Retrospective Analysis of Opportunistic Brain Abscesses in Patients With Hematologic Malignancies

Retrospective Analysis of Opportunistic Brain Abscessesin Patients With Hematologic Malignancies

Rita Raturi, BS,* Carlos Palacio, MD,Þþ Aliyah Baluch, MD, MSc,Þ§ Johan Vargas, MD,||¶Patrick Kenney, DO,Þ§ and John N. Greene, MD, FACP*Þ

Background: Patients with hematologic malignancies have a high rateof opportunistic infections (OIs) with pathogens that could lead to theformation of brain abscesses. Nocardia, toxoplasmosis, Aspergillus,zygomycetes and Fusarium are a few of these organisms, which may beincreasing in prevalence. Several immunologic defects such as severeneutropenia (absolute neutrophil count G 500), impaired B-cell immu-nity, hypogammaglobulinemia, and defective T-cell immunity are relatedwith increased risk of OIs. Recipients of hematopoietic stem celltransplantation (HSCT) are similarly at an increased risk of these OIsdue to prolonged neutropenia and defective T-cellYmediated immunity.Design and Methods: A retrospective case series analysis at MoffittCancer Center, a tertiary cancer hospital, screened for patients withhematologic malignancies and microbiological proven diagnosis of op-portunistic brain abscess (OBA) from January 1998 to January 2010.The OBAs were diagnosed via positive cultures from cerebrospinalfluid, brain tissue, or bronchoalveolar lavage for one of the followingmicroorganisms: Nocardia species, Toxoplasmosa species, Aspergillusspecies, zygomycetes, or Fusarium species; 5 of the 13 cases involvedrecipients after allogeneic HSCT. A literature review of the most com-mon pathogens related to OBAs in hematologic patients from PubMedbetween 1998 and 2011 is also included.Results: The OBAs documented by culture included Nocardia (5/13,38%), zygomycetes (3/13, 23%), toxoplasmosis (2/13, 15%), Aspergil-lus (2/13, 15%), and a single case of disseminated Fusarium (1/13, 8%).The underlying hematologic malignancies were as follows: lymphoma(4/13, 2 cases involved Hodgkin lymphoma and 2 cases involved non-Hodgkin lymphoma), chronic myeloid leukemia (3/13), acute lym-phoblastic leukemia (ALL) (3/13), acute myelogenous leukemia(AML) (1/13), multiple myeloma (1/13), and myelodysplastic syn-drome (1/13). The age range at diagnosis was 26 to 76 years, with amedian age of 51 years at the time of diagnosis with OBA. The male-to-female ratio was 3.3:1 (10 males, 3 females). The most common pre-disposing factors were severe neutropenia for 7 to 15 days withinthe month before the diagnosis (6/13, 46%), chronic graft-versus-hostdisease (GVHD) after allogeneic HSCT (5/13, 38%), lymphoma(4/13, 30%), chronic lymphocytic leukemia, and ALL (3/13, 23%).Of the 13 patients, 7 (54%) had severe neutropenia (absolute neu-trophil count G 500 cell/HL) within the month before OBA diagno-sis, but only 1 had a prolonged neutropenia for more than 6 months.None of the patients with Nocardia brain abscesses were neutrope-nic during the year before the diagnosis. The most common presentingsymptoms were focal neurologic deficits (7/13, 54%), headaches (5/13,38%), and altered mental status (5/13, 38%).

Conclusions: An OBA should be highly suspected in patients withlymphoma, chronic lymphocytic leukemia, ALL, or chronic GVHDpresenting with headache and focal neurologic deficits. The most im-portant risk factor for OBA in allogeneic transplant after engraftmentis the development of chronic GVHD and effects of its subsequentimmunosuppressive treatment. Chronic GVHD is associated with per-sistently depressed T-cell and humoral immunity. Perhaps Trimethoprim-and sulfamethoxazole-based prophylaxis should be considered for theprevention of OBA infections in HSCT with chronic GVHD complica-tions. Early OBA diagnosis, surgical intervention if indicated, and culture-directed treatment is vital for decreased morbidity and mortality.

Key Words: Nocardia, Toxoplasma, Aspergillus, Fusarium,zygomycetes

(Infect Dis Clin Pract 2014;22: 96Y103)

PURPOSEWe wished to study opportunistic brain abscess (OBA)

trends in hematologic patients in a tertiary cancer facility todescribe their clinical presentation and microbiological etiology.We also reviewed the medical literature from 1998 to 2011 inPubMed to attempt to identify the main immunologic and cancertreatment factors related with OBA.

BACKGROUNDPatients with hematologic malignancies (HMs) have an

increased frequency of infections by opportunistic pathogenswith the potential to disseminate, leading to invasive disease.Opportunistic brain abscesses have steadily increased in fre-quency during the last 2 decades, contributing to increasedmorbidity and mortality, often linked to Aspergillus species andNocardia species.1Y4 Predominant specific immunologic de-fects are associated with each type of HM. Myelodysplasticsyndrome (MDS) and acute leukemia are associated withprolonged neutropenia, whereas chronic lymphocytic leukemiaand multiple myeloma (MM) are associated with impairedB-cell immunity and hypogammaglobulinemia. Non-Hodgkin’slymphoma is more commonly associated with defective B-cellimmunity. Hairy cell leukemia, Hodgkin lymphoma, andadult T-cell lymphoma/leukemia are linked with defectiveT-cell immunity.

