the underlying disease, the presence of comorbidity, the site of the infection, and any previous antifungal drugs received. Opportunistic infections Candida species Risk factors for developing CNS candidiasis are similar to those for developing disseminated candidiasis and include being a premature neonate, having a central venous catheter, receiving antibiotics and corticosteroids, undergoing haematopoietic or solid organ transplantation, having AIDS, having prolonged periods of neutropenia, being severely burned, and having a history of neurosurgery, placement of prosthetic materials, or diabetes mellitus. Although Candida albicans is the most common species of Candida identified in CNS infections, other Candida spp. such as C. tropicalis, C. parapsilosis, C. glabrata and C. lusitaniae have also been reported (Sarma et al, 1993; Voice et al, 1994; Fernandez et al, Table I. Antifungal agents and their penetration into the cerebrospinal fluid. Drugs with acceptable CSF penetration 5-Flucytosine (drug penetration 74% serum concentration) Fluconazole (drug penetration 60% serum concentration) Voriconazole (drug penetration 50% serum concentration) Drugs with poor CSF penetration Amphotericin B dexochycolate (drug penetration <4% serum concentration) Itraconazole (drug penetration <5% serum concentration) Lipid formulations of amphotericin B (AmBisome >ABLC or ABCD) Caspofungin Posaconazole ABLC, amphotericin B lipid complex; ABCD, amphotericin B colloidal dispersion. 2000; Hawkins & Baddour, 2003; Chen et al, 2004). Among adult patients with cancer and systemic candidiasis, 1 6% have been shown to have CNS involvement at autopsy (Bodey et al, 1992; Kume et al, 2003), but the diagnosis is made before autopsy in <20% of cases (Black, 1970; Go et al, 2000). The most common manifestations of CNS candidiasis in adult patients are cerebral microabscesses, meningitis, and cerebral macroabscesses; vascular complications, such as cerebral infarcts, aneurysms and subarachnoid haemorrhaging, have also been described. Clinical and radiographic characteristics of these manifestations are summarised in Table III. Other less common presentations include meningoencephalitis, granuloma and ependymitis. The antemortem diagnosis of CNS candidiasis is difficult, particularly in immunosuppressed patients. In patients with candidal microabscesses, analyses of the cerebrospinal fluid (CSF) are non-diagnostic because culturing and Gram staining often lead to negative results or non-specific findings of cellularity; results of biochemical panels also are often negative as well. Candidal macroabscesses, on the other hand, usually produce moderate pleocytosis and slightly elevated protein levels in the CSF. Candidal meningitis also usually manifests as pleocytosis in the CSF, generally with neutrophils or monocytes predominating, as well as mildly elevated protein levels and low glucose levels (Sanchez-Portocarrero et al, 2000; Chen et al, 2004). However, patients with cancer and candidal meningitis may show minimal signs of meningitis and few abnormalities in the CSF as a consequence of neutropenia and impaired inflammatory response. In general, immunocompetent patients without significant risk factors in whom only one CSF culture tests positive for Candida spp. should undergo repeat CSF cultures to rule out contamination of the original specimen. On the other hand, immunocompromised patients, premature infants, and patients with prior CNS device implantations should be given antifungal therapy immediately when a CSF culture is positive for Candida spp. Any indwelling CNS devices should be removed as soon as the diagnosis of CNS candidiasis is suspected. Mannan is an immunodominant surface antigen on the cell walls of C. albicans serotypes A and B, and it can be detected in the serum and CSF of patients with candidal meningitis. Although measurement of mannan in serum has produced variable results, measurements of CSF have been promising in terms of identifying patients with CNS candidiasis. In one report, mannan was detected in the CSF in all three patients with proven CNS candidiasis but was not detected in a CSF sample from a fourth patient that was thought to be contaminated (Verduyn Lunel et al, 2004). These results, although preliminary, suggest that the detection of mannan in CSF may be useful for distinguishing candidal meningitis from culture contamination. Further studies are needed to assess the usefulness of this technique in the diagnosis of CNS candidiasis. The recommended treatment for CNS candidiasis is amphotericin B (0Æ7 1 mg/kg/d) plus 5-flucytosine (25 mg/kg q.i.d.) 288 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

3 Table II. Common fungi and spectra of CNS infections caused by them. Clinicopathological manifestations of CNS disease Genus Incidence Predilection for CNS Setting Meningitis Abscess Infarct Candida Common + Neurosurgery Neutropenia Systemic candidiasis IV drug use Aspergillus Occasional ++ Neutropenia Invasive sinusitis HIV infection IV drug abuse Zygomycetes* Occasional ++ Diabetes Neutropenia Histoplasma Occasional + HIV infection Steroid use Blastomyces Occasional + Normal host + + ) Cryptococcus Common ++++ HIV infection Steroid use Normal host Coccidioides Common +++ Normal host HIV infection Key: ++++, very common; +/), very rare. *Among the zygomycetes, Rhizopus is the most common cause of invasive disease, but other genera include Mucor sp. and Cunninghamella sp. More common for C. neoformans var. gatti than C. neoformans var. neoformans. Modified from Gottfredsson and Perfect (2000). Table III. Clinical and radiographic presentations