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Monitoring antifungal treatment response in neutropenic patient with aspergillosis

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Monitoring antifungal treatment response in neutropenic patient with aspergillosis Cl vis Arns da Cunha, MD Professor at Infectious Diseases Division, UFPR – PowerPoint PPT presentation

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Title: Monitoring antifungal treatment response in neutropenic patient with aspergillosis


1
Monitoring antifungal treatment response in
neutropenic patient with aspergillosis
  • Clóvis Arns da Cunha, MD
  • Professor at Infectious Diseases
    Division, UFPR
  • Bone Marrow Transplant Service,
    HC-UFPR
  • Hospital Nossa Sra das Graças,
    ID Chief

2
Transparency declarations regarding antifungal
agents
  • Speaker Pfizer, Merck Sharp Dohme, United
    Medical, Bagó e Schering-Plough
  • Member of advisory boards Merck Sharp
    Dohme, United Medical, and Schering-Plough
  • Clinical trials Pfizer, Schering-Plough,
    Astellas, and Basilea Pharmaceutica

3
Topics 5 lessons in 20 min
  • Patient with Pulmonary Invasive Aspergillosis
    (PIA) presents clinical improvement, but
    worsening of radiological findings coincident
    with neutrophil recovery. What should we do ?
  • Patient with Pulmonary Invasive Aspergillosis
    (PIA) experienced transient clinical and
    radiological pulmonary deterioration during
    neutrophil recovery. What should be done ?

4
Topics 5 lessons in 20 min
  • Patient has started on voriconazole for possible
    invasive pulmonary aspergillosis and is not doing
    well. What should we do ?
  • Serial assessment of galactomannan antigenemia
  • How useful is it in therapeutic monitoring ?
  • Does it perform differently for different
    antifungal agents?

5
Therapeutic monitoring of Invasive Aspergillosis
(IA) is based on
  • Clinical outcome
  • Follow-up radiological findings (CT scan)
  • Surrogate detection biomarkers (specially
    galactomannan)

6
Lesson 1 Worsening of radiological findings in
a pt recovering from neutropenia
  • Day 10 allo BMT pt has started on voriconazole
    for fever, pleuritic pain and 2 pulmonary
    macronodules on chest CT, one of them surrounded
    by a perimeter of ground-glass opacity (halo
    sign). ANC 10.
  • 15 days later, Day 25, ANC 500, afebrile for
    last 7 days, and less thoracic pain. Follow-up
    chest CT worsening of radiological findings
    halo sign nodule increased and now air
    crescent sign is evident other nodule is
    bigger, and a new nodule appeared.
  • What should be done ?

7
Allo HSCT, neutropenic phaseCT halo sign
Voriconazole was started
8
Worsening of radiological findings coincident
with neutrophil recovery. Pt doing better
clinically
9
Lesson 1 Worsening of radiological findings
with neutrophil recovery
  • How is the patient doing ?
  • Better !
  • Rule of Internal Medicine If what you are doing
    seems to be working, keep doing it !
  • It is common to find worsening of chest
    radiological findings in a pt with IA recovering
    from neutropenia.
  • If patient is doing well clinically, keep doing
    it !

10
Lesson 2 Worsening of radiological findings
with neutrophil recovery
  • AND IF
  • Pt experienced transient clinical AND
    radiological pulmonary deterioration during
    neutrophil recovery ?
  • Galactomannan (GMI) can be useful in this
    setting.
  • Normalization of serum GMI ? immune
    reconstitution inflamatory syndrome (IRIS) has to
    be suspected
  • Keep the same antifungal therapy and consider
    corticosteroids
  • Miceli MH, Maertens J, Buve K, et al.
    Immune reconstitution inflammatory syndrome in
    cancer patients with pulmonary aspergillosis
    recovering from neutropenia proof of principle,
    description, and clinical and research
    implictions. Cancer 2007110-11220.

11
Lesson 3 Pt on voriconaze for possible IA and
is not doing well. What should be done ?
  • AML pt, 10 days after starting first chemo
    presented thoracic pain and fever. Chest X ray
    was normal. WBC 200. Weight 80 kg.
  • What should be done ?

