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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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Brain MRI

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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QS#4. Treatment ?

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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)

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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Case #2 – QS#3

Brain abscess, HIV with CD4 < 200/mm3, serology toxoplasmosis +

–How would you manage this case ?

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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Case#3 – QS#2: Additional investigations ?

Chong GM et al. J Clin Microbiol 2016

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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

@ ESCMID eLibrary .

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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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