In patients with HM, chemotherapy-induced or disease-related severe neutropenia (absolute neutrophil count [ANC]G 500) is one of the major risk factors for infections. Granulo-cyte deficiency results in a weakened inflammatory response,facilitating rapid dissemination of bacterial and fungal in-fections. The duration and depth of the neutropenia helps riskstratify the risk of acquiring a fungal infection. Autologous andallogeneic hematopoietic stem cell transplantation (HSCT) aretypically associated with weeks of neutropenia, followed byweeks or months of defective T-cellYmediated immunity. Au-tologous transplants are also traditionally associated with fewerinfectious complications compared with allogeneic transplants.

ORIGINAL ARTICLE

96 www.infectdis.com Infectious Diseases in Clinical Practice & Volume 22, Number 2, March 2014

From the *University of South Florida College of Medicine; †H. Lee MoffittCancer Center and Research Institute; ‡Department of Internal and HospitalMedicine, and §Division of Infectious Diseases, University of South FloridaCollege of Medicine, Tampa, FL; ||Hisponoamericana University, San Jose,Costa Rica; and ¶USF BRIDGE Healthcare Clinic, Tampa, FL.Correspondence to: John N. Greene, MD, FACP, Moffitt Cancer Center,

University of South Florida College of Medicine, 12902 Magnolia Dr,FOB-3, Tampa, FL 33612. E-mail: [email protected].

The authors have no funding or conflicts of interest to disclose.Copyright * 2013 by Lippincott Williams & WilkinsISSN: 1056-9103

Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

mailto:[email protected]

The most important risk factor for infection in allogeneictransplant after engraftment is the development of graft-versus-host disease (GVHD) and its immunosuppressive treatment.Chronic GVHD is especially associated with persistently de-pressed T-cell and humoral immunity.5

Opportunistic brain abscesses in immunocompromisedhosts have a poor prognosis. Brain abscesses are difficult tomanage owing to nonspecific presentation and diagnosticchallenges. Blood cultures are usually negative (with the ex-ception of Fusarium species).6 Lumbar punctures for cerebro-spinal fluid analysis can and should be performed unlessotherwise contraindicated, for example, if thrombocytopenia orelevated intracranial pressure is present.7,8 Culturing the fluidremoved from an abscess is the ideal way to obtain a microbi-ological source, but 24% to 40% of intracerebral abscessesresult in negative cultures owing to patients receiving antimi-crobial therapy before drainage of the abscess. An estimated30% to 60% of abscesses are polymicrobial, representing an-other diagnostic challenge.7 Computed tomography (CT) andMagnetic resonance imaging (MRI) have been a great ad-vancement for the diagnosis of brain abscesses; however, thetraditional description of ‘‘ring-enhancing lesion with sur-rounding edema’’ is generally only associated with mature brainabscesses without identifying its cause.6,7 Ideally, if possibleand not harmful to the patient, the standard practice calls forantibacterial and antifungal medication to be given only afterdiagnostic needle aspiration is performed, therefore leading topotential delays of treatment.2 Computed tomographyYguidedstereotactic aspiration of brain abscesses is a minimally invasiveprocedure that permits for rapid and effective surgical drainage,especially effective for small and deep-seated abscesses.9 Cra-niotomy and excision of the abscess is usually performed onsuperficial abscesses. To cite the medical literature, brain ab-scess mortality ranges from 6% to 24%, with an acknowledg-ment that there is a higher rate in patients with HM. The majorcomplication of brain abscesses is permanent focal neurologicdeficits, which have been reported in almost 18% of patientswith HM.10

METHODSA retrospective chart review was conducted at the Moffitt

Cancer Center from January 1998 to January 2010. The mi-crobiology laboratory provided records for patients with con-firmed diagnosis for Nocardia, toxoplasmosis, Aspergillus,Fusarium, and zygomycosis via culture or histopathologicalfindings consistent with the organism in patients with knownHM. In clinical scenarios where patients had both lung andbrain lesions thought to be of the same etiology, they often weretreated based on the microbiological cultures from the lung le-sions. The electronic medical records were reviewed for patientsreported as having brain lesions shown by CT or MRI fromJanuary 1998 to January 2010. After cross-referencing these2 lists, 13 patients met our inclusion criteria. Our inclusioncriteria were as such: patients’ age between 18 to 85 years, brainlesion detected with at least 1 nodule, HM diagnosis, and nopredisposing invasive cranial procedures or trauma. Eligiblepatients had to have been diagnosed with a HM such as MDS,lymphoma, myeloma, or leukemia.

From patient files, we collected data baseline demographicsand clinical characteristics such as age, sex, height, weight athospital admission, underlying comorbidities, neutropenic statusbased on ANC, symptoms at the time of detection, treatmentsused, length of hospital stay, and outcome. Decimals were roundedto the nearest whole number. Absolute neutrophil count was

calculated using data collected closest to the time of diagnosiswith a brain abscess.

A review of literature was performed using the wordshematological malignancies and brain abscesses in a PubMedsearch. The specific pathogen names were also included, andrelevant articles were reviewed. Case reports were found usingthe organism name and brain abscess in the same line. Limi-tations included the dates 1998 to 2011 and English languageonly. Case reports were reviewed with the exception of pedi-atric cases. Relevant cases were included in Figures 1 and 2.

RESULTSThirteen brain abscess cases in patients with HM were

treated at Moffitt Cancer Center from January 1998 to January2011. Patients in this study had the following underlying HM:MM (1/13), acute lymphoblastic leukemia (ALL) (3/13), lym-phoma (4/13), acute myelogenous leukemia (AML) (1/13),chronic myeloid leukemia (CML) (3/13), and MDS (1/13). Theage at the time of diagnosis with a brain abscess ranged from26 to 76 years with a peak at 51 to 66 years (6/13, 46%) anda median age of 51 years. The male-to-female ratio was 3.33:1(10 males, 3 females). The common predisposing factors wereGVHD (5/13, 38%), CML (3/13, 23%), and ALL (3/13, 23%).Patients who underwent a previous allogeneic HSCT (5/13,38%) were diagnosed with the brain abscess after an average of336 days after transplantation. Of the 13 patients, 7 (54%) hadsevere neutropenia (ANC G 500 cell/HL) within the monthbefore the brain abscess diagnosis, whereas only 1 patient had aprolonged neutropenia for more than 6 months.

