We note that in 8 of 14 patients (57.1%), previous brain pathology was noted in their medical histories or in previous brain imaging. One patient had ischemic changes, 2 had brain infarctions, 2 had malignant metastases to the CNS, 1 had sign of microhemorrhages, and 2 had CNS infections, including 1 case of multiple Candida species with spinal cord involvement and 1 case with dystrophic brain calcifications of unknown etiology.
Most of the MGH patients with CNS aspergillosis had primary lung involvement with subsequent dissemination to the CNS. More specifically, 11 of 14 patients had primary pulmonary invasive aspergillosis (IA), 2 had primary paranasal sinus involvement, and 1 had primary spine aspergillosis. Two of the patients with primary lung aspergillosis had dissemination of IA to other organs in addition to the CNS. Both of these patients had simultaneous thyroid and gastrointestinal tract involvement; 1 also had metastasis of Aspergillus to the heart, and the other had metastases to the kidneys and paraspinal soft tissues.
Of the 2 patients with paranasal involvement, 1 was on corticoid treatment (daily prednisone 60 mg) for a presumed inflammatory process extending to the optic nerve. A biopsy of that lesion showed no evidence of infection, and after steroid treatment for the next 2 months the patient’s clinical situation deteriorated. A subsequent CNS biopsy done at that time confirmed the presence of Aspergillus hyphae. The other patient with primary paranasal aspergillosis had an extensive history of diabetes, chronic renal failure, prolonged total parenteral nutrition, and chronic pancreatitis. All other 11 patients with lung involvement had some history of immunosuppression, such as hematologic malignancies. Of note, most MGH patients were receiving either chronic steroids (71.4%) or cancer chemotherapy (21.4%) for underlying conditions, except 1 patient for whom medications and previous medical history at the time of admission were not available.
The clinical presentation of patients with CNS aspergillosis was variable and nonspecific. Fever was the predominant symptom, noted in 8 of 14 patients (57.1%). Other signs and symptoms included focal neurologic abnormalities in 5 patients (35.7%), seizures in 4 (28.6%), mental status changes in 3 (21.4%), and headaches in 2 patients (14.3%).
Cerebrospinal fluid (CSF) is rarely helpful for the diagnosis of CNS aspergillosis, although cases of Aspergillus meningitis with positive CSF culture have been reported.36 Notably, in 7 of the 14 MGH patients with a CSF culture, none was positive for Aspergillus. Regarding CSF chemical evaluation, glucose was high in 4 cases. In 2 cases, the CSF protein was 85 mg/dL and 235 mg/dL respectively, in 3 cases it was not measured, and in 2 cases it was in the reference range (15–60 mg/dL). White blood cell counts were elevated in 4 patients, although they were significantly variable (range, 6–530 cells/μL): 530 cells/μL, 200 cells/μL, 11 cells/μL, and 6 cells/μL, respectively. We identified differential CSF counts in only 2 patients who had, respectively, 91% and 98% neutrophil predominance.
Radiologic imaging is useful for diagnosing CNS aspergillosis; however, there were no unique characteristics that could differentiate an infection from other types of space-occupying lesions. Four MGH patients underwent CT scans, which revealed 1 ring-enhancing lesion, 2 brain hemorrhages (probably due to angioinvasion from Aspergillus), and 1 expanding lesion from the paranasal sinuses. Findings from MRI, which was performed in 9 patients, consisted of ring-enhancing lesions (n = 4), nonspecific hyperintense foci (n = 3) and expansion of infection from the paranasal sinuses (n = 2).
Regarding the infecting species of Aspergillus, 5 cases were associated with A. fumigatus, while in all other cases the causative microorganism was identified only to the genus level. Speciation of fungi such as Aspergillus is clinically important, since some species have been associated with higher antifungal resistance, such as A. terreus.87 Galactomannan, which is another important adjunct to the diagnosis of IA, was measured in only 2 patients. One patient had a positive galactomannan assay result of 0.79 ng/mL in the CSF, and the other patient had a result of 1.56 ng/mL (a value >0.5 ng/mL was considered positive).
