1. Élie AZOULAY Hôpital Saint-Louis, Service de Réanimation Médicale Université Paris-Diderot, Sorbonne Paris-Cité Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH)

3. Respiratory events in hematology patients Author PatientsIncidenceTimeFindingMortality Azoulay 2004 Medicine All7-12% (203/3782) ~Undetermined diagnosis 47.7% Puig. 2007 Leuk Lymphoma Auto- BMT 15% (49/326) J11Myeloma Neutropenia 51% vs. 8% Specchia 2003 Leuk Lymphoma AL27.7% (80/288) /AML>ALL No remission Age Sortie d’aplasie Chaoui 2004 Leukemia AL46% (30/65) /ICU admission35% vs. 6%

5. Three major advances: -Leukemic infiltrates -Non invasive diagnostic strategy -ARDS

6. Pneumonia during chemotherapy in Patients with Acute Leukemia 801 AML/ ALL/ MDS 85 Early Stage = 11% 148 throughout induction = 21% MDS > AML > ALL Risk factor for pneumonia are Age>60 years, AML, Low platelet count, Low albumin level, Neutropenia 28-day mortality 6% without pneumonia 26% with pneumonia ↑ ICU length of stay ↑ Hospital length of stay ↑ Costs Garcia et al. Annals of the ATS, Vol. 10, No. 5 (2013), pp. 432-440.

8. Leukemic infiltrates: Vincent F, Rev Mal Respir 2012 Pulmonary leukostasis Leukemic infiltration Lysis pneumopathy

9. Pulmonary leukostasis: ALI Quantitative “Pulmonary hyperviscosity” Rapidly growing hyperleukocytic AML. Constant if >200 000/mm3. Endothelial injury and activation from microvascular invasion related to hyperviscosity, leukocytic microthrombi, oxygen steal and hypoxia.

10. Clinical manifestations of leukostasis

11. Rapidly rising white-cell count Cell type (monoblasts) A postmortem examination revealed profound leukostasis in the heart, lungs, adrenal glands, liver, and spleen.

12. Sludging of high numbers of leukocytes in small vessels (brain, lungs, and kidneys)

13. Leukemic pulmonary infiltrates Blasts are aggregated in vascular lumens The infiltrates typically follow the lymphatic routes along the bronchovascular bundles, interlobular septa, and pleural interstitial tissue.

14. Lysis pneumopathy: DAD Occurs immediately or early after chemotherapy Diffuse alveolar damage

15. leukemic infiltration of the alveolar capillaries LEUKEMIC INFILTRATION Filling of a pulmonary artery with leukemic cells, as well as leukemic infiltration of alveolar capillaries. LEUKOSTASIS

16. Catching up errors Valentino et al. CHEST. 2005,128(5):3629-3633

18. monoblaste Timing

21. Poumon leucémique: prise en charge Infiltration pure: VNI, chimiothérapie classique, inhibition de l’adhésion du monoblaste sur l’endothélium pulmonaire (DXM?) Leucostase ou leucostase + infiltration: Essai de VNI, cytoréduction (Hydréa) DXM? Poumon de lyse (DAD) Intubation et optimisation des échanges gazeux Attendre et éviter l’infection Moreau AS et al. Submitted 2012 Mamez & Lengliné. In preparation

22. Three major advances: -Leukemic infiltrates -Non invasive diagnostic strategy -ARDS

23. Invasive or noninvasive ? Invasive: Biopsy Semi-invasive: FO-BAL Non invasive: Blood cultures Sputa Induced sputa NPA/swabs Viral PCR Pan-PCR Mass spectrometry Antigenes Echography HRCT

25. Clinical Assessment for Identifying Causes of Acute Respiratory Failure in Cancer Patients Schnell D et al. European Respiratory Journal 2012

26. Culture based and non-culture based tools Culture-based Sang Crachats LBA Pathogènes colonisant Faux positifs Faux négatifs Pas de gold standard Non culture-based Scanner Aspergillus galactomannan (GM), 1,3-beta-D-glucan Méthodes moléculaires Trop sensibles? Colonisation ou infection Pertinence?