The microbiology laboratory cultured brain abscesses withthe following microorganisms: Nocardia (5/13, 38%), zygomycetes(3/13, 23%), toxoplasmosis (2/13, 15%), Aspergillus (2/13, 15%),and disseminated Fusarium (1/13, 8%). The most commonpresenting symptoms were focal neurologic deficits (7/13, 54%),headaches (5/13, 38%), mental status changes (5/13, 38%), andfever (3/13, 23%). Other symptoms included fatigue (2/13, 15%),nausea (2/13, 15%), and seizures (3/13, 23%), Patient’s presentingnumber of symptoms ranged from 1 to 7, with the average number

FIGURE 1. Magnetic resonance image of the brain with andwithout intravenous contrast depicting a 3.3 � 3.0-cmring-enhancing Aspergillus abscess in the left temporal lobe,with a significant amount of surrounding vasogenic edema.

Infectious Diseases in Clinical Practice & Volume 22, Number 2, March 2014 Opportunistic Brain Abscesses

* 2013 Lippincott Williams & Wilkins www.infectdis.com 97


of presenting symptoms being 2.92. The radiographic methodof diagnosis were as follows: MRI only (11/13, 85%), bothMRI and CT scan (1/13, 8%), and CT only (1/13, 8%).

Brain Abscess Cases by Infectious Agent

Aspergillus SpeciesBetween January 1998 and January 2010 at our tertiary

cancer facility, 153 patients with HM had a positive Aspergillusculture obtained in microbiological diagnosis. Of those, 2 pa-tients were found to have radiological findings consistent withbrain abscesses on MRI. Both cases involved white men aged34 and 38 years diagnosed with CML status postallogenicHSCTs with ongoing issues of chronic GVHD requiring treat-ment with significant doses of glucocorticosteroids (prednisone45Y60 mg daily). Both patients had concurrent pulmonary in-fections requiring workup with bronchoalveolar lavage. None ofthe brain abscesses qualified for resection owing to the patient’sclinical status. One patient presented with severe delirium wenton to have multiple abnormal brain parenchyma fluid attenuatedinversion recovery signals on MRI. He was not treated owingto the severity of his hematologic condition and expired inhospice care 5 days after brain lesion diagnosis. Conversely,the second patient presented with mild mental status changesand headache. He had a single large lesion in the left temporallobe. Treatment included itraconazole followed by 1 month ofvoriconazole 300 mg twice daily before being segued to 6 monthsof treatment with intravenous liposomal amphotericin B. By 81days after diagnosis, there was resolution of the brain abscess viaCT imaging. Unfortunately the patient expired 156 days after OBAdiagnosis owing to causes unrelated to the infectious disease. Ofnote galactomannan levels were not obtained (Fig. 1).

Fusarium SpeciesBetween January 1998 and January 2010, only one case of a

Fusarium-associated brain lesion was confirmed via positiveculture. The patient was a 76-year-old white male with AMLwhose course was complicated with significant prolonged

neutropenia. He was receiving antifungal prophylaxis withitraconazole 200 mg twice daily owing to a recent history ofcutaneous Fusarium infection. At presentation, the patientcomplained of increased fatigue from baseline, new onsetdiplopia, and a new skin finding involving his 3rd, 4th, and5th toes consistent with a recurrence of his Fusarium skininfection. A CT head and MRI brain confirmed the findingsof a cerebellar lesion 80 days after diagnosis of his originalcutaneous Fusarium infection. Treatment included increasinghis itraconazole dosage to 400 mg twice daily for 6 daysfollowed by switching to voriconazole at 300 mg twice dailyfor a total of 10 weeks. The patient’s central nervous system(CNS) symptoms and skin lesions resolved 41 days after hisbrain abscess diagnosis and adjustment of therapy (Fig. 2).

NocardiaBetween January 1998 and January 2010, 32 patients with

HM had positive Nocardia cultures, of which 6 were in patientswith brain abscesses. One patient was excluded owing to apredisposing craniotomy because the OBA was thought to berelated to traumatic inoculation. The remaining 5 patients weremen with ages ranging from 26 to 70 years, with a median ageof 51 years at the time of diagnosis. Sixty percent (3/5) of thepatients had concomitant pulmonary infections, and one patienthad skin-related lesions. The underlying hematologic diseaseswere MM (1/5), ALL (1/5), and lymphoma (2/5), and a patienthad secondary MDS status postallogenic HSCT with ongoingissues related to GVHD (1/5). None of the patients were neu-tropenic within a month of diagnosis of nocardiosis. Nocardiawas cultured from brain lesions (4/5, 80%) and from lung le-sions (1/5, 20%) to receive a definitive diagnosis. Commonsymptoms at presentation were headache (3/5), seizures (2/5),and nausea (2/5). All abscesses were described per radiology assingular enhancing lesions with 60% (3/5) also being describedwith associated edema. The majority (5/6) required surgicalevacuation of the brain abscesses followed by 1 year of treat-ment doses of trimethoprim-sulfamethoxazole (TMP/SMX)dosed accordingly to renal function. The one patient who didnot receive resection had presented with multiple occipital andcerebral lesions and was successfully treated with TMP/SMX(160 mg/800 mg), 2 pills daily for 13 days, and ceftriaxone 2 gtwice a day for a period of 26 days. Sixty percent (3/5) of thepatients were on long-term (9120 days) steroid treatment foroncologic-related issues at the time of diagnosis with a brainabscess (Fig. 3).