Regarding antifungal strategies, we divided patients into 3 groups: patients who received antifungal therapy only, patients who received antifungal treatment and underwent neurosurgery, and patients who received no therapy (no patient underwent neurosurgery without receiving antifungal agents). The group with antifungal therapy only comprised 5 patients, all of whom subsequently died. One patient received prophylactic fluconazole and was subsequently treated with amphotericin B, 1 received amphotericin B, 1 received voriconazole as prophylaxis, 1 received fluconazole as prophylaxis and then switched to micafungin and then to voriconazole, and the fifth patient received empiric coverage with amphotericin B, which was switched to caspofungin, and then, when diagnosis was established, changed to voriconazole.
The second group comprised 8 patients who received antifungal treatment and underwent neurosurgery. The type of neurosurgery performed included left frontotemporal craniotomy and debridement of orbital roof and dural biopsies (1 patient), bifrontal craniotomy with intradural and extradural debridement with left orbital exenteration (1 patient), left orbital exenteration (1 patient), and a resection of an aspergilloma (1 patient) and abscess drainage (4 patients). In this group only 2 patients died (25% mortality). Of the 2 patients who died, 1 had primary lung aspergillosis and received empirical liposomal amphotericin B but died before the results of brain cultures were finalized. The second patient, who had primary paranasal sinus aspergillosis, received a triple combination of liposomal amphotericin B, voriconazole, and micafungin, and subsequently died.
The third group consisted of 1 patient who received no medical or surgical therapy and died (the diagnosis was established at autopsy).
Regarding contraindications in the 6 patients who did not have surgery, 2 patients did not have surgery because of end-stage liver disease. Another patient had myelodysplastic conversion to acute myeloid leukemia and pancytopenia, and we could not assess the reason for the last 3 patients. The mean number of days from the onset of symptoms to death was 9 days. Eight of 14 patients died during their initial hospitalization (57.1% mortality). For the 6 patients who were alive on discharge, we reviewed their medical records to determine their outcome. Two patients were alive after 2 years, and another 2 patients were alive at 2 and 3 months postdischarge, respectively, although no subsequent follow-up was available. One patient died after 4 years from hematologic malignancy. For 1 patient no follow-up was available.
We identified 123 published cases of proven CNS aspergillosis.1–4,6,7,9–12,14–20,24–26,28,29,31–38,40–49,51,52,54–56,58–71,73,75–79,83–86,88–92,94–101 Baseline characteristics are presented in Table 3.
The mean age of the patients was 42.6 years (range, 2 d to 78 yr), with a male predominance (56.1%). Patients had a wide spectrum of comorbidities, such as diabetes (17.9%), hematologic malignancies (11.4%), transplantation (8.9%), HIV (8.1%), autoimmune diseases requiring steroids (4.9%), hepatic insufficiency (3.2%), bone marrow transplantation (2.4%), and chronic obstructive pulmonary disease (0.8%). Some patients had more than 1 comorbidity, but 29 patients (23.6%) had no reported associated conditions.10,14,18,24,27,29,31,34,37,38,41,45,46,48,51,52,56,59,62,64,66,73,76,85,86,92 Six of 123 patients (4.9%) had a wide spectrum of brain/cranial pathology in their previous histories or imaging. The 4.9% rate is low compared to our finding in the MGH patients of 57.1%. Since to the best of our knowledge, no other study has identified this finding as a potential risk factor, it is reasonable to assume that it was not rigorously sought in the previously reported cases.
Potential sites of primary infection included paranasal sinuses (34 patients; 27.6%); lungs (33 patients; 26.8%); ear canal (3 patients; 2.4%); cranial bones from trauma or surgical contamination (3 patients; 2.4%); and aortic, cardiac, or vertebral disc involvement (1 patient each; 0.8%). It is noteworthy that 28 patients (22.8%) had primary CNS involvement with no obvious primary site.20,27–29,31,55,62,63,67,86,92 In 7 of the patients with primary CNS involvement, infection was associated with contamination of the epidural catheterization kit permitting direct seeding of the CNS.34,36,52,76 Twenty patients did not have an apparent primary site of infection. In addition to the CNS, 14 patients (11.4%) had metastasis of Aspergillus to distant sites. Organs most commonly involved were the kidneys (3.3%), heart (3.3%), thyroid (2.4%), liver (1.6%), and spleen (0.8%).