12
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13
Lesson 3 Pt on voriconazole for possible IA is
not doing well. What should be done ?
  • Voriconazole was started 6mg/kg IV q12h x 2
    doses, followed by 4mg/kg IV q12h x 1 week,
  • folllowed by 200mg PO q 12h.
  • 7 days later, pt is still febrile, thoracic pain
    is worsen, and presents mild shorten of breath.
    ANC 100.
  • What should be done ?

14
Lesson 3 Pt on voriconaze for possible IA and
is not doing well. What should be done ?
  • Internal Medicine Rule If what you are doing
    seems NOT to be working, think to do something
    different!
  • What should be done ?
  • Repeat chest CT
  • Ask for galactomannan (and ß 1-3 glucan, and PCR
    ??)
  • (upgrade the diagnosis !)
  • Is it possible to decrease immunosuppression ?
  • (Not in this case, but in GVHD...)

15
Lesson 3 Pt on voriconaze for possible IA and
is not doing well. What should be done ?
  • What should be done ?
  • Optimize vorico dosage ? Drug level ?
  • On 200mg PO q12h, but
  • 4mg/kg x 80 kg 320mg/dose
  • 200mg PO q12h ? 300mg PO q12h
  • Reevaluate the diagnosis BAL ?
  • Could it be zygomycosis ?
  • Change antifungal agent or combination therapy ?

16
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17
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18
  • Pleural effusion aspiration yielded
  • Absidia sp (Zygomycosis or mucormycosis, what
    term do you prefer ?
  • Order Mucorales subphylum Mucormycotina)

Hibbett DS, et al. A higher-level phylogenetic
classification of the fungi. Mycol Res
2007111509-47.
19
Zygomycosis or Mucormycosis
  • Rhizopus arrhizus (oryzae)
  • Rhizopus microsporus var rhizopodiformis
  • Rhizomucor pusillus
  • Cunninghamella bertholletiae
  • Apophysomyces elegans
  • Saksenaea vasiformis
  • Conidiobolus coronatus
  • Rhizopus microsporus var microsporus
  • Absidia corymbifera
  • Mucor circinelloides
  • Syncephalastrum racemosum
  • Cokeromyces recurvatus
  • Mortierella spp
  • Basidiobolus ranarum (haptosporus)

20
Early Diagnosis of Pulmonary Mucormycosis
  • Presence of multiple ( gt 10) macronodules on
    chest CT 1
  • Presence of pleural effusion 1
  • Reverse halo sign focal area of ground-glass
    attenuation surrounded by a ring of consolidation
    2
  • Spellberg, B et al. Recent Advances in the
    Management of Mucormycosis
  • From Bench to Bedside. Clinical Infectious
    Diseases 2009 48174351
  • 1 Chamillos G, et al. Clin Infect Dis
    20054160-6
  • 2 Wahba H, et al. Clin Infect Dis
    2008461733-7.

21
CT halo sign IPA is the first
diagnosis (Aspergillosis is highly likely,
though not pathognomonic)
Fig 1. CT halo sign. This first thoracic CT scan
(day 0) was performed in a patient with febrile
neutropenic leukemia. The ground glass
attenuation surrounding the nodule was considered
a typical halo sign. The diagnosis of IPA was
considered highly likely, and antifungal
treatment was started.
Journal of Clinical Oncology, Vol 19, No 1
(January 1), 2001 pp 253-259
22
CT Reversed Halo Sign Mucormycosis is the
first diagnosis It is na early sign, seen in
4 of pts with pulmonary mold infections,
usually with zygomycosis (mucormycosis)
Images from a 49-year-old woman who presented
with febrile neutropenia during treatment for
recurrent acute myelogenous leukemia. A,
Contrast-enhanced chest CT image at presentation,
showing the reversed halo sign, a solid ring
(arrows) with central ground-glass opacities.
Clinical Infectious Diseases 2008 4617337
23
Serial assessment of galactomannan antigenemia
24
Serum Aspergillus galactomannan antigen values
correlate with outcome of invasive aspergillosis
  • 56 adults with hematologic cancer (90 had
    myeloma)
  • 2 consecutive positive serum galactomannan (GMI)
    gt 0.5
  • The survival outcome of patients with
    aspergillosis strongly correlated with serum GMI,
    using a kappa correlation coefficient test (KCC)