ZygomycosisBetween January 1998 and January 2010, 3 cases of

zygomycosis-related OBAs were diagnosed at our tertiary carefacility. Two patients had a history of recent severe neutropeniafor a duration of 11 days; they were diagnosed with CNS in-fections at 21 days and 32 days, after their period of neutropeniahad resolved. None of the 3 patients underwent surgical resec-tion. Of the patients, 66% (2/3) were women, with a median ageof 56 years at the time of diagnosis. Underlying malignanciesincluded ALL (66%, 2/3) and lymphoma (33%, 1/3). Graft-versus-host disease was a predisposing factor in 1 of 3 pa-tients, but the other 2 remaining patients were on high doses ofprednisone ranging from 60 to 100 mg at the time of diagnosis.The microorganism diagnosis was made via sinus cultures(66%, 2/3) and by biopsy of orbital lesion with sinus involve-ment (33%, 1/3). Atypical headache or mental status changeswere present in all cases as well as either unilateral or bilateralweakness on physical examination. Treatment regimens included

FIGURE 2. Computed tomography of the head withoutintravenous contrast showing a 1.0 cm anteroposterior� 1.8 cmin transverse diameter with a focus of low attenuation in the leftcerebellum, consistent with resolving Fusarium abscess.

Raturi et al Infectious Diseases in Clinical Practice & Volume 22, Number 2, March 2014

98 www.infectdis.com * 2013 Lippincott Williams & Wilkins


voriconazole, posaconazole, or amphotericin B lipid form, andtreatment courses were limited by survival time, which rangedfrom 23 to 53 days (median survival time, 49 days). None of ourcases showed improvement or resolution of the brain abscess withtreatment (Fig. 4).

ToxoplasmosisBetween January 1998 and January 2010, 2 cases of

Toxoplasma-associated brain abscesses were diagnosed from thepatients with HM via a positive culture for Toxoplasma gondii.

One male with CML and one female with lymphoma werediagnosed with brain abscesses via MRI brain, with a medianage of 53 years. The clinical presentation for both patients wasaltered mental status. It is noted that neither patient was onchronic steroids. The first patient was neutropenic for 25 days,and the second was neutropenic for 13 days. Notably, both werediagnosed with brain abscesses within 2 weeks of neutropenicresolution. Radiological findings were described as severalareas of enhancement for 1 patient, whereas the second patienthad a milliary pattern, that is, the presence of microabscesses.The 40-year-old male was not a candidate for an allogeneicHSCT, and he requested discharge to hospice 4 days after di-agnosis via lumbar puncture. The 66-year-old female was day29 postautologous HSCT at the time of diagnosis and survivedfor 13 days after the diagnosis of the brain abscesses. The for-mal diagnosis was gathered during autopsy. Neither patient wason toxoplasmosis prophylaxis (Fig. 5).

Table 1 shows data collected from the 13 patients from ourretrospective series compared with relevant case reportssearched on PubMed meeting our inclusion criteria (ie, 10 casereports involving patients with HM with brain abscesses wereincluded). Our data are overall consistent with previously de-tailed findings in the literature search. The first notable differ-ence is the difference in median age at the time of diagnosis forinvasive Aspergillus brain abscesses between our cohort andthat found in previous articles. Second, as seen in Figure 1, theprevalence of brain abscesses in patients with HM is higher inmen than in women at a ratio of 10:7. The high incidence inmen, although may be biased because of the higher baselineincidence of malignancy in the male population than in the fe-male population. According to the Leukemia and LymphomaSociety Facts 2011, men account for 57% or new cases ofleukemia.19

Table 2 depicts the symptoms that our tertiary care cancerhospital’s patients presented compared with those in the case re-ports. The symptoms for brain abscesses are generally nonspecific,contributing to the difficult diagnosis. Variations in presentingsymptoms may be due to different criteria at different institutions.

FIGURE 3. Magnetic resonance image of the brain with andwithout intravenous contrast showing left frontal intra-axialNocardia abscess. The lesion also has increased signal ondiffusion-weighted images consistent with left frontal abscess.

FIGURE 4. Magnetic resonance image of the brain with andwithout intravenous contrast showingmultiple zygomycosis-relatedbrain lesions in both hemispheres and a ring-enhancing lesion in theleft occipital area with enhancement on diffusion-weighted images.

FIGURE 5. Magnetic resonance image of the brain with andwithout intravenous contrast showing abnormal edema signalintensity in the left temporal cortex and a ring-enhancingToxoplasma abscess in the posterior left parieto-occipital cortex.




Table 3 includes the species of the organisms isolated fromthe 13 cases of brain lesions.

Discussion Per Organism

AspergillusAspergillus describes a diverse genus of filamentous fungi

found in soil and decomposing vegetation.22 It is an opportu-nistic pathogen normally not leading to invasive disease inhealthy individuals but is prevalent in the immunocompromisedhost.1,22,23 Aspergillus is the most common mold infectionfound in HSCT patient population. Central nervous systemaspergillosis infection in this population is especially lifethreatening, with a mortality rate approaching 100%.24 TheTransplant Associated Infections Surveillance Network dem-onstrated that the incidence of proven or probable invasive As-pergillus at 12 months was 0.5% for autologous HSCT, 2.3%for allogeneic human leukocyte antigenYmatched donor, 3.2%after an human leukocyte antigen mismatchedYrelated donor,and 3.9% from an unrelated donor.25 Aspergillus disseminates

to the brain hematogenously from the intestines or lungs but canalso spread directly from adjacent sinuses via vascular channels,favoring the frontal and temporal lobes.1,25 The mechanism ofinvasion is unknown, but immunodeficiency likely contributesto dissemination. Typically, CNS aspergillosis infection formsone or more abscesses with varying degree of blood vessel in-vasion leading to thrombosis, infarct, or even meningitis.1,25