of neurocandidiasis. Clinical and radiographic features Cerebral microabscesses Diffuse encephalopathy Cerebral CT scan and lumbar puncture not diagnostic Diagnosis is usually postmortem Meningitis Subacute onset with fever and headache Cerebral CT scan could show hydrocephalus Culture of CSF often gives the diagnosis Cerebral macroabscesses Less frequent Focal neurological signs and seizures Diagnosis based on neuroimaging studies and biopsy Vascular complications Cerebral infarction Mycotic aneurysms Subarachnoid haemorrhage Adapted from Sanchez-Portocarrero et al (2000), with permission from Elsevier. (Rex et al, 2000; Pappas et al, 2004). The rationale for the combination is to achieve a synergistic effect against Candida spp. Treatment should be continued for at least 4 weeks after resolution of signs and symptoms associated with the infection. In a murine model of candidal meningitis, liposomal amphotericin B was shown to have better efficacy than other amphotericin B lipid formulations and comparable efficacy to that of amphotericin B deoxycholate (Groll et al, 2000). However, the only data available on the clinical use of liposomal amphotericin B are for newborn infants (Scarcella et al, 1998; Tweddle et al, 1998). The combination of fluconazole with 5-flucytosine for candidal meningitis has been reported in one case (Marr et al, 1994); however, given reports of refractory and relapsed disease in patients treated with fluconazole, the combination of fluconazole and 5-flucytosine should be reserved for patients who cannot tolerate amphotericin B or have previously had severe toxic reactions to amphotericin B therapy. Caspofungin has relatively poor brain penetration; nevertheless, caspofungin treatment has been successful in 10 neonates and one adult with refractory and progressive candidal meningitis (Liu et al, 2004; Odio et al, 2004). Thus, caspofungin could be considered an option in severe cases that do not respond to other treatments. Voriconazole, on the other hand, has good CSF penetration and excellent activity against Candida spp; in a neutropenic animal model of disseminated C. krusei, voriconazole led to significantly greater clearance of yeast from the brain than did amphotericin B or fluconazole (Ghannoum et al, 1999). Although no reports have been published on the use of voriconazole for the treatment of Candida meningitis in immunocompromised patients, its efficacy against invasive candidiasis has been well documented (Ostrosky-Zeichner et al, 2003; Perfect et al, 2003). Thus ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

4 voriconazole should be considered as an alternative to amphotericin B for patients with CNS candidal infection. Aspergillus species The incidence of invasive aspergillosis has increased significantly over the past few decades because of increases in the numbers of patients at risk and in the use of more aggressive and immunosuppressive treatment regimens for malignancies and other diseases. The risk factors for invasive aspergillosis are well known and include immunosuppression for bone marrow, stem cell, lung, or liver transplantation; acute leukaemia or lymphoma; use of high-dose corticosteroids; and late-stage AIDS. Among immunocompromised patients, between 10% and 20% of cases of invasive aspergillosis involve the CNS, and the mortality rate for CNS aspergillosis exceeds 80% (Denning, 1996; Ribaud et al, 1999; Lin et al, 2001). Cerebral aspergillosis occurs most often after haematogenous dissemination of the infection from the lungs, but primary cerebral aspergillosis, rhinocerebral disease and direct spread to the brain from external otitis have been also reported in immunocompromised patients (Walsh et al, 1985). Central nervous system aspergillosis can present as solitary or multiple lesions, meningitis, or granuloma; less common presentations include mycotic aneurysms, myelitis, dural abscesses and carotid artery invasion (Gottfredsson & Perfect, 2000; Kleinschmidt-DeMasters, 2002). Patients with CNS aspergillosis usually experience persistent fever, altered mental status, focal neurologic deficits, and, less often, meningeal symptoms. Severely immunocompromised patients are less likely to show symptoms, and disease progression is often rapid. Findings from CSF evaluations are usually non-specific, as CSF cultures are almost always negative for Aspergillus spp. Definitive diagnosis requires an aspiration or other biopsy of the lesion, but such procedures are rarely performed in patients with haematological disease because of the substantial risks associated with thrombocytopenia. Given the limitations of clinical and laboratory tests for diagnosing invasive aspergillosis in the CNS, sophisticated imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) can be useful for this purpose. In immunocompromised patients, the appearance of poorly defined, low-density lesions with little or no mass effect and minimal contrast enhancement on CT are suggestive of infarcts. On T2-weighted MRI scans, Aspergillus lesions of the brain manifest as heterogeneous high-signal intensity areas surrounded by low-density signal at the peripheral rim, resembling haemorrhagic infarcts. Any of these findings is usually associated with rapidly fatal outcome. In less severely immunocompromised patients or in patients recovering from immunosuppression, the presence of rings or nodular enhancement on contrast-enhanced T 1 -weighted MRI scans is consistent with abscess or granuloma (Miaux et al, 1995; Okafuji et al, 2003). Serological methods involving the detection of antigen, metabolites, or nucleic acids offer promising