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 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 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 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 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 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 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)

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.

IPA is “the first diagnosis” 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 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

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