Symptoms also include focal neurologic disturbances owingto infarction of the anterior or middle cerebral artery. Centralnervous system aspergillosis should be considered in immu-nosuppressed patients with mental status changes, headaches,sinusitis, or mood disorders. Risk factors include underlyinglung disease or infection, immunosuppressive therapy, alloge-neic HSCT, diabetes, and prolonged neutropenia. Consistentwith our findings, our literature review demonstrated that leu-kemia is the most common underlying malignancy that pre-disposes patients to invasive Aspergillus infection.21,22 Theradiological finding associated with Aspergillus CNS lesionsvaries but is frequently associated with edema, areas consistentwith infarction, and ring enhancement. Cerebrospinal fluid find-ings are generally nondiagnostic.6,25

Literature referencing Aspergillus brain abscess cite avarying degree of lethality. The mortality rate of CNS asper-gillosis was 100%, with a median survival of only 10 days,using only amphotericin BYbased antifungal therapy in differentforms according to Schwartz et al.25 This study is consistentwith our patient who died 5 days after being diagnosed with abrain abscess due to Aspergillus. The data of Schwartz et al arefrom their study in 1999 detailing that 56 of 58 patients whowere diagnosed with brain abscess died after diagnosis. On theother hand, a more recently published retrospective analysisshowed that treatment with voriconazole and neurosurgicalmanagement in 14 patients yielded partial or complete remis-sion in 35% of the patients.24 This study is consistent withthe other patient who survived for 156 days after abscess di-agnosis status posttreatment combining voriconazole andamphotericin BYbased products. Neurosurgery (eg, cranioto-my, abscess resection, or drainage) in eligible patients also

TABLE 1. Demographic and Hematologic Characteristics

Characteristic (N/n) Aspergillus Fusarium Nocardia Zygomycosis Toxoplasma

Brain abscess 2/2 1/0 5/1 3/ 0 2/ 7Median age, y 36/49 76/V 42.8/40 55.7/V 53/52Male 2/2 1/V 5/0 1/V 1/5Female V V 0/1 2/V 1/2AML 0/1 1/0 V V 0/1ALL V V 1/0 2/V 0/1Chronic lymphocytic leukemia/CML 2/0 V 0/1 1/4Lymphoma V 2/0 1/V 1/1Aplastic anemia/MDS/MM 0/1 V 2/0 V VGVHD 2/0 V 1/0 1/V 0/3HSCT 2/1 V V 1/3*Positive culture from the lungs 2/2 V 1/1 2/V VPositive culture from the skin 0/1 V V V VDiabetes V V 1/V 0/1Chronic steroid use 2/V 0/V 2/V 2/V 0/VNeutropenia 1/V 1/V 0/V 2/V 2/V

Moffitt data are shown before the virgule (/). Data are compared with relevant case reports,11Y19 which are reported after the virgule (/).

*Received an autologous HSCT, not an allogeneic HSCT.

N indicates number of patients in the study; n, number of patients in case reports.11Y19

TABLE 2. Signs and Symptoms of Brain Abscess

Signs/Symptoms (N/n) 13/10

Focal neurologic deficits 7/7Headaches 5/0Mental status changes 8/3Chest pain 0/1Fever 3/3

Most common presenting signs and symptoms of patients with brainabscesses.

Moffitt data are shown before the virgule (/). Collected data arecompared with data collected from relevant case reports (consistent withFig. 1)11Y21 reported after the virgule (/).

N indicates number of patients in the study; n, number of patients incase reports.11Y21




contributes to improved overall survival in patients with cere-bral aspergillosis.1,26

The 2 Moffitt patients with Aspergillus-associated brainabscesses were similar in age, sex, underlying diagnosis (CML),and time between HSCT and brain abscess diagnosis. A notabledifference between the patient who survived the brain abscessand the patient who expired soon after diagnosis is presumed tobe fungal load of Aspergillus in the brain. For example, multiplebrain foci (3) of Aspergillus was found in the terminal patient,whereas the survivor only had 1 focus in the temporal lobe ofhis brain. The surviving patient was also, as mentioned before,given aggressive double antifungal treatment. Increasing num-bers of sources state that voriconazole is highly effective com-pared with amphotericin BYbased products for the treatmentof invasive Aspergillus infections regardless of the site of in-fection.1 Flucytosine is contraindicated in patients with HMdue to high myelotoxicity.4

FusariumFusarium is an emerging fungal infection in patients with

HM, associated with a high mortality rate most likely owing todelayed diagnosis.27 Fusarium is a filamentous fungus found insoil and plumbing systems as biofilms. Fusarium has septatehyphae and acute angle branching morphology. It usuallycauses localized infections such as onychomycosis, keratitis incontact lens wearers, or localized skin infection at the site oftrauma. Owing to the rapid spread and difficulty of treatment,infections can quickly become disseminated in immunocom-promised patients.28 Skin lesions as seen in our patient isfrequently the primary lesion that leads to the diagnosis of Fu-sarium. Systemic antifungals combined with aggressive surgicaldebridement form the cornerstone of treatment for Fusarium.The antifungal resistance pattern of Fusarium leads to the oftenuse of a combination of antifungal treatments to increase apatient’s ability to clear the infection and survive.27 AmphotericinBYbased products are associated with poor outcomes, yet otherstrains remain susceptible to voriconazole.4 In contrast to othermolds, Fusarium is cultured frequently from blood, suggestingthat hematogenous dissemination is the mechanism of invasionespecially to distant sites.28 Our patient responded well to early

voriconazole (300 mg twice daily) treatment and recoveredfrom the disseminated Fusarium infection.