Imaging findings were not thoroughly presented in the literature, thus we omitted these data from our report and focused on the imaging data from our case series.
Regarding signs and symptoms, fever (>38°C) was noted in 43 patients (35%), while low-grade fever (37–38°C) was present in 3 patients (2.4%). Also, 51 patients (41.5%) experienced headaches, 30 (24.4%) had mental status changes, and 11 (8.9%) had generalized seizures. Thirty-five patients (28.5%) had some form of focal neurologic abnormality such as hemiplegia (n = 18), and/or cranial nerve palsy (n = 34), and/or vision changes (n = 21).
Of the 123 literature patients, 60 (48.8%) received some form of immunosuppressant medication: 27 (21.9%) were receiving steroids, 8 (6.5%) cancer chemotherapy, 6 (4.9%) cyclosporin, 5 (4.1%) antithymocyte globulin, 5 (4.1%) mycophenolate, 5 (4.1%) tacrolimus, 1 (0.8%) anti-tumor necrosis factor (TNF)-alpha, 1 (0.8%) cyclophosphamide, 1 (0.8%) leflunomide, and 1 (0.8%) methotrexate. Among patients with lung involvement, 26 of 33 (78.8%) had some form of immunosuppression such as HIV infection, hematologic malignancy, or inherited immune deficiency. On the other hand, among 34 patients with paranasal sinus aspergillosis, 13 had an unknown immune status, and of the remaining 21 cases, 15 (71.5%) were immunosuppressed.
A. fumigatus was the predominant species causing infection in 41 patients (33.3%), with A. flavus, A. versicolor, and A. granulosus causing infections in 7, 1, and 1 patient, respectively. In 29 patients, Aspergillus was identified only to the genus level (23.6%). Galactomannan serologic levels were reported in 8 cases (reference range, <0.5 ng/mL). Levels were 1.3 ng/mL in 1 patient, 5.44–9.4 ng/mL in another patient, and 1.9–5 ng/mL, 1.3 ng/mL, and 0.475 ng/mL for 3 other patients, respectively. One additional result was reported as “negative,” and 2 results were reported as “positive” without any detailed values.
The choice of antifungal treatment reported in the literature is summarized in Table 4. Only a minority of patients received prophylactic treatment (n = 7), including fluconazole (n = 4), itraconazole (n = 2), and amphotericin B (n = 1); or empiric antifungal treatment (n = 6), including amphotericin B (n = 3), voriconazole (n = 2), and fluconazole (n = 1). Also, only 24.4% of patients received voriconazole, and 55.3% received amphotericin B, 20.3% received itraconazole, 9.8% caspofungin, 5.7% fluconazole, 4% micafungin, 2.4% 5-flucytosine, and 0.8% terbinafine. Regarding combination therapy, amphotericin was administered with the following: itraconazole (10 cases), voriconazole (4 cases), 5-flucytosine (3 cases), fluconazole (3 cases), caspofungin (3 cases), and voriconazole along with caspofungin (3 cases). Two patients received voriconazole with caspofungin. All 16 patients who did not receive antifungal treatment subsequently died, and treatment data were not available for 11 patients. Overall, 53 patients survived, 64 died, and the outcome was not reported for 6 patients. Mortality with amphotericin monotherapy was 62.5% (15 of 24) and with voriconazole monotherapy it was 35.4% (4 of 11). One patient who died in the voriconazole monotherapy group discontinued maintenance voriconazole therapy at 6 weeks against medical advice and had symptom recurrence and rapid deterioration in the hospital.
As in the MGH patient group, neurosurgical procedures were performed in a significant number of the cases from the literature (n = 49). Eighteen patients underwent abscess removal or drainage, 18 had excision of infected mass, 4 orbital exenterations, 1 debridement of inner ear, and 1 debridement of the skull base; 7 patients underwent neurosurgery but the type of operation was not mentioned. Of the 49 patients who underwent a neurosurgical procedure, 6 had an unknown outcome (12.2%) and 14 patients died (28.6%). Of the 74 patients who did not undergo neurosurgery, 50 died (67.5%). Of the 74 patients who did not undergo neurosurgical procedure, 54 received antifungal treatment, and 60.4% of them died during hospitalization. (Due to insufficient data, we cannot report the reasons for not performing neurosurgery among patients from the literature.)