strategies for early diagnosis of invasive aspergillosis. In one study, use of an enzyme-linked immunosorbent assay (ELISA) for galactomannan, a cell-wall component of Aspergillus, in the serum of patients with haematological malignancies at high risk for invasive aspergillosis showed a sensitivity of 90%, a specificity of 98%, and a negative predictive value of 98% (Maertens et al, 2001). The critical finding in that study was that galactomannan was detected in these patients 2 8 d before the appearance of clinical symptoms or signs of infection on chest radiography. Identification of 1,3-b-d-glucan, a fungal cell-wall component of molds and yeasts, has also shown promising results for the early detection of invasive fungal infections (Verweij et al, 2000). In one recent study, serum samples from 283 patients with acute myelogenous leukaemia or myelodysplastic syndrome undergoing induction chemotherapy were tested for this component. At least one sample was positive for 1,3-b-dglucan at a median of 10 d before the clinical diagnosis could be made in 100% of the patients with proven or probable invasive fungal infections, including four patients with invasive aspergillosis (Odabasi et al, 2004). Real-time polymerase chain reaction (PCR) analysis can also be effective in the early diagnosis of invasive aspergillosis, but concerns have been expressed about specificity and the incidence of false-positive results (Loeffler et al, 1999). Although antigenic tests are usually done with blood samples, some investigators have tested CSF from patients with CNS aspergillosis. Verweij et al (1999) reported a case of an immunocompetent patient with Aspergillus meningitis for whom a galactomannan-positive CSF sample was the initial indicator of aspergillosis; the pattern of the antigen titre for that patient also corresponded with the clinical response to treatment. In another study of five patients with leukaemia and CNS aspergillosis (two with multiple haemorrhagic infarctions and three with cerebral abscesses) with invasive pulmonary disease, the authors evaluated the patients CSF samples for Aspergillus by using PCR, latex agglutination, and ELISA to detect galactomannan (Kami et al, 1999). Although no evidence of aspergillosis was found in any CSF culture, CSF samples from all five patients showed positive results on PCR and samples from four patients showed positive results for both latex agglutination and ELISA. These findings, although preliminary, suggest that serological testing could facilitate the early diagnosis of CNS aspergillosis and hence hasten the initiation of therapy for this life-threatening disease. However, additional testing of many more patients is needed to clarify the reasons for falsepositive results, the influence of prophylactic drugs on the results, the reliability of the tests for patients with different mycoses or different underlying disease states (e.g. profound neutropenia), the reliability of the tests for detecting different Aspergillus spp. and so on. 290 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

5 Key factors influencing outcome in invasive aspergillosis include early diagnosis, prompt and aggressive treatment, and recovery of immune function. Patients with CNS involvement have by far the poorest outcome of all patients with invasive aspergillosis despite the use of high-dose antifungal monotherapy or combination therapy. Guidelines from the Infectious Diseases Society of America published in 2000 recommend amphotericin B for the treatment of CNS aspergillosis (Stevens et al, 2000). Since that time, other therapeutic approaches have been explored, and some have produced encouraging results. For example, the efficacy of voriconazole in invasive aspergillosis has been documented in several studies (Denning et al, 2002; Herbrecht et al, 2002; de Lastours et al, 2003; Marbello et al, 2003; Troke et al, 2003). Perhaps the strongest findings, reported by Denning et al (2002), demonstrated an overall response rate (partial response + stable disease) of 42% for patients with CNS disease who were given voriconazole as primary or salvage therapy. This response rate was superior to that with amphotericin B and comparable with the response rate to itraconazole, at least in some studies. The superiority of voriconazole over amphotericin B was also confirmed by Herbrecht et al (2002). In that study of patients with invasive aspergillosis, primary therapy with voriconazole was superior to that with amphotericin B, with successful outcomes (complete + partial response) reported for 52Æ3% of those given voriconazole versus 31Æ6% for those given amphotericin B. Only 10 patients with CNS disease were included in this study, five in each treatment group, and the outcome for them was not reported. Nevertheless, these results strongly support consideration of voriconazole for patients with CNS aspergillosis. Finally, caspofungin monotherapy was recently shown to have modest effects in refractory invasive aspergillosis, with a response rate of 45% (Maertens et al, 2004; Kartsonis et al, 2005). However, only two patients with CNS disease were included in these studies, and thus the role of caspofungin as salvage therapy for CNS aspergillosis remains unclear. The increasing incidence of invasive aspergillosis and the poor prognosis associated with it have also led to the exploration of combination antifungal therapy. For CNS aspergillosis, the combination of caspofungin with voriconazole (Damaj et al, 2004), itraconazole (Rubin et al, 2002) or liposomal amphotericin B (Ehrmann et al, 2005) as salvage therapy has produced good outcomes. However, prospective