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European Study Group for Infectious diseases of the Brain (ESGIB)

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Brain abscess in immunocompromised patients

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Prof. Pierre Tattevin

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Infectious Diseases & ICU

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Pontchaillou University Hospital, Rennes, France

M I o r
C u t h
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Case #1
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• 64 year-old woman
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Retired, never left France, lives in a farm
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Diabetes mellitus
•
ID r
Renal transplant in Sept. 2014 for ESRD
• M o
CMV disease in Dec. 2014 => valganciclovir
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•
S C u
Admitted in May 2015 for a 3-week history of
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– weight loss

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– cough
– low-grade fever
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Case #1
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• Usual treatment
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– insulin
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– tacrolimus, corticosteroids (prednisolone, 10 mg/d)
– calcium
I D r
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(valganciclovir & trimethoprim/sulfa discont’d in March)

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• PhysicalS C onuadmission (May 2015)
examination
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– T = 38°C

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– unusually ‘slow’ (understanding, speech, basic tasks)
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QS #1
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• What are the main causes of neurological diseases
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in SOT recipients ?
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1. Neurotoxicity related to IS drugs
ID r
- calcineurin inhibitors (tacrolimus)

M h o
- corticosteroids
t
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2. CNS opportunistic infections
S
E ya- meningitis, encephalitis

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- brain abscess
3. Others (cardiovascular events, CNS neoplasms…)
Senzolo M et al. Transplant Intern 2008
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Case #1
• Tacrolimus plasma concentration =a
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– Target, 3-5 i b r 4 mg/L

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• Basic lab
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– WBC count, 4 G/L
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– Na+ 135 mmol/L, Calcium 2.4 mmol/L, glucose 5 mmol/L
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– Creatininemia 110 umol/L (N)
– CRP 50 mg/L
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Thoracic imaging

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ID r
M t h o
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 Brain MRI
.
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ID r
M t h o
S C u
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QS#2. What could it be ?
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• Bacteria
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• Parasites
– tuberculosis
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– toxoplasmosis
– nocardiosis
e – cysticercosis
– listeriosis
ID • Lungrcancer with brain
M t h o
• Fungi
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metastasis

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– aspergillosis
– cryptococcosis
@ b
– mucormycosis
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QS#3. Additional investigations
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• BAL
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– if meningitis (WBC > 5/mm3)

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• Gram stain, prolonged incubation
– macroscopic findings
– tests for OI (contact with
your microbiology lab !)e L •
•
•
PCR toxo & BK
Galactomannan & cryptococcal Ag
(1-3)-beta-D glucan

ID r
• appropriate media & prolonged
incubation
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• Blood
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• parasitology (PCR toxo)
h
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• mycology (galactomannan Ag) • BCs, prolonged incubation

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If no diagnosis => biopsy
a •
•
Galactomannan Ag
cryptococcal Ag

@
– Lung
– Brain abscess
b • (1-3)-beta-D glucan
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Case #1
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• BCs & BAL grew:
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– weakly gram-positive bacilli
– branching filaments
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– partially acid-fast e
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• MALDI-TOF
M t h o
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– Nocardia farcinica
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• Drug Susceptibility
a
?
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– Sent to reference center
– Please, wait… http://thunderhouse4-yuri.blogspot.fr
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QS#4. Treatment ?
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ID r
M t h o
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Nocardiosis in SOT recipients
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• Nocardia spp.
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– Actinomycetes (slow-growing, gram + bacilli)
– Environment => exposure to dust & soil (farmers, construction workers)
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– Nosocomial outbreaks reported in transplant units

I D r
brain abscesso
• A major cause ofM
C u t h in SOT recipients

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– Median delay, 8-17 months

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– TMP-sulfa prophylaxis not obviously protective
– Risk factors => see Coussement J et al. Abs #0444 (this afternoon)
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Mathisen JE et al. Clin Infect Dis 1998
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ID r
M t h o
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Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013
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ID r
M t h o
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@ b Fishman J. N Engl J Med 2007
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Nocardiosis in SOT recipients
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• Median time from transplantation
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– 17 months (range, 2-244)

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• Nocardiosis brain abscess e
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– 25% of all nocardiosis in SOT recipients
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– >90% associated with lung lesions (nodules)
t
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– 44% had no neurological sign
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– Median diagnosis delay = 20 days (range, 1-139)
=> (Suspicion of) Pulmonary nocardiosis in SOT should prompt brain MRI

@ b Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013

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Nocardiosis in SOT recipients
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• Two distinct features r a
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– Multiple brain abscess (80%), mostly supra-tentorial

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– Isolated, multiloculated (20%)

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• Diagnostic work-out
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– Extra-neurological samples (blood, lungs)
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– Consider brain biopsy

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Coussement J et al. ECCMID 2016, abs. #0444
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ID r
M t h o
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QS#4. Antibacterial treatment ?
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• Key words
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– Bactericidal

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– Brain diffusion & tolerability (multiple drugs, interactions)
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• Caveats ID r
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– Reliable DST takes long (> 2 weeks)
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• broth microdilution = standard (E-test = ‘proxy’

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– Technical challenges => reference lab
– Clinical relevance unclear

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Early probablistic treatment (provided appropriate sampling)
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M t h o
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Lebeaux D et al. Eur J Clin Microbiol Infect Dis 2013
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Case #2
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• 74 year-old man
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•
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Primary school teacher, retired, never left France
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• e
Medical history unremarkable, except for tobacco use

