Aspergillosis in Pediatric Patients

Transcription

1 Aspergillosis in Pediatric Patients Emmanuel Roilides, MD, PhD, FIDSA, FAAM 3rd Department of Pediatrics Aristotle University School of Medicine Thessaloniki, Greece 1

2 Transparency disclosures Independent Contractor (research grants) of significant value from Pfizer, Gilead, Merck, Sanofi, Astellas, Astra-Zeneca, Cubist Scientific Advisor (Review Panel or Advisory Committee) of Schering, Gilead, Astellas, Pfizer, Merck Speaker's Bureau of Gilead, Pfizer, Merck, Aventis, Astellas, GSK 2

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5 1.5-yr old boy with ALL, fever and an infiltrate in his lung Had multiple episodes of fever+neutropenia treated with broad spectrum antibiotics An implantable (Port a cath ) catheter in place Poor general condition Challenges: Is this aspergillosis or another more rare invasive mold disease? Is galactomannan or PCR appropriate assays in pediatrics? How should I treat this young patient with suspected pulmonary aspergillosis? 5

6 Why a separate talk for aspergillosis in pediatrics? Differences from adults children are not little adults Epidemiology Diagnosis Management 6

7 Forms & sites of Aspergillus infection Transient asymptomatic colonization Pulmonary hypersensitivity reactions (ABPA) Colonization of airway cavities Tissue invasive infection (IA) The most frequent site of IA lung Dissemination particularly to CNS in ~30% 7

8 Which pediatric pts suffer from invasive aspergillosis? Neonates Host Pediatric ICU patients Primary immunodeficiencies (CGD) Acquired immunodeficiencies (hem/onc, SOT) Cystic fibrosis Candida IFIs More Candida, less Aspergillus (in immunocompromised pts) Aspergillus and other filamentous fungi Aspergillus, Candida, others Aspergillus, other filamentous fungi 8

9 Aspergillosis in pediatric vs. adult pts Similarities Vulnerability to IA Presentations Distributions Patterns of IA Differences Underlying disorders (ie type of leukemia) Co-morbidities Fungal pathogens - species Pharmacology Dosing of antifungal agents Absence of RCTs for guidance of evidence-based decisions in management 9

10 Risk factors for invasive aspergillosis in children: are they different from adults? Children with acquired immunodeficiencies Treatment for cancer Bone marrow failure syndromes Allogeneic HSCT Solid organ transplantation Children with primary immunodeficiencies Defects of phagocytic host defenses Children receiving immunosuppressive therapy Children with chronic airway diseases (i.e. CF) Low-birthweight infants Children with advanced HIV infection Children with acute illnesses or trauma 10

11 Risk for IA in Cancer/HSCT Pediatric Pts Risk High ( 10%) Low ( 5%)* Sporadic occurrence* Patient population Acute myeloblastic leukemia Recurrent acute leukemia s Allogeneic HSCT High-risk acute lymphoblastic leukemia** Acute lymphoblastic leukemia** Non-Hodgkin lymphoma s Autologous HSCT Solid tumors Brain tumors Hodgkin s lymphoma * Low and sporadic risks are not equal to no risk ** Depending on protocol and additional factors, risk for IFD may be near or >10% Groll et al. 1999; Hovi et al. 2000; Lin et al. 2001; Benjamin et al. 2002; Zaoutis et al. 2004; Zaoutis et al. 2005; Zaoutis et al. 2006; Rosen et al. 2005; Kobayashi et al. 2008; Kaya et al. 2009; Castagnola et al. 2010; Hale et al. 2010; Mor et al

12 Invasive aspergillosis Underlying diseases Allogenic SCT 4.5% AML 4.0% Risk factors Corticosteroid Therapy 69% Neutropenia (>3 days) 59% Primary immunodeficiency 3.2% Immunosuppressive Therapy 43% Aplastic anemia 1.4% ALL 0.6% Lymphoma 0.4% Autologous BMT 0.3% Solid tumors 0.1% Malignancy (non BMT) 38% Allogeneic SCT 37% GVHD 12% Prim immunodeficiency 12% Solid Organ Transplant 11% Zaoutis et al. Pediatrics 2006;117:711 Burgos et al. Pediatrics. 2008;121:

13 Primary immunodeficiencies and risk for invasive aspergillosis IFD unlikely Humoral X-linked/autosomal recessive agammaglobulinaemia IgA deficiency Complement Classic, late or alternative complement defects Mannose-binding lectin pathway defects Variable risk for IFD Phagocytic Chronic granulomatous disease, Myeloperoxidase deficiency Leukocyte adhesion deficiency, Congenital neutropenias Cellular and combined Severe combined immunodeficiency, DiGeorge syndrome X-linked hyper-igm syndrome, Wiskott-Aldrich syndrome Other Hyper-IgE syndrome, defects in the IFN-g-IL-12 axis Antachopoulos C & Roilides E. Clin Microbiol Infect 2010;16:

14 IFD (+IA) in CGD patients Of 155 CGD patients, 42.6% developed at least one episode of IFD 0.040/patient-years (1862 patient-years of total follow-up) The most common fungal genus was Aspergillus spp. accounting for 40% of all IFDs CGD, chronic granulomatous disease; IFD, invasive fungal disease. Beaute J et al. Ped Infect Dis J 2011:30;57 62.

15 Invasive aspergillosis: CGD vs haematological patients Similarities A. fumigatus is the most frequent Aspergillus spp. Mostly pneumonia Differences A. nidulans important and fatal pathogen Atypical symptoms and signs of infection Concurrent bacterial and fungal infections Lack of angio-invasion (no halo sign, cavitation, infarction, etc.) No GM circulation, low sensitivity in the serum CGD, chronic granulomatous disease; GM, galactomannan.

16 Aspergillus osteomyelitis in CGD patients 46 cases of osteomyelitis due to Aspergillus spp. (43 CGD patients) 50% due to A. fumigatus 43.5% due to A. nidulans 2.17% due to A. flavus A. nidulans: Causes osteomyelitis frequently Affects small bones in connection with lungs more frequently Is associated with higher mortality than A. fumigatus CGD, chronic granulomatous disease; GM, galactomannan. Dotis J, Roilides E. Mycoses 2011;54:e

17 Standard and Newer Diagnostic Markers Standard diagnostic markers in pediatric patients do not differ from adults Cultures, microscopy, histology, etc Differences on newer diagnostic markers, CT imaging Imaging studies as mandated by clinical findings Antigen markers (GM & BDG assays) PCR 17

18 Radiologic features of IPA In adults Halo sign, crescent or meniscus sign, peripheral nodules In children Atypical, nodules, no halo sign frequently, crescent sign rarely 18

19 Typical radiologic features of IPA Nodule with halo sign Crescent sign 19

20 Tragiannidis et al. Clin Infect Dis 2011 Burgos et al. Pediatrics

21 Imaging studies in children Tragiannidis et al CID 2011 Thomas et al Pediatr Radiol

22 GM, BG & PCR for detection of IFD in hem/onc pediatric patients Systematic review and analysis of the available data for GM, BG & PCR based assays to detect IFD in pts w pediatric cancer or HSCT used as screening tools during immunosuppression diagnostic tests in patients presenting with FN 1532 studies screened, 25 studies reported on GM (n=19), BG (n=3), PCR (n=11) All fungal biomarkers demonstrated highly variable sensitivity, specificity, and positive predictive values, and these were generally poor in both clinical settings GM negative predictive values were high (85%-100% for screening and 70%-100% in the diagnostic setting) However, failure to identify non-aspergillus molds limits its usefulness Future work could focus on the usefulness of combinations of fungal biomarkers in pediatric cancer and HSCT Lehrnbecher et al. / CID 2016; 63:

23 Recommendation Clinical decisions in children currently should not be based on BG Lehrnbecher et al. / CID 2016; 63:

24 PCR for Aspergillus European Aspergillus PCR Initiative (EAPCRI) Yes Will be added in EORTC/MSG definitions for diagnosis of IA A meta-analysis of diagnostic performance: 2 (+) PCR highly indicative of an active Aspergillus sp. infection Use of EAPCRI recommendations by clinical laboratories can further enhance PCR performance Arvanitis et al. JCM 2014; 52:

25 Lehrnbecher et al. / CID 2016; 63:

26 Prospective biomarker screening for diagnosis of IA in high-risk pediatric pts 39 children monitored shortly before and after allogeneic SCT 2x/wk by GM and pan-aspergillus PCR Clinical data recorded and IA classified by EORTC/MSG criteria Among 39 high-risk children, 4 pts (10.3%) with probable and 2 (5.1%) with possible IA. All pts with probable IA were repeatedly positive for both tests (mean of 9.5 and 6.8 positive GM and PCR samples), whereas both possible cases were detected by PCR Sensitivity and specificity was 67% and 89% for GM, 100% and 63% for PCR. Positive and negative predictive values were 50% and 100% for GM and 27% and 100% for PCR. For the combined testing approach both values were 100%. Combined monitoring for GM and fungal DNA results in a high diagnostic accuracy also in paediatric patients. Loffler et al. JCM 2016; accepted 26

27 GM in BAL / CSF 1 study evaluating GM in BAL reported sensitivity, specificity, PPV, and NPV for proven/probable IA of 82%, 88%, 82%, and 87%, respectively GM testing in the CNS is supported by case reports and a small case series: GM levels in the CSF of 5 patients with probable CNS aspergillosis were significantly higher than those of 16 control patients indicating the potential diagnostic value of GM in CSF de Mol M, et al. Pediatr Pulmonol 2013; 48: Viscoli et al. JCM 40: 1496, 2002 Roilides et al. Pediatr Nephrol 18: 450,

28 Management As in adults, cornerstones for successful management of invasive aspergillosis include prompt initiation of appropriate antifungal therapy reversal of the patient s underlying deficiency in host defenses if exists and is feasible, and in select circumstances, surgical interventions 28

29 Antifungal agents for therapy of IA in pediatric pts P. Frange et al. / Me decine et maladies infectieuses 45 (2015) 189

30 Antifungal prophylaxis High-risk populations with incidence rates of ~10% or higher acute leukemia, bone marrow failure syndromes, allogeneic HSCT particularly when immunosuppression is augmented for GVHD primary immunodeficiency, ie CGD Posaconazole is not approved for <13 years Voriconazole is not approved for <2years

31 The Lancet Oncology 2014;15:e Based on Efficacy in phase II and III trials in adults Availability / assessment of pediatric quality PK data safety data supportive efficacy data regulatory approval 31

32 Targeted therapy Options for first-line antifungal treatment of invasive aspergillosis in patients 2 years voriconazole or liposomal amphotericin B For children <2 years liposomal amphotericin B is the only option with an existing pediatric dosage and safety profile 32

33 Conclusions Primary immunodeficiencies are an important part of ped. pts prone to IA Diagnosis in young children is more challenging due to less helpful laboratory findings Antifungal agents not all appropriately studied, formulated for infants & children Antifungal drug stewardship a necessary complement of recently developed guidelines 33

34 DOMINIC: Diagnosis and Outcomes of Pulmonary Mold Infections in Immunocompromised Children

35 European Pediatric Mycology Estonia Germany Greece Italy Netherlands UK Network Steering Group: A. Warris (chair), A. Groll, A. Cant, C. Giaquinto, E. Castagnola, E. Roilides, I. Lutsar, M. Sharland, N. Klein, P. Manzoni, R. Brüggemann, T. Lehrnbecher

36 Thank you