clinical trials are needed to determine whether (or which) combination therapy is the most appropriate for primary treatment of CNS aspergillosis. Other approaches have included single case studies of high-dose oral itraconazole (Sanchez et al, 1995; Mikolich et al, 1996; Palanisamy et al, 2005). The drawbacks of itraconazole are its variable bioavailability after oral doses and its poor brain penetration (CSF concentrations are typically <0Æ2% of the plasma concentrations). Posaconazole has been used as salvage therapy for refractory invasive aspergillosis (Maertens et al, 2004), but no data are available on its use for CNS disease. Finally, immune-boosting strategies with colony-stimulating factors and white blood cell transfusions have been attempted for patients with invasive fungal infections, but their numbers are too few to draw definitive conclusions. Such strategies, although beyond the scope of this review, deserve additional study. Zygomycetes Infections with zygomycetes (which include the order Mucorales) have become more common in immunocompromised patients during the past two decades (Kontoyiannis et al, 2000; Marr et al, 2002). Proposed reasons for this increase include environmental factors, use of more potent myeloablative and immunosuppressive regimens, and perhaps the excessive use of some antifungal agents (Kauffman, 2004). Like Aspergillus spp., Mucor spp. have a remarkable affinity for vascular invasion and tissue necrosis, with resultant haemorrhage and necrotic lesions. Mucormycosis is the second most common mycosis caused by filamentous fungi. It has an acute, rapidly progressing course and carries a poor prognosis. Patients with acute leukaemia or lymphoma, recipients of bone marrow transplants, patients with prolonged neutropenia, patients with poorly controlled diabetes mellitus or renal disease, and patients receiving corticosteroid therapy are at high risk for this infection. Mucormycosis can manifest as rhinocerebral, pulmonary, disseminated, cutaneous, or gastrointestinal disease. Rhinocerebral involvement begins with the nasal mucosa, from which the organism extends to the palate, paranasal sinuses, orbit, face and brain. Thus, patients with rhinocerebral mucormycosis experience facial pain or headache that is often located in the frontal or retro-orbital regions. Spread of the infection to the eyes is not uncommon. Because the fungus has a predilection for invading blood vessels, infarction of invaded areas is common. Extension of the infection from the sinuses to the brain takes place via the dura and can lead to loss of function of the cranial nerves, thrombosis of the internal carotid artery, hemiplegia, lethargy and seizures (Morrison & McGlave, 1993; Pagano et al, 2004a). Cerebrospinal fluid analyses usually produce non-specific findings, and the growth of zygomycetes in blood cultures is rare. Tissue samples, rather than exudates from the surface of a lesion, are preferable for culturing, but such cultures are also negative for the fungus 40% of the time. CT scans of the brain are quite sensitive for the diagnosis of mucormycosis, which manifests as ring-enhancing lesions in the frontal or temporal lobes after administration of a contrast agent. Achieving a positive treatment outcome in mucormycosis requires managing the underlying risk factors, such as controlling hyperglycemia in patients with diabetes, discontinuing corticosteroid or immunosuppressive therapy and enhancing recovery from neutropenia. Transfusions of colony-stimulating factors or granulocytes may also be helpful for controlling the infection, but more data are needed before the use of such factors ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

6 can be recommended for this purpose (Sahin et al, 1996; Dignani et al, 1997). Treatment of CNS mucormycosis should also include appropriate debridement of devitalised tissue, although surgery may be difficult in some situations (e.g. when patients have neutropenia or thrombocytopenia or when the infection is located at an inaccessible site). Treatment of mucormycosis should also include pharmacologic agents. The currently favoured approach is high-dose amphotericin B (1Æ2 1Æ5 mg/kg/d), although high-dose amphotericin B lipid formulations (doses in excess of 10 mg/kg/d) have shown some success and should be considered for patients who cannot tolerate conventional amphotericin B or those with refractory disease (Herbrecht et al, 2001; Walsh et al, 2001; Barron et al, 2005; Perfect, 2005). In fact, Pagano et al (2004a)) found, in a retrospective review of 59 patients with haematological malignancies, that use of liposomal amphotericin B was the only factor associated with recovery from mucormycosis. As for the triazoles, posaconazole has been shown to have good activity in vitro against Mucor spp. and several other zygomycetes, with minimum inhibitory concentrations of 0Æ5 2Æ0 mg/l; this represents significantly greater activity than that of voriconazole and fluconazole and slightly greater than that of itraconazole (Uchida et al, 2001; Sun et al, 2002). Clinically, posaconazole has been used as salvage therapy for patients with zygomycosis refractory to antifungal therapy (Greenberg et al, 2003). Most of the 24 patients in that single preliminary study had haematological malignancies or had undergone haematopoietic stem cell transplantation and had been treated with posaconazole at 800 mg/d for a mean of 137 d. The overall response rate (complete plus partial) was 70%, but the number of patients with CNS disease was not reported. The in vitro activity of posaconazole and this preliminary