We present 14 patients with CNS aspergillosis who were treated at MGH from 2000 to 2011. We also review 123 cases reported in the literature during the same period. Hematologic malignancies and concomitant neutropenia were the major underlying diseases; the most common primary sites of aspergillosis were the lungs and the paranasal sinuses. Neutropenia and steroid therapy were the most common predisposing factors. In the MGH series, a significant number of patients had a history of previous brain pathology, which could predispose them to metastasis of infection to the CNS, presumably due to a disruption of the blood brain barrier. We note that a significant number of patients with CNS aspergillosis reported in the literature had no apparent immune suppression, while diabetes was associated with a significant number of paranasal aspergillosis cases. Mortality was high even among patients who received voriconazole, and, as discussed below, our findings suggest that patients who underwent neurosurgery had better survival than those who received only medical therapy, although this could reflect a selection bias.
Neutropenia was the major underlying condition in the MGH series: it complicated 6 of 14 patients. Unfortunately, neutrophil counts were not widely reported in the literature (for example, 52 published cases did not report white blood cell counts), thus we reported results only from our series. Neutrophils have a major contribution in the extracellular killing of Aspergillus hyphae.22 The immune system has the ability to clear conidia by employing macrophages that phagocytose and then kill them. Complement is another form of defense, and has the ability to bind to swollen conidia and hyphae.8 Neutrophils are recruited by macrophages and release reactive oxygen species and other proteolytic substances. In the setting of neutropenia or dysfunctional neutrophils, such as in chronic granulomatous disease, the risk of IA is increased and the risk for subsequent metastasis of Aspergillus to other organs such as the CNS is high. Steroids have traditionally been shown to increase the risk for aspergillosis; the proposed mechanism involves their immunosuppressant effect on immune cells and also their presumed direct trophic effect on Aspergillus.22
In the MGH series, 8 of 14 patients had some previous form of brain pathology. This finding could underline a possible mechanism of invasion. For example, an abnormal blood brain barrier, such as in areas of glial scars, could possibly aid the attachment and subsequent invasion of Aspergillus in the CNS. A larger comparative study could perhaps lead to better conclusions; however, a previous history of brain damage or proof of older imaging abnormalities in immunocompromised patients should alert the physician to the risk of subsequent CNS aspergillosis.
Our results indicate that even though IA is more common among individuals with a compromised immune system, it can also infect patients with no obvious immune suppression. All 14 MGH patients had some form of immunosuppression; however, 29 of 123 literature patients had no underlying immunocompromising disease, such as hematologic malignancy, cancer, or HIV infection.10,18,24,29,34,46,52,56,59,64,74,76,85,86,92 Recent experimental research in this field has shown that certain immune receptor deficiencies may predispose to aspergillosis despite what appears to be a normal immune system. We assume that this phenomenon could be explained by defects in toll-like receptors13 or defects in dectin-1, which is able to recognize β-glucan,30,57 a component of numerous fungal cell wall species like Aspergillus. Presumably in the latter case, the host may have normal quantitative and qualitative aspects of the immune system, but inherent defects in pattern recognition molecules like dectin-1 may cause increased susceptibility to invasive fungal infections.
A noteworthy finding in the current study is the high prevalence of diabetes mellitus in both the MGH and the literature patients. Fourteen of the 22 diabetic patients from the literature had primary diabetes mellitus with no other comorbidities, whereas all 3 MGH patients with diabetes mellitus had other comorbidities, such as chronic renal failure, transplantation, or hematologic malignancy. Diabetes is known to have an immunosuppressive effect, but the association between diabetes mellitus and IA has not been studied extensively. We can assume that depressed phagocyte activity induced by diabetes might aid in the increased survival of Aspergillus in mucosal surfaces through a decrease in fungal mucosal clearance.39 Diabetes mellitus has been associated with other forms of fungal sinusitis, including mucormycosis.
