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
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
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 ?
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?
Therapeutic monitoring of Invasive
Aspergillosis (IA) is based on:
• Clinical outcome
• Follow-up radiological findings (CT scan)
• Surrogate detection biomarkers (specially
galactomannan)
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 ?
Allo HSCT, neutropenic phase
CT halo sign
Voriconazole was started
Worsening of radiological findings coincident
with neutrophil recovery.
Pt doing better clinically
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” !
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 2007;110-112:20.
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 ?
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 ?
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 β 1-3 glucan, and PCR ??)
(upgrade the diagnosis !)
 Is it possible to decrease immunosuppression ?
(Not in this case, but in GVHD...)
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 ?
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 2007;111:509-47.
Zygomycosis or Mucormycosis
• Rhizopus arrhizus (oryzae)
• Rhizopus microsporus var
rhizopodiformis
• Rhizopus microsporus var
microsporus
• Absidia corymbifera
• Rhizomucor pusillus
• Mucor circinelloides
• Cunninghamella bertholletiae
• Syncephalastrum racemosum
• Apophysomyces elegans
• Cokeromyces recurvatus
• Saksenaea vasiformis
• Mortierella spp
• Conidiobolus coronatus
• Basidiobolus ranarum
(haptosporus)
Early Diagnosis of Pulmonary Mucormycosis
• Presence of multiple ( > 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; 48:1743–51
1 Chamillos G, et al. Clin Infect Dis 2005;41:60-6
2 Wahba H, et al. Clin Infect Dis 2008;46:1733-7.
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
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; 46:1733–7
Serial assessment of galactomannan
antigenemia
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) > 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 15;110(4):830-4
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 15;110(4):830-4
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.
Clinical Infectious Diseases 2008; 46:1412–22
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.
Clinical Infectious Diseases 2008; 46:1412–22
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 (<50% of patients with progressive disease)
Boutboul F, et al. Clin Inf Dis 2002; 34:939-43.
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; 46:12–23.
Petraitis V, et al. Antimicrob Agents Chemother 2002; 46:1857–69.
Scotter JM et al. Clinical and Diagnostic Laboratory immunology, 2005, p. 1322–1327
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; 41:e9–14
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; 41:e9–14
Take Home Messages: 5 Lessons
1) Worsening of radiological findings with neutrophil recovery
“If pt is doing well clinically, keep doing it”
2) 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
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
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