clinical experience with it suggest that posaconazole could be considered an option for treatment of refractory zygomycosis; additional studies are needed to clarify its role, if any, as primary therapy. With regard to other commonly used antifungal agents, 5-flucytosine and fluconazole are ineffective against zygomycetes, and itraconazole has only minimal activity. Caspofungin and voriconazole have also been shown to be ineffective against clinical isolates of mucormycetes (Diekema et al, 2003; Greenberg et al, 2004). Endemic pathogens Endemic or primary pathogens are consistently acquired from known geographic locations, but over the past decade, the incidence of these infections has increased greatly in areas where these infections were previously considered uncommon (Tietz et al, 2001; Kamei et al, 2003). Possible explanations for this change include the expanding number of international travelers, increased migration of susceptible persons into endemic areas and, conversely, increased immigration from countries where the pathogens are endemic to those where they are not. Mycoses caused by endemic pathogens share several characteristics. Firstly, the pathogenesis is characterised by exposure to an environmental source of the fungus, usually through inhalation of spores and subsequent pulmonary infection. The second characteristic is that among immunocompromised hosts, disease nearly always becomes disseminated and has a more aggressive clinical course. The final common characteristic is that the disease can remain dormant for up to several years (e.g. histoplasmosis) and can be reactivated by an underlying disease (e.g. AIDS, bone lymphomas) or treatment (e.g. corticosteroids, chemotherapy). Thus, mycoses should be included in the differential diagnosis for patients with haematological malignancies and a history of residing in endemic areas that present with neurologic symptoms, alone or as part of a constellation of symptoms. Histoplasma capsulatum Histoplasmosis is endemic in Argentina, Brazil, Colombia, Peru, Venezuela, and Mexico. In the US, histoplasma is endemic mostly in the Ohio and Mississippi River valleys. In immunocompromised hosts, reactivation of latent histoplasmosis rather than a new infection is usually the apparent cause of disseminated disease. Disseminated disease is more common than localised disease among immunocompromised patients, occurring in up to 80% of such patients, but only 20% of patients with disseminated disease have any form of CNS involvement (Wheat et al, 1990). Patients intensively treated for acute lymphocytic leukaemia, advanced Hodgkin disease or chronic lymphocytic leukaemia are at high risk of developing disseminated histoplasmosis; moreover, such patients are not necessarily neutropenic at the time the histoplasmosis is diagnosed (Kauffman et al, 1978; Carrillo et al, 1981; Adderson, 2004). CNS histoplasmosis can manifest as chronic meningitis or as a mass lesion that can easily be mistaken for a malignancy or abscess (Wheat et al, 2000). Clinically, CNS involvement is usually characterised by lethargy, headache, cranial nerve deficits, and changes in mental status. CSF findings can include hypoglycorrhachia, normal to elevated protein levels and normal cell counts. The diagnosis of histoplasmosis is confirmed by identifying the organism in blood, tissue or sputum specimens. Serological and skin testing are of limited benefit for patients with haematological malignancies, but the presence of intracellular yeast cells in peripheral blood smears may indicate the presence of disseminated disease (Kauffman, 2002a). The recommended treatment for CNS histoplasmosis is amphotericin B deoxycholate, given at 0Æ7 1Æ0 mg/kg/d for a total of 35 mg/kg (Wheat et al, 2000). Liposomal amphotericin B (administered at 3 5 mg/kg/d for 3 4 months) is considered an attractive alternative (Wheat et al, 2000) because it is less nephrotoxic and because higher concentrations can be achieved in the CSF compared with the non-liposomal form. Itraconazole does not reach adequate therapeutic levels in the CSF and therefore is not recommended for the initial 292 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

7 treatment of CNS histoplasmosis; however, after successful treatment with another agent, such as amphotericin B, chronic suppressive therapy with itraconazole suspension (400 mg/d) is recommended to avoid relapse for all patients with CNS histoplasmosis (Kauffman, 2002a; Perea & Patterson, 2003). Although fluconazole achieves therapeutic concentrations in the CSF, it is less active than itraconazole against histoplasmosis, and thus fluconazole (800 mg/d) should be considered only for maintenance therapy (Wheat et al, 2000). Among the newer antifungal drugs, voriconazole and posaconazole have shown good activity against H. capsulatum in vitro (Li et al, 2000; Uchida et al, 2001), but the only clinical information available is a single case report of an immunocompetent patient who was successfully treated for an intramedullary histoplasmosis abscess in the spinal cord with a 3-month course of intrathecal amphotericin B and voriconazole (Hott et al, 2003). No clinical data are available as yet to compare the efficacy of voriconazole and posaconazole with that of amphotericin B for CNS histoplasmosis. Caspofungin has shown only limited activity against Histoplasma in vitro and in a mouse model of pulmonary histoplasmosis, even when given at high doses (5 mg/kg b.i.d.). Hence, caspofungin is not recommended for the treatment of histoplasmosis (Kohler et al, 2000). Blastomyces dermatitidis Areas in North America where Blastomyces dermatitidis