NocardiaNocardia species are gram-positive, filamentous bacterial

rods traditionally found in the environment in soil, water, andvegetable matter.28 Nocardia brain abscess represent an oppor-tunistic infection that occurs most often in immunosuppressedpatients and rarely in immunocompetent individuals.29 Nocardiaastesoides, Nocardia farcinica, Nocardia nova, and Nocardiabrasiliensis are the most important causes of human infection.The mortality rate for disseminated nocardiosis was for 64% in1 study from Spain.29 The respiratory tract is the most commonsite of Nocardia infection, but hematogenous disseminationcan lead to the involvement of the brain, kidneys, bones, andeye.29 Long-term corticosteroid use, malignancy, and localizedpulmonary disease are recognized risk factors for Nocardiainfection. Nocardia species have relatively slow growth, making itmore difficult to culture in the laboratory, owing to the con-tamination by faster growing competitors, so informing thelaboratory of the suspicion for Nocardia is recommended.29,30

A reliable way to identify Nocardia species is the 16S rRNA geneuniversal polymerase chain reaction (PCR) method.29 Treat-ment challenges include antibiotic resistance, rapid spread ofthe infection, and the integration of optimum surgical inter-vention.31 Aspiration or craniotomy with excision has beenrecommended for brain abscesses larger than 2.5 cm, for ab-scesses that enlarged after 2 weeks of antibiotic treatment, andabscesses that fail to shrink after 4 weeks of aggressive anti-biotic therapy.29 In 40% (2/5) of our patients with nocardiosis,imaging showed complete resolution of the brain abscesses.All patients were treated with at least 2 or more of the fol-lowing antibiotics: ceftriaxone, SMX-TMP, minocycline, andmeropenem. Aspiration and antibiotic therapy is an ideal combi-nation treatment for patients with multiple deep lesions.29

ZycomycosisZygomycota falls into a distinctive phylum characterized

by the formation of ribbon-like aseptate hyaline hyphae and theformation of zygospores.32 They are ubiquitous saprophytic

TABLE 3. Pathogens and Species Identification

Organisms Isolated (n = 13) Species Method of Diagnosis

Nocardia species (n = 5) Nocardia asteroides (n = 2) Culture of brain abscessNocardia cyriacigeorgica (n = 1) Culture of lung lesion, CT head with left cerebellar ring enhancing lesionNocardia transvalensis (n = 1) Culture of brain abscess

Unspecified (n = 1) Gram stain of frontal brain abscess consistent with filamentousgram positive rods

Zycomycosis (n = 3) Rhizopus species (n = 2) Culture of ethmoid sinus, MRI head with left frontal abscessand CT chest findings clinically consistent with Zygomyces

Culture of biopsy from left orbital lesionRhizomucor species (n = 1) Cultured from upper respiratory tract with concomitant

multiple ring enhancing lesions on MRI headAspergillus species (n = 2) Aspergillus species (n = 1) Cultured in bronchoalveolar lavage with multiple lesions

visualized on MRI head and CT chestAspergillus flavus (n = 1) Culture of sinus, MRI head with ring enhancing

lesion consistent with Aspergillus

Toxoplasmosis (n = 2) Toxoplasma bradyzoites (n = 1) Cultured from autopsy result from the brainUnspecified (n = 1) Lumbar puncture consistent with toxoplasmosis

and positive Toxoplasma IgGFusarium species (n = 1) Fusarium solani (n = 1) Cultured Fusarium from skin lesions, MRI head with low-attenuation

lesions consistent with hematogenously disseminated Fusarium




organisms common in tropical climates found on bread, soil, air,and decaying vegetation.1 Healthy individuals have strong nat-ural immunity to zygomycota, but diabetic patients are prone toinfections specifically during episodes diabetic ketoacidosis.1

Immunocompromised patients and neutropenic patients arealso prone to infections by this opportunistic pathogen. Pro-longed use of voriconazole has also recently been evaluatedas a risk factor perhaps as inadvertently selecting out forzygomycosis.9 The respiratory tract is the most common pri-mary site of infection.1 Zygomycota infections have a highassociated mortality rates ranging from 96% to 100% unlesstreatment is prompt and appropriate.32 In an infected host, thezygomycota infection rapidly invades vessels and disseminatesvia the hematogenous route. Vascular invasion, infarction, andnecrosis are characteristic of zygomycota infections.1 Our 3patients were treated with systemic liposomal amphotericinBYbased products with aggressive dosing but still 2 died within2 months of diagnosis with a zygomycosis-related brain ab-scess. The third patient was discharged without treatmentowing to patient’s decision. In patients with HM, delayingappropriate treatment with liposomal amphotericin BYbasedtreatment leads to increased mortality rates.1,33

ToxoplasmaT. gondii is an obligate intracellular protozoan that is

usually self-limited or subclinical in immunocompetent in-dividuals, where 33% of the population worldwide is seropos-itive.12 Neurotoxoplasmosis is a leading cause of CNS infectionsin patients after HSCT, with a higher prevalence in Europe ratherthan in North America.1 The higher incidence rate of T. gondiiinfection in Europe can be accounted for by the high prevalence ofthe organism. Up to 80% of European populations are infectedwith T. gondii compared with only 20% of the population in theUnited States.34