• D
Headache (2 weeks) + weight loss & low-grade fever
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Lethargic (1 week)
• M t h o
•
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Motor deficit: right leg and right hand (2 days)
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Confusion => refuses to go to the hospital
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@ b
=> Brain MRI ordered by the GP
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Case #2
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ID r
M t h o
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 Diffusion Weighted Imaging (DWI) .
Apparent Diffusion Coefficient (ADC)
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ID r
M t h o
S C u
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High ADC =>
non-pyogenic abscess
Low ADC =>
Pyogenic abscess
Muccio CF et al. J Neuroradiol 2014
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DWI & ADC for differential diagnosis (malignancies)

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M t h o
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Glioblastoma Metastasis (cancer)

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Muccio CF et al. J Neuroradiol 2014
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Case #2 – QS#1
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=> Patient referred to your ID consultation, and admitted

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• Investigations ?
ibHIV testing should be
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– Rapid HIV testing
considered for all patients

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– Blood cultures (40-60 mL)
with unexplained cerebral
mass lesions

M t
– Chest X-ray
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S C u
Mathisen GE et al. Clin Infect Dis 1997

– Hematology, biochemistry, coagulation tests

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– Contact with neurosurgeons for stereotactic biopsy ASAP

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HIV positive, confirmed !
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Case #2 – QS#2
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HIV-infected, CD4+ 47/mm3, brain abscesses (n=3, max 2.5 cm)

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• Pick one test that may be enough to initiate treatment ?
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– Toxoplasmosis serology
ID r
–
–
Cryptococcal antigen
M t h o
–
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PCR CMV

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Fundoscopic exam
–
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Syphilis serology

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Toxoplasma encephalitis in AIDS patients
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• #1 cause of brain abscess in this population
– 75% have CD4 < 100/mm3 ib
• Sub-acute (1-3 weeks) eL

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– Headache, focal signs, seizures
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• Pathophysiology = Reactivation
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=> Toxoplasmosis serology positive in >90% of confirmed cases, but:
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- Positive & negative predictive values depend on local prevalence
(e.g. 20% in the US, vs. >75% in El Salvador)

@ b
Montaya JG et al. Lancet 2004
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Case #2 – QS#3
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Brain abscess, HIV with CD4 < 200/mm3, serology toxoplasmosis +
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– How would you manage this case ?
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M t h o
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Case #2 – QS#3
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• Probabilistic treatment
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– Pyrimethamine / sulfadiazine / leucovorin
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– Close monitoring (efficacy / tolerability)
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– Control MRI (D14) => 95% of CNS toxoplasmosis improved
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after 14 days of probabilistic treatment
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If improved clinically, and control MRI ‘at least not worse’
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=> Initiate ARV treatment
Skiest DJ. Clin Infect Dis 2002
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If worse under probabilistic treatment...
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Main differential diagnosis for space-occupying lesions in AIDS:

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CNS lymphoma
L ib Cerebral tuberculosis Cryptococcoma

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M t h o
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Skiest DJ. Clin Infect Dis 2002
Sitapati AM et al. Clin Infect Dis 2010

Cardenas et al. Neurosurgery 2010

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Case #3
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• 40 year-old man
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L ib
• Acute myeloblastic leukemia, February 2015
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– WBC 270 G/L Platelets < 10 G/L

ID r
– ARDS + diffuse interstitial lung lesions

M o
– Intubated => ICU
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S C u
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• Induction therapy (cytarabine / anthracycline)
– Ceftriaxone / ofloxacin

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– Improvement => extubated (day 10)
– Confusion / desorientated / coma => re-intubation
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Brain imaging
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M t h o
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T1 gadolinium FLAIR
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Thoracic imaging
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ID r
M t h o
S C u
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Case#3 - QS#1. What could it be ?
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• Bacteria
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– mucormycosis
– tuberculosis ib
• Parasites
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– non-TB mycobacteria – toxoplasmosis
(NTM)
ID • CNS rLeukemia
– pyogenic abscesses
M t h o
• Fungi
S C u
E ya
– aspergillosis

@ b
– cryptococcosis
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Case#3 – Main results
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• BAL • Bloodra
ib
– No pathogen (including OI)
L – BCs, prolonged incubation
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– Streptococcus viridans, 106 => negative

ID r – galactomannan 0.6 (n<0.5)

• CSF
M t h o – cryptococcal Ag negative

S C
– WBC 7/mm3
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– Gram stain, PCR toxo, PCR
BK, cryptococcal Ag negative
@ b
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Case#3 – QS#2: Additional investigations ?
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ra
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ID r
M t h o
S C u
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@ b De Pauw B et al. Clin Infect Dis 2008
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Case#3 – QS#2: Additional investigations ?
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ra
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ID r
M t h o
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@ b Chong GM et al. J Clin Microbiol 2016
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ID r
M t h o
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• CSF beta-D-glucan
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– Positive in 5/5 CNS fungal infections

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• 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 ?
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• Voriconazole: many assets
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– Superior to AmB for invasive aspergillosis overall, including for survival
Herbrecht et al. N Engl J Med 2002

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– Tolerability (with TDM => target plasma 2-5.5 mg/L)
– Good CNS diffusion

ID r
M t h o
S C u
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@ b
Weiler S et al. Antimicrob Agents Chemother 2011
Brain abscess in immunocompromised:
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Take-home messagesy
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• The usual suspects in 3 different rsettings
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– Nocardiosis in SOT (mild neurological symptoms)
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– Toxoplasmosis in AIDS (HIV may be undiagnosed)

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– Aspergillosis in haematological malignancies
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M t h o
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• Indirect diagnosis may avoid
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brain biopsy
– Extra-neurological sites (BAL, skin, blood)
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– Innovative assays (PCR, Ag, etc.)

@ b
• The impact of prophylaxis