is endemic include the southeastern and central southern states, especially those bordering the Mississippi and Ohio Rivers; the midwestern states and Canadian provinces that border the Great Lakes; and a small area in New York and Canada along the St Lawrence River. Blastomycosis is also endemic in Africa. In immunocompromised patients, blastomycosis often occurs as disseminated or recurring fungal infection. CNS infection is rare in healthy hosts but is relatively common in patients with disseminated or relapsed blastomycosis. The most common CNS manifestations are meningitis and intracranial mass lesions; epidural or vertebral abscesses have also been reported in about 20% of patients with CNS disease. Disseminated blastomycosis has been described in patients with haematological malignancies (Recht et al, 1982; Pappas et al, 1993; Isotalo et al, 2002). In such patients, blastomycosis is usually more aggressive, relapses more frequently, and has a higher mortality rate than in normal hosts (Pappas et al, 1993). In the largest series studied to date of 34 immunocompromised patients with blastomycosis, 10 (29%) had haematological malignancies (mostly chronic lymphocytic leukaemia). Only one patient with haematological malignancy (3%) developed CNS disease, and that patient died despite treatment with amphotericin B (Pappas et al, 1993). The diagnosis of blastomycosis requires microscopic demonstration of the fungus in clinical specimens and confirmation by culture. However, because routine fungal cultures may not produce recoverable organisms for several weeks, the presence of large, broad-based, budding yeasts in clinical specimens should alert physicians to the possibility of blastomycosis. Serological tests have very low sensitivity and specificity and are not useful for diagnosis. Given the aggressiveness and high mortality rate of blastomycosis in immunocompromised patients (30 40%), all such patients should be treated for this disease. The treatment of choice for patients with CNS blastomycosis is amphotericin B deoxycholate at 0Æ7 1 mg/kg/d (Chapman et al, 2000). Depending on the initial response to (and toxicity of) this therapy, amphotericin B can be continued for a full course (to a total dose of 1 2 g) or the therapy can be changed to an itraconazole oral suspension (200 mg b.i.d.) once the disease has stabilised, and continued for 6 12 months (Chapman et al, 2000; Kauffman, 2002b). Patients who remain immunosuppressed should receive long-term therapy with itraconazole oral suspension to prevent relapse. Liposomal formulations of amphotericin B have been shown to be effective in animal models of blastomycosis, but clinical data regarding its use for CNS blastomycosis are scarce (Chowfin et al, 2000). Because fluconazole has excellent CSF penetration, it should be considered for patients who cannot tolerate, or develop toxic reactions to, itraconazole. The recommended dose is 800 mg/ d; however, relapse after use of fluconazole has been reported (Chapman et al, 2000). In vitro studies have shown that voriconazole is superior to fluconazole and has comparable activity to itraconazole against B. dermatitidis (Li et al, 2000; Sugar & Liu, 2001). Bakleh et al (2005) recently reported a case of a patient with non-hodgkin lymphoma and a history of disseminated blastomycosis treated with fluconazole who developed CNS blastomycosis. The CNS infection was treated with voriconazole (400 mg daily for 4 weeks, and then 600 mg daily for 12 months), which led to clinical and radiographic resolution of the disease (Bakleh et al, 2005). This single case report should not be taken as a recommendation to use voriconazole as initial therapy for CNS blastomycosis; however, its good CNS penetration and its effectiveness against Blastomyces in vitro suggest that voriconazole should be considered for treating CNS blastomycosis. Whether voriconazole is better suited as a primary or maintenance therapy remains to be determined. Finally, posaconazole has similar antifungal activity in vitro to that of itraconazole and lower minimum inhibitory concentrations than amphotericin B (Sugar & Liu, 1996; Uchida et al, 2001); however, posaconazole has yet to be used in clinical settings for patients with blastomycosis. Cryptococcus neoformans Cryptococcosis usually begins in the lung after the inhalation of fungal cells; the cryptococci can remain dormant there until the immune system weakens, at which time they become reactivated and disseminate haematogenously to the CNS. In the brain, cryptococci can cause life-threatening meningitis or meningoencephalitis. ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

8 The major lines of defence against cryptococcal infection are the alveolar macrophages, inflammatory phagocytic cells and T and B cells. Individuals with AIDS, lymphoproliferative disorders, sarcoidosis or diabetes mellitus and those who have undergone organ transplantation (especially kidney) or corticosteroid therapy are at high risk for C. neoformans infection. Among patients with haematological malignancies, those with lymphoma, chronic lymphocytic leukaemia and acute myeloid leukaemia are at highest risk (Pagano et al, 2004b; Rimek et al, 2004). Several factors have been associated with mortality in cryptococcal meningitis, specifically the presence of an underlying haematological malignancy or a high yeast burden (determined by India ink capsule staining and high antigen titres); the development of increased intracranial pressure; a poor inflammatory response; a leucocyte count <0Æ cells/l; and altered mental status and lack of headache on presentation (Pappas