The route of initial infection predominantly is from ex-posure via infected feline feces to the human host either di-rectly or via another infected human host. Lifelong colonizationoccurs thereafter and can be seen as having positive serology, IgG.Under the pressure of immunosuppression, quiescent toxoplas-mosis infections can reactivate, leading to active infection andserious sequelae for the host. Infection prevalence has decreasedin the United States and Europe in the last 2 decades presumablyowing to improved food storage methods and hygiene.34 Treat-ments do not eradicate T. gondii, so immunocompromised pa-tients may experience reactivation. Periodic screening and routinePCR testing of peripheral blood mononuclear cells are likelyeffective as preventive measures in HSCT patients.26 PCR mayhelp with early diagnosis because levels in the blood have beenshown to precede a clinically relevant T. gondii infection.14

Toxoplasmosis appears as a ring-enhancing lesion, similar toNocardia, but tends to involve the basal ganglia.35 Owing todelayed diagnosis, our 2 patients were treated with antimicrobialssolely without neurosurgical intervention. One died within 2 weeksof diagnosis, whereas the other survived. Pyrimethamine com-bined with sulfadiazine is the mainstay of treatment for T. gondii,but the duration and role of maintenance therapy are not as clearespecially in the HSCT population who are on immunosup-pressants for varying lengths of time.11

CONCLUSIONSWith regard to our literature review using PubMed re-

sources, it was limited by our criterion of articles published inEnglish only, thus excluding articles with valuable informationpublished in other languages. Because the review covereda large number of years, the use of different antifungals for

invasive fungal infections also changed significantly with theincrease of synthetic triazoles and a decrease use of liposomalamphotericin BYbased products. In terms of the limitations ofour retrospective study, our study design is a limiting factor,which is also affected by the small sample size of 13. Ideally, alarger prospective study either at a single center with highvolume of patients with HM or a multicenter study evaluatingOBAs and treatments would be needed to further evaluate ques-tions about these often aggressive infections.

In terms of the conclusions from our study, we can onlyreport trends of correlation because causality cannot be con-cluded in a retrospective trial. Our increased risk of OBA inmen may be related to an increased frequency of new cases ofleukemia in men and therefore represent a bias in our study.Chemotherapy-induced or disease-related severe neutropenia(ANC G 500) for 7 to 15 days was seen as a major risk factor forbrain abscesses cause by zygomycota infection, toxoplasmosis,and Aspergillus in our series. Patients with prolonged neutro-penia, as shown in Table 3, should also be considered fortoxoplasmosis prophylaxis ideally with TMP/SMX if feasible.Unfortunately, there can be issues with the use of TMP/SMX inpatients who are already pancytopenic or neutropenic due to thebone marrow suppressive adverse effect profile of the drug. Themost important risk factor for infection in allogeneic transplantafter engraftment is the development of GVHD and its resultantimmunosuppressive treatment. Chronic GVHD is associatedwith persistently depressed T-cell and humoral immunity, andtherefore, prophylaxis for invasive infections such as Nocardia,zygomycosis, Toxoplasma, and Aspergillus infections shouldbe considered. In patients on chronic steroid therapy, a shownin Table 3, investigations into the use of posaconazole forzygomycosis prophylaxis should also be further investigated andclinically considered. Unfortunately, good oral intake is required toadequately absorb posaconazole, which is not always apparent inimmunocompromised hosts. On the other hand, Nocardia in-fections develop in nonneutropenic patients and are mainly relatedto long-term corticosteroid use and chronic localized pulmonaryinfections. Risk-versus-benefit ratio of Aspergillus prophylaxisshould be further investigated because Aspergillus is the mostcommon culprit of brain abscesses, followed by zygomycosis as thesecond most frequent cause.4 Aggressive workup with blood cul-tures and cultures from deep-seeded sources is required early whentrying to find amicrobiological diagnosis for radiographic findings.Having a good relationship with neurosurgery, ENT specialists,and other surgical subspecialties helps get samples in a timelymanner, leading to the correct diagnosis. Working hand in handwith microbiology to get Gram stain information, which helpdelineate between invasive fungi that require voriconazoleversus amphotericin BYbased products, is also very important.Having a high pretest probability in immunocompromisedhosts, such as patients with HM, leads to early brain abscessdiagnosis; surgical therapy and culture-directed treatmentsare the keys for the patient survival.

REFERENCES

1. Rai M, G Kovics. Progress in Mycology. Jodhpur, India: ScientificPublisher; 2010:141Y176.

2. Schmidt-Hieber M, Zweigner J, Uharek L, et al. Central nervous systeminfections in immunocompromised patientsVupdate on diagnostics andtherapy. Leuk Lymphoma. 2009;50(1):24Y36.

3. Moorthy RK, Vedantam R. Management of brain abscess: an overview.Neurosurg Focus. 2008;24(6):1Y6.

4. Kao PT, Hsiang-Kuang T, Liu CP, et al. Brain abscess: clinical analysisof 53 cases. J Microbiol Immunol Infect. 2003;36(2):129Y136.




5. DeVita VT, Lawrence SL, Rosenberg SA, et al. Devita, Hellman andRosenberg’s Cancer Principles and Practice of Oncology. Vol 2. 8th ed.Philadelphia, PA: Lippincott Williams and Wilkins; 2008. 2569Y2579.

6. Douglas RG, Mandell D. Bennett’s Principles and Practice of InfectiousDiseases. 5. 1. Philadelphia, PA: Churchill Livingstone; 2001.

7. Pagano L, Caira M, Candoni A, et al. The epidemiology of fungalinfections in patients with hematologic malignancies: theSEIFEM-2004 Study. Haematologica. 2006;91(8):1068Y1075.

8. Pagano L, Morena C, Falcucci P, et al. Fungal CNS infections in patientswith hematologic malignancy. Expert Rev Anti Infect Ther.2005;3(5):775Y785.

