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Brain abscess in immunocompromised patients
Prof. Pierre Tattevin
Infectious Diseases & ICU
Pontchaillou University Hospital, Rennes, France
European Study Group for Infectious diseases of the Brain (ESGIB)
@ ESCMID eLibrary .
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Case #1
• 64 year-old woman
• Retired, never left France, lives in a farm
• Diabetes mellitus
• Renal transplant in Sept. 2014 for ESRD
• CMV disease in Dec. 2014 => valganciclovir
• Admitted in May 2015 for a 3-week history of
– weight loss
– cough
– low-grade fever@ ESCMID eLibrary .
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Case #1
• Usual treatment
– insulin
– tacrolimus, corticosteroids (prednisolone, 10 mg/d)
– calcium
(valganciclovir & trimethoprim/sulfa discont’d in March)
• Physical examination on admission (May 2015)
– T = 38°C
– unusually ‘slow’ (understanding, speech, basic tasks)@ ESCMID eLibrary .
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QS #1
• What are the main causes of neurological diseasesin SOT recipients ?
1. Neurotoxicity related to IS drugs
- calcineurin inhibitors (tacrolimus)
- corticosteroids
2. CNS opportunistic infections
- meningitis, encephalitis
- brain abscess
3. Others (cardiovascular events, CNS neoplasms…)
Senzolo M et al. Transplant Intern 2008
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Case #1
• Tacrolimus plasma concentration = 4 mg/L
– Target, 3-5
• Basic lab
– WBC count, 4 G/L
– Na+ 135 mmol/L, Calcium 2.4 mmol/L, glucose 5 mmol/L
– Creatininemia 110 umol/L (N)
– CRP 50 mg/L@ ESCMID eLibrary .
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Thoracic imaging
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Brain MRI
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QS#2. What could it be ?
• Bacteria
– tuberculosis
– nocardiosis
– listeriosis
• Fungi
– aspergillosis
– cryptococcosis
– mucormycosis
• Parasites
– toxoplasmosis
– cysticercosis
• Lung cancer with brainmetastasis
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QS#3. Additional investigations
• BAL
– macroscopic findings
– tests for OI (contact withyour microbiology lab !)• appropriate media & prolonged
incubation
• parasitology (PCR toxo)
• mycology (galactomannan Ag)
If no diagnosis => biopsy– Lung
– Brain abscess
• CSF
– if meningitis (WBC > 5/mm3)• Gram stain, prolonged incubation
• PCR toxo & BK
• Galactomannan & cryptococcal Ag
• (1-3)-beta-D glucan
• Blood• BCs, prolonged incubation
• Galactomannan Ag
• cryptococcal Ag
• (1-3)-beta-D glucan@ ESCMID eLibrary .
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Case #1
• BCs & BAL grew:– weakly gram-positive bacilli
– branching filaments
– partially acid-fast
• MALDI-TOF– Nocardia farcinica
• Drug Susceptibility ?– Sent to reference center
– Please, wait… http://thunderhouse4-yuri.blogspot.fr
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QS#4. Treatment ?
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Nocardiosis in SOT recipients
• Nocardia spp.– Actinomycetes (slow-growing, gram + bacilli)
– Environment => exposure to dust & soil (farmers, construction workers)
– Nosocomial outbreaks reported in transplant units
• A major cause of brain abscess in SOT recipients– Median delay, 8-17 months
– TMP-sulfa prophylaxis not obviously protective
– Risk factors => see Coussement J et al. Abs #0444 (this afternoon)
Mathisen JE et al. Clin Infect Dis 1998
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Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013
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Fishman J. N Engl J Med 2007
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Nocardiosis in SOT recipients
• Median time from transplantation– 17 months (range, 2-244)
• Nocardiosis brain abscess– 25% of all nocardiosis in SOT recipients
– >90% associated with lung lesions (nodules)
– 44% had no neurological sign
– Median diagnosis delay = 20 days (range, 1-139)
=> (Suspicion of) Pulmonary nocardiosis in SOT should prompt brain MRI
Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013
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Nocardiosis in SOT recipients
• Two distinct features– Multiple brain abscess (80%), mostly supra-tentorial
– Isolated, multiloculated (20%)
• Diagnostic work-out– Extra-neurological samples (blood, lungs)
– Consider brain biopsy
Coussement J et al. ECCMID 2016, abs. #0444
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@ ESCMID eLibrary .
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QS#4. Antibacterial treatment ?
• Key words– Bactericidal
– Brain diffusion & tolerability (multiple drugs, interactions)
• Caveats– Reliable DST takes long (> 2 weeks)
• broth microdilution = standard (E-test = ‘proxy’
– Technical challenges => reference lab
– Clinical relevance unclear
Early probablistic treatment (provided appropriate sampling)@ ESCMID eLibrary .
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Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013
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Case #2
• 74 year-old man
• Primary school teacher, retired, never left France
• Medical history unremarkable, except for tobacco use
• Headache (2 weeks) + weight loss & low-grade fever
• Lethargic (1 week)
• Motor deficit: right leg and right hand (2 days)
• Confusion => refuses to go to the hospital
=> Brain MRI ordered by the GP@ ESCMID eLibrary .