et al, 2001; Sepkowitz, 2002). In patients with haematological malignancies, the onset of CNS cryptococcosis is more acute (1 2 weeks) than it is in patients without a haematological malignancy who are also not infected with the human immunodeficiency virus (HIV) (up to 29 d). The clinical presentation of CNS cryptococcosis in patients with haematological malignancies is often atypical, with fever, confusion, headache and diplopia (Shih et al, 2000; Pagano et al, 2004b). Although the CSF panel usually shows minimal abnormalities in patients with AIDS or severe immunosuppression, identifying C. neoformans in the CSF with India ink capsule staining is easy because of the high fungal burden. Positive blood cultures probably indicate extensive disease and occur most often in association with AIDS, high-dose corticosteroid treatment and neutropenia. The detection of cryptococcal polysaccharide antigen in body fluids is highly useful for prompt diagnosis. Antigen detection by latex agglutination is the most commonly used test. Positive findings on a serum antigen test at a dilution of 1:4 are strongly suggestive of C. neoformans infection, and a titre of 1:8 or more is indicative of active disease. In patients with C. neoformans meningitis, the antigen detection test tends to be less sensitive in serum (85Æ5%) than in the CSF (98Æ5%), although some studies have shown 100% sensitivity for serum antigen tests (Pagano et al, 2004b). CT scanning can show normal findings (in about 50% of cases), meningeal enhancement, single or multiple nodules or hydrocephalus (Shih et al, 2000). The suggested optimal treatment for immunosuppressed, HIV-negative patients with CNS cryptococcosis is amphotericin B (0Æ7 mg/kg/d) for at least 2 weeks, followed by fluconazole ( mg/d) for at least 10 weeks. Suppressive therapy with low-dose fluconazole (200 mg/d) for 6 12 months should be considered for patients with continuing immunosuppression or evidence of persistent disease. Itraconazole (200 mg b.i.d.) can be used for patients who cannot tolerate fluconazole (Saag et al, 2000). The use of amphotericin B lipid complex has been studied in both HIV-positive and - negative patients with CNS cryptococcosis (Sharkey et al, 1996; Baddour et al, 2005). Compared with amphotericin B, amphotericin B lipid complex produces higher clinical response rates (86% vs. 65%) and less toxicity (Sharkey et al, 1996). Results from the Collaborative Exchange of Antifungal Research (CLEAR) study, which included 83 patients with CNS cryptococcosis, showed acceptable response rates of 65% for those with CNS disease and 56% for those whose disease was refractory to prior antifungal therapy (Baddour et al, 2005). Similarly, other studies of HIV-positive patients with CNS cryptococcosis showed that liposomal amphotericin B was as effective as, and less toxic than amphotericin B (Leenders et al, 1997; Hamill et al, 1999). Interestingly, patients treated with liposomal amphotericin B had showed CSF culture conversion significantly earlier than did patients given amphotericin B (Leenders et al, 1997). Lipid formulations of amphotericin B can be particularly useful for patients with renal dysfunction. Voriconazole is more active in vitro than either fluconazole or itraconazole against C. neoformans (Pfaller et al, 1999). In a clinical evaluation of voriconazole for 18 patients with refractory cryptococcosis, most of whom had AIDS, the response rate for those with cryptococcal meningitis was low (<39%), but most of the patients showed stabilisation of disease and more than 90% were still alive at a 90-day followup evaluation (Perfect et al, 2003). Cryptococcus neoformans is highly susceptible to posaconazole in vitro (Uchida et al, 2001). In animal models of Cryptococcus meningitis, the activity of posaconazole seems to be equivalent to that of fluconazole (Perfect et al, 1996). In a murine model of systemic cryptococcosis, the combination of posaconazole and amphotericin B seemed to be more effective in reducing the fungal burden in the brain than use of either drug alone (Barchiesi et al, 2004). Additional studies are needed to evaluate the role of posaconazole in the treatment of Cryptococcus meningitis. The echinocandins have poor in vitro activity against C. neoformans and are not recommended for treatment of patients with cryptococcosis. Coccidioides immitis Areas endemic for coccidioidomycosis include the southwestern US, Central America (particularly Mexico, Guatemala, Honduras and Nicaragua), and South America (particularly Venezuela, Colombia, Argentina and Paraguay). Individuals with deficiencies in cellular immunity, such as those undergoing organ or stem-cell transplantation, those receiving corticosteroids or chemotherapy, and those with AIDS, are at risk of developing disseminated coccidioidomycosis upon infection. The most common sites of disseminated disease are the skin, joints and bones. CNS coccidioidomycosis, the most severe form of disseminated disease, is caused by haematogenous spread from primary pulmonary lesions. A relatively rare event, C. immitis meningitis usually develops within a few 294 ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