Unfortunately, the differential diagnosis of CNS aspergillosis can be broad, and clinical symptoms are not a sensitive diagnostic tool. For example, in the current MGH series only about half (8/14; 57.1%) of patients had fever, and focal neurologic abnormalities were evident in about 36% of patients (n= 5). Seizures, mental status deterioration, and headaches were reported in 29%, 21%, and 14% of the 14 patients in the MGH series, respectively. These numbers coincided with results from the literature, where 42% of patients had headaches, 37% had fever, 29% focal neurologic abnormalities, 24% mental status changes, and 9% seizures. More specific assays are needed to diagnose IA; rapid diagnostic polymerase chain reaction (PCR) techniques performed in the CSF and serum could facilitate a faster and simpler diagnostic approach in the future.40
Since its approval by the United States Food and Drug Administration (FDA), voriconazole has become the standard of care in most cases of IA. In treating CNS aspergillosis, voriconazole can achieve CSF levels that are above its minimum inhibitory concentration.21,72,82 Although low voriconazole levels have been linked to clinical failure,93 they were scarcely reported in our review. Clinicians treating patients with CNS aspergillosis should monitor serum voriconazole levels, usually starting 5 days after the initiation of therapy.93 Voriconazole levels in the CSF can range widely, and the therapeutic CSF levels have not been established. For example, in a small study that evaluated the pharmacokinetics of voriconazole, 1 patient with CSF levels of 2.41 μg/mL 2 hours after the first oral dose of voriconazole (6.3 mg/kg) had partial response to therapy, whereas another patient on voriconazole dose 4 mg/kg had a significantly lower level (0.23 μg/mL) and did not respond to treatment.53 Additional studies should evaluate the clinical significance of CSF levels in the management of CNS aspergillosis. Voriconazole levels were not measured during the hospitalization of MGH patients, and in the literature they were scarcely reported.
Of special interest is that not all of our patients received voriconazole, even though it is the single most important antifungal agent used in CNS aspergillosis.80 Voriconazole was used in only 8 of 14 MGH patients. Although during the first 5 years of our review this could be partially explained by a delay in clinical acceptance, even during the last 5 years voriconazole was used in only about half of our patients. The reasons for this are unclear. A potential explanation could be the delay in diagnosis that prompts clinicians to use empiric amphotericin B, which provides broader antifungal coverage until definitive diagnosis. Also, clinicians might feel uncomfortable using voriconazole due to the lack of data on the appropriate therapeutic levels for the management of CNS aspergillosis. Thus, until definitive diagnosis, patients are often exposed to suboptimal antifungal coverage.
Neurosurgery had a favorable outcome for both MGH and literature patients. All MGH patients who survived had some type of neurosurgery, and among literature patients, neurosurgery had a favorable outcome. More specifically, mortality among MGH and literature patients was 25% and 28.6%, respectively, compared to 100% and 60.4%, respectively, among patients who received only medical treatment. This underlines the importance of surgical intervention in the management of CNS aspergillosis; however, there is also the possibility that patients who underwent surgery were in better clinical condition. The good rates of survival with neurosurgery reported in the literature might also be biased, because it is more common for significant results to be published.23 Until more efficacious treatment becomes available, the combination of effective antifungal therapy with neurosurgery should be strongly considered.
CNS aspergillosis usually involves immunocompromised patients; however, immunocompetent patients and those with “mild” immunosuppression, such as diabetes mellitus, may also be affected. CNS involvement often results from dissemination of the infection from the lungs and paranasal sinuses. A history of prior brain pathology in an immunocompromised patient with IA could be associated with a higher risk of CNS dissemination. The combination of antifungal therapy with neurosurgery appears to be the most promising approach. However, mortality is still unacceptably high, and more efficacious therapeutic approaches are needed. Although the rarity of CSF aspergillosis precludes conducting randomized controlled trials, large prospective cohorts can significantly help improve the outcome in these patients.
CNS: central nervous system
CSF: cerebrospinal fluid
CT: computed tomography
EORTC/MSG: European Organization for Research and Treatment of Cancer/Mycoses Study Group
HIV: human immunodeficiency virus
IA: invasive aspergillosis
MGH: Massachusetts General Hospital
MRI: magnetic resonance imaging
TNF: tumor necrosis factor
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