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Case #2
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Diffusion Weighted Imaging (DWI) Apparent Diffusion Coefficient (ADC)
Muccio CF et al. J Neuroradiol 2014
High ADC =>
non-pyogenic abscessLow ADC =>
Pyogenic abscess@ ESCMID eLibrary .
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DWI & ADC for differential diagnosis (malignancies)
Muccio CF et al. J Neuroradiol 2014
Glioblastoma Metastasis (cancer)
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Case #2 – QS#1
=> Patient referred to your ID consultation, and admitted
• Investigations ?
– Rapid HIV testing
– Blood cultures (40-60 mL)
– Chest X-ray
– Hematology, biochemistry, coagulation tests
– Contact with neurosurgeons for stereotactic biopsy ASAP
HIV positive, confirmed !
HIV testing should be
considered for all patients
with unexplained cerebral
mass lesions
Mathisen GE et al. Clin Infect Dis 1997
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Case #2 – QS#2
HIV-infected, CD4+ 47/mm3, brain abscesses (n=3, max 2.5 cm)
• Pick one test that may be enough to initiate treatment ?
–Toxoplasmosis serology– Cryptococcal antigen
– PCR CMV
– Fundoscopic exam
– Syphilis serology
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Toxoplasma encephalitis in AIDS patients
• #1 cause of brain abscess in this population
– 75% have CD4 < 100/mm3
• Sub-acute (1-3 weeks)
– Headache, focal signs, seizures
• Pathophysiology = Reactivation=> Toxoplasmosis serology positive in >90% of confirmed cases, but:
- Positive & negative predictive values depend on local prevalence
(e.g. 20% in the US, vs. >75% in El Salvador)
Montaya JG et al. Lancet 2004
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Case #2 – QS#3
Brain abscess, HIV with CD4 < 200/mm3, serology toxoplasmosis +
–How would you manage this case ?
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Case #2 – QS#3
• Probabilistic treatment
– Pyrimethamine / sulfadiazine / leucovorin
– Close monitoring (efficacy / tolerability)
– Control MRI (D14) => 95% of CNS toxoplasmosis improvedafter 14 days of probabilistic treatment
If improved clinically, and control MRI ‘at least not worse’
=> Initiate ARV treatmentSkiest DJ. Clin Infect Dis 2002
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If worse under probabilistic treatment...
Main differential diagnosis for space-occupying lesions in AIDS:
CNS lymphoma Cerebral tuberculosis Cryptococcoma
Skiest DJ. Clin Infect Dis 2002
Cardenas et al. Neurosurgery 2010
Sitapati AM et al. Clin Infect Dis 2010@ ESCMID eLibrary .
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Case #3
• 40 year-old man
• Acute myeloblastic leukemia, February 2015
– WBC 270 G/L Platelets < 10 G/L
– ARDS + diffuse interstitial lung lesions
– Intubated => ICU
• Induction therapy (cytarabine / anthracycline)
– Ceftriaxone / ofloxacin
– Improvement => extubated (day 10)
– Confusion / desorientated / coma => re-intubation@ ESCMID eLibrary
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Brain imaging
T1 gadolinium FLAIR@ ESCMID eLibrary .
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Thoracic imaging
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Case#3 - QS#1. What could it be ?
• Bacteria
– tuberculosis
– non-TB mycobacteria(NTM)
– pyogenic abscesses
• Fungi
– aspergillosis
– cryptococcosis
– mucormycosis
• Parasites
– toxoplasmosis
• CNS Leukemia
@ ESCMID eLibrary .
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Case#3 – Main results
• BAL
– No pathogen (including OI)
– Streptococcus viridans, 106
• CSF
– WBC 7/mm3
– Gram stain, PCR toxo, PCR BK, cryptococcal Ag negative
• Blood
– BCs, prolonged incubation
=> negative
– galactomannan 0.6 (n<0.5)
– cryptococcal Ag negative
@ ESCMID eLibrary .
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Case#3 – QS#2: Additional investigations ?
De Pauw B et al. Clin Infect Dis 2008
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Case#3 – QS#2: Additional investigations ?
Chong GM et al. J Clin Microbiol 2016
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• CSF beta-D-glucan
– Positive in 5/5 CNS fungal infections• median, 331 pg/mL (range, 103-523)
– negative in 18/19 with no fungal infection• median, 32 pg/mL (range, 7-115) Mikulska M et al. Clin Infect Dis 2013
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Case#3 – QS#3: Treatment ?
Weiler S et al. Antimicrob Agents Chemother 2011
• Voriconazole: many assets– Superior to AmB for invasive aspergillosis overall, including for survival
Herbrecht et al. N Engl J Med 2002
– Tolerability (with TDM => target plasma 2-5.5 mg/L)
– Good CNS diffusion
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Brain abscess in immunocompromised: Take-home messages
• The usual suspects in 3 different settings– Nocardiosis in SOT (mild neurological symptoms)
– Toxoplasmosis in AIDS (HIV may be undiagnosed)
– Aspergillosis in haematological malignancies
• Indirect diagnosis may avoid brain biopsy– Extra-neurological sites (BAL, skin, blood)
– Innovative assays (PCR, Ag, etc.)
• The impact of prophylaxis@ ESCMID eLibrary
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