9 Table IV. Recommended treatments for CNS fungal infections. Disease IDSA recommended treatment Dose Alternative treatments* Candida Amphotericin B + 5-flucytosine 0Æ7 1 mg/kg/d (25 mg/kg q.i.d.) Ambisome or ABLC (3 5 mg/kg/d) Voriconazole Aspergillus Amphotericin B Voriconazole High-dose AmBisome High-dose itraconazole Combination therapyà Mucormycosis Amphotericin B 1Æ2 1Æ5 mg/kg/d High-dose AmBisome or ABLC Histoplasma capsulatum Initial therapy with amphotericin B; Suppressive therapy with itraconazole 0Æ7 1Æ0 mg/kg/d 400 mg/d AmBisome (3 5 mg/kg/d) Blastomyces dermatitidis Cryptococcus neoformans Coccidioides immitis Initial therapy with amphotericin B; Suppressive therapy with itraconazole Initial therapy with amphotericin B, then fluconazole Fluconazole 0Æ7 1Æ0 mg/kg/d 400 mg/d 0Æ7 1Æ0 mg/kg/d mg/d (10 weeks), then 200 mg/d 800 mg/d mg/d AmBisome (3 5 mg/kg/d); Fluconazole (800 mg/d) Voriconazole ( mg/d) Itraconazole (400 mg/d) instead of fluconazole Ambisome/ABLC 5 mg/kg/d Voriconazole Itraconazole** ( mg/d) Voriconazole IDSA, Infectious Diseases Society of America. AmBisome and ABLC (amphotericin B lipid complex) are liposomal formulations of amphotericin B. *Based on clinical data. Few data reported. àsome reports (largely retrospective studies) suggest echinocandin + azoles or echinocandin + AmBisome; no large or prospective studies have confirmed the superiority of combination therapy over high-dose monotherapy. Relapses reported. Relapse rate 30%. **Most of the data come from patients infected with HIV. weeks of the initial infection, although in some cases it can take up to 6 months (Williams et al, 1992; Vincent et al, 1993). The most commonly reported symptoms of meningeal involvement are headache, vomiting, cranial nerve palsies and altered mental status (Kauffman, 2002b). The major complications of CNS infection include basilar meningitis, vasculitis, encephalitis and space-occupying lesions (Williams et al, 1992). In the largest series reported to date of patients with haematological malignancies and coccidioidomycosis (Blair et al, 2005), 52 of the 55 patients reviewed (95%) had pulmonary involvement, and the other three patients had disseminated disease with no evidence of pulmonary involvement. Nine patients had disseminated (extrathoracic) infections, with the skin, spleen and CNS the most common sites of dissemination. The overall mortality rate during the median 40-month follow-up period was 28%. Disseminated disease was associated with a higher mortality rate (50%) than that associated with pulmonary infection alone (27%). Factors associated with mortality in this series were a diagnosis of chronic myeloid leukaemia, use of chemotherapy and use of corticosteroids (Blair et al, 2005). Because CSF cultures are often negative for C. immitis in the setting of meningitis, serological testing may be useful for diagnosing CNS or disseminated coccidiomycosis. However, in patients with haematological malignancies, serological studies may give positive results in low titres or may even yield negative results. The suggested treatment for coccidioidal meningitis in immunocompromised patients is fluconazole at 800 mg/d. In one study, itraconazole, at mg/d, was reported to be equally effective for non-meningeal coccidioidomycosis; however, the relapse rates were higher than 30% (Galgiani et al, 2000). The optimal duration of treatment has not been defined, but treatment should continue through periods of immunosuppression to prevent relapse. In in vitro studies, voriconazole has shown activity against C. immitis, with a minimum inhibitory concentration for 90% of the isolates tested of 0Æ25 lg/ml (Li et al, 2000). Again, the clinical literature is sparse, but two case reports in which voriconazole was successful in the treatment of refractory Coccidioides meningitis (Cortez et al, 2003; Proia & Tenorio, 2004) suggest that this agent could be considered for cases that do not respond to initial therapy. Liposomal amphotericin B was proven superior to oral fluconazole or i.v. amphotericin B in a rabbit model of coccidioidal meningitis (Clemons et al, 2002), but no clinical data are available to support its use in patients with coccidioidal meningitis. Caspofungin effectively reduced ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 131,

10 organ fungal burdens in a murine model of non-meningeal coccidioidomycosis, but this agent had poor activity against Coccidioides in vitro (Gonzalez et al, 2001). In the only reported case of a patient treated with caspofungin for coccidioidal meningitis, the patient died without responding to treatment (Hsue et al, 2004). Finally, posaconazole is effective against Coccidioides in vitro and in animal models (Gonzalez et al, 2001), and it has shown some success in a small series of patients with refractory non-meningeal coccidioidomycosis (Anstead et al, 2005). Stevens et al (2004) presented preliminary results from 15 patients with refractory coccidioidomycosis, including one patient with CNS disease. The response rate was 73%, of which four responses were complete and seven were partial. The patient with CNS disease showed a response, but the type was not reported. These preliminary results suggest that posaconazole should be considered for the treatment of refractory coccidioidomycosis, but its role in CNS disease remains to be defined. Conclusions Central nervous system fungal infections can be life-threatening events for anyone but are particularly dangerous for patients with haematological malignancies. Prompt diagnosis and early and aggressive therapy (Table IV) when such infections are suspected are key factors for a positive outcome. Despite major advances in diagnostic techniques and the increased availability of new therapeutic agents, mortality from these infections remains unacceptably high. Our challenge is to develop new non-invasive tests for making an early diagnosis and to conduct appropriately powered clinical trials to demonstrate their usefulness in large numbers of patients. 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