Woods, G et al. Serum Aspergillus Galactomannan
Antigen Values Strongly Correlate With Outcome of
Invasive Aspergillosis A Study of 56 Patients
With Hematologic Cancer. Cancer. 2007 Aug
15110(4)830-4
25
Woods, G et al. Serum Aspergillus Galactomannan
Antigen Values Strongly Correlate With Outcome of
Invasive Aspergillosis A Study of 56 Patients
With Hematologic Cancer. Cancer. 2007 Aug
15110(4)830-4
26
Strong Correlation between Serum Aspergillus
Gallactomannan Index and Outcome of Aspergillosis
in Patients with Hematological Cancer Clinical
and Research Implications
  • Review of 27 studies, 257 pts (chemo and
    BMT/HSCT) with proven or probable IA
  • Correlation between GMI and aspergillosis outcome
    using the k correlation coefficient (KCC)
  • Decreasing GMIs are associated with response and
    that persistent or increasing values indicate
    progressive aspergillosis

Miceli, MH et al. Strong Correlation between
Serum Aspergillus Galactomannan Index and Outcome
of Aspergillosis in Patients with Hematological
Cancer Clinical and Research Implications. Clinic
al Infectious Diseases 2008 46141222
27
Strong Correlation between Serum Aspergillus
Gallactomannan Index and Outcome of Aspergillosis
in Patients with Hematological Cancer Clinical
and Research Implications
  • Serum GMI is a good marker of aspergillosis
    outcome
  • Strong correlation between GMI and survival

Miceli, MH et al. Strong Correlation between
Serum Aspergillus Galactomannan Index and Outcome
of Aspergillosis in Patients with Hematological
Cancer Clinical and Research Implications. Clinic
al Infectious Diseases 2008 46141222
28
Invasive Aspergillosis in Allogeneic Stem Cell
Transplant Recipients increasing antigenemia is
associated with progressive disease
  • Good and bad responses (37 allogeneic SCT
    recipients)
  • Baseline GMI values were not significantly
    different between 2 groups
  • GMI values became significantly higher in the
    treatment failure group during follow-up (bad
    response)
  • An increase in the GMI value of 1.0 over the
    baseline value during the first week of treatment
    was predictive of treatment failure (lt50 of
    patients with progressive disease)

Boutboul F, et al. Clin
Inf Dis 2002 34939-43.
29
Galactomannan and Caspofungin Caution in
interpretation
  • Animal models suggest that neutropenic rabbits
    given echinocandins for treatment of IA may have
    persistent galactomannan antigenemia or a
    paradoxical increase in antigen titer, despite
    clinical and/or radiographic evidence of
    improvement.

Petraitiene R,et al. Antimicrob Agents Chemother
2002 461223. Petraitis V, et al. Antimicrob
Agents Chemother 2002 46185769. Scotter JM et
al. Clinical and Diagnostic Laboratory
immunology, 2005, p. 13221327
30
Galactomannan and Caspofungin Controversial
findings
A, Galactomannan ELISA results for 5 patients who
had favorable outcomes with caspofungin therapy.
Day 1 is the first day of caspofungin therapy.
Clinical Infectious Diseases 2005 41e914
31
Galactomannan and Caspofungin Controversial
findings
C, ELISA results for patient 11, showing the
temporal association of clinical, radiographic,
and serological findings. The patient experienced
an unfavorable response to caspofungin therapy,
but ELISA results had become negative (i.e., OD
values were !1). Exam examination RUL, right
upper lobe.
Clinical Infectious Diseases 2005 41e914
32
Take Home Messages 5 Lessons
  • Worsening of radiological findings with
    neutrophil recovery
  • If pt is doing well clinically,
    keep doing it
  • Pt experienced transient clinical and
    radiological pulmonary deterioration during
    neutrophil recovery.
  • If normalization of serum GMI ? immune
    reconstitution inflamatory syndrome (IRIS) has to
    be suspected !
  • Keep the same antifungal therapy and consider
    corticosteroids

33
Take Home Messages 4 Lessons
  • 3) Patient has started on voriconazole for
    possible invasive pulmonary aspergillosis and is
    not doing well. What should we do ?
  • Upgrade the diagnosis possible ?
    probable IA
  • Look for multiple macronodules,
    pleural effusion, or reverse halo sign ?
    mucormycosis

34
Take Home Messages 5 Lessons
  • 4) Serum galactomannan index strongly correlates
    with survival and response outcome in patients
    with IA
  • 5) Galactomannan and caspofungin (echinocandins)
    caution
  • in interpretation
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