Monitoring antifungal treatment response in neutropenic patient with aspergillosis

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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

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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

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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 ?

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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?

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Therapeutic monitoring of Invasive Aspergillosis
(IA) is based on

• Clinical outcome
• Follow-up radiological findings (CT scan)
• Surrogate detection biomarkers (specially
  galactomannan)

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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 ?

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Allo HSCT, neutropenic phaseCT halo sign
Voriconazole was started
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Worsening of radiological findings coincident
with neutrophil recovery. Pt doing better
clinically
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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 !

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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.

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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 ?

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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 ?

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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...)

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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 ?

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• 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.
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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)

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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.

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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
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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
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Serial assessment of galactomannan antigenemia
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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
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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
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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
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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
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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.
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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
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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
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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
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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

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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

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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