9. Carpenter J, Stapleton S, Holliman R. Retrospective analysis of 49 casesof brain abscesses and review of the literature. Eur J Clin MicrobiolInfect Dis. 2007;26(1):1Y11.

10. White PL, Linton CJ, Perry MD, et al. The evolution and evaluation ofa whole blood polymerase chain reaction assay for the detection ofinvasive aspergillosis in hematology patients in a routine clinicalsetting. Clin Infect Dis. 2006;42(2):487Y89.

11. Khoury H, Adkins D, Brown R, et al. Successful treatment of cerebraltoxoplasmosis in a marrow transplant recipient: contribution of a PCRtest in diagnosis and early detection. Bone Marrow Transplant.1999;23(4):409Y411.

12. Herold MA, Kuhne R, Vosberg M, et al. Disseminated toxoplasmosisin a patient with non-Hodgkin lymphoma. Infection. 2009;37(6):551Y554.

13. Desmond R, Lynch K, Gleeson M, et al. Progressive multifocalleukencephalopathy and cerebral toxoplasmosis in a patient with CLL.Am J Hematol. 2010;85(8):607.

14. Gonzalez MI, Caballero D, Lopez C, et al. Cerebral toxoplasmosis andGuillain-Barre syndrome after allogeneic peripheral stem celltransplantation. Transpl Infect Dis. 2000;2(3):145Y149.

15. Abedalthagafi M, Rushing E, Garvin D, et al. Asymptomatic diffuse‘‘encephalitic’’ cerebral toxoplasmosis in a patient with chroniclymphocytic leukemia: case report and review of the literature.Int J Clin Exp Pathol. 2010;3(1):106Y109.

16. Laurence AD, Peggs KS. Cerebral and pulmonary nocardia in a bonemarrow transplant patient. Br J Haematol. 2005;129(6):711.

17. Matsuo Y, Takeishi S, Miyamoto T, et al. Toxoplasmosis encephalitisfollowing severe graft-vs.-host disease after allogeneic hematopoieticstem cell transplantation: 17 yr experience in Fukuoka BMT group.Eur J Haematol. 2007;79(4):317Y321.

18. Cibickova L, Horacek J, Prasil P, et al. Cerebral toxoplasmosis in anallogeneic peripheral stem cell transplant recipient: case report andreview of literature. Transpl Infect Dis. 2007;9:332Y335.

19. Leukemia Society. Facts and statistics. LLS; 2011. Available at:http://www.lls.org/diseaseinformation/getinformationsupport/factsstatistics/.Accessed December 3, 2012.

20. Nenoff P, Kleim C, Mittag M, et al. Secondary cutaneous aspergillosisdue to Aspergillus flavus in an acute myeloid leukaemia patientfollowing stem cell transplantation. Eur J Dermatol. 2002;12(1):93Y98.

21. Wandroo F, Stableforth P, Hasan Y, et al. Aspergillus brain abscess in apatient with acute myeloid leukaemia successfully treated withvoriconazole. Clin Lab Haematol. 2006;28(2):130Y133.

22. Fedorova N, N Khaldi, Joarder V, et al. Genomic islands in thepathogenic filamentous fungus Aspergillus fumigatus. PLoS Genet.2008;4(4):1Y2.

23. Kwon-Chung K, Sugui J. Sexual reproduction in Aspergillus speciesof medical or economical importance: why so fastidious? TrendsMicrobiol. 2009;17(11):481Y487.

24. Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in centralnervous system aspergillosis, using voriconazole treatment. Blood.2005;106:2641Y2645.

25. Schwartz S, Ruhnke M, Ribaud P, et al. Poor efficacy of amphotericinB-based therapy in CNS aspergillosis. Mycoses. 2007;50:196Y200.

26. Martino R, Bretagne S, Einsele H, et al. Early detection of Toxoplasmainfection by molecular monitoring of Toxoplasma gondii in peripheralblood samples after allogeneic stem cell transplantation. Clin Infect Dis.2005:40(1):67Y78.

27. Forrest G, Walsh T. Approaches to management of invasive fungalinfections in patients with hematologic malignancies. Support CancerTher. 2004;2(1):21Y30.

28. Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen inpatients with hematologic malignancy: ten years’ experience at acancer center and implications for management. Blood. 1997;90(3):999Y1008.

29. Chung TT, Lin LC, Hsieh CT, et al. Nocardia farcinica brain abscess inan immunocompetent patient treated with antibiotics and two surgicaltechniques. J Clin Neurosci. 2009;16(12):1675Y1677.

30. Clauss HE, Lorber B. Listeriosis and Nocardiosis. Current Clinical

Oncology. New York: Humana Press; 2011:435Y442.

31. Lee GY, Daniel RT, Brophy BP, et al. Surgical treatment of nocardialbrain abscesses. Neurosurgery. 2002;51:668Y671.

32. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease.Clin Microbiol Rev. 2000;13(2):236Y301.

33. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericinBYbased frontline therapy significantly increases mortality amongpatients with hematologic malignancy who have zygomycosis.Clin Infect Dis. 2008:47:503Y509.

34. Buffolano W. Congenital toxoplasmosis: the state of the art.Parassitologia. 2008;50:37Y43.

35. Guermazi A, Gluckman E, Tabti B, et al. Invasive central nervoussystem aspergillosis in bone marrow transplantation recipients:an overview. Eur Radiol. 2003;13(2):377Y388.




http://www.lls.org/diseaseinformation/getinformationsupport/factsstatistics/

Retrospective Analysis of Opportunistic Brain Abscesses in Patients With Hematologic Malignancies

Documents

Transcript of Retrospective Analysis of Opportunistic Brain Abscesses in Patients With Hematologic Malignancies