27. The MiniMax study, Azoulay et al. 2010

29. Diagnoses CPO: 10 Fungi: 23 Aspergilus: 18 Virus: 26 Malignancy: 16 Pneumocystis: 19 Bacteria: 86 Diagnosis made by NIT 10 (100%) 22 (95.6%) 17 (94%) 24 (92.3%) 13 (81%) 15 (79%) 57 (66.3%)

30. Need for mechanical ventilation P=0.62

31. Day-28 survival

32. MiniMax dans le détail Rentabilité du LBA Rentabilité du LBA TOUS18%Nodules centrolobulaires 5% Neutropéniques10%Nodules sous pleuraux 4% Non Neutropéniques 20%Consolidations alvéolaires 20% Lymphoïde40%Verre dépoli diffus isolé 40%

33. MiniMax 2 Corrélation clinico – radiographique – morphologique Stratégie diagnostique adaptative Utilisation de PCR pan-pathogène: bactéries, fungiques, virus … Critères de jugement clinique pour éviter d’inclure 2000 patients: morbi-mortalité

34. Three major advances: -Leukemic infiltrates -Non invasive diagnostic strategy -ARDS

35. Five evidence in the literature Heterogeneous (at least) disease Few positive trials, good negative trials Clinical – pathological discrepancies Berlin Definition Scarce data

36. ARDS and neutropenia Funny paradox (Frederic Ognibene) Pathophysiology Infection / infiltration / toxicity Used to be associated with poor outcomes Neutropenia recovery

37. Two recent papers Turkoglu et al. (2013) Acute respiratory distress syndrome in patients with hematological malignancies. Hematology 18:123-130 68 patients with hematological malignancies and ARDS. PO2/FiO2 was 104 (74-165). 10 (15%) NIV, 21 (31%) VM, and 36 (53%) both ICU mortality was 77% in the cohort. >two organ failures was the only independent risk factor for mortality (P = 0.045), whereas NIV was associated with low mortality (P = 0.001). Soubani et al. (2014) The outcome of cancer patients with acute respiratory distress syndrome. J Crit Care 29:183 e187-183 e112 ARDS Network randomized controlled trials: 116/ 2515 patients Patients with cancer had significantly higher mortality (55.2%) compared with those without cancer (24.3%) (P <.0001): OR 2.54 (95% confidence interval [CI], 1.570-4.120). APACHE III and age

38. Grrr-OH, 1990-2011

39. Median (IQR) or n (%) Study population (N=1004) Survivors (N=364) Non- survivors (N=640) P value Male gender 642 (63.9%)240 (65.9%)402 (62.8%) 0.32 Age (y) 58 [48-67]57 [47-67]58 [48-67] 0.33 Underlying malignancy Acute leukemia 298 (29.7%) 96 (26.4%)202 (31.6%)0.08 Non-Hodgkin’s lymphoma 318 (31.7%) 115 (31.6%)203 (31.7%)0.97 Myeloma 113 (11.3%) 34 (9.3%) 79 (12.3%)<0.0001 Solid tumor 147 (14.6%) 60 (16.5%) 87 (13.6%)0.21 Miscellaneous 95 (9.5%) 46 (12.6%) 48 (7.7%)0.01 Allogeneic BMT/HSTC* 115 (11.5%) 36 (9.9%)79 (12.3%)0.23 Neutropenia 444 (44.2%)148 (40.7%)296 (46.3%)0.08 Stage 0.0003 Progressive 458 (45.6%)171 (47.0%)287 (44.8%) Partial/complete remission 237 (23.6%)100 (27.4%)137 (21.4%) Newly diagnosed 72 (7.2%) 33 (9.1%) 39 (6.1%) Unknown 237 (23.6%) 60 (16.5%)177 (27.7%)

40. Etiologies Median (IQR) or n (%). Study populati on (N=1004) Survivors (N=364) Non- survivors (N=640) P value* Cause of ARDS Pulmonary infection # 662 (65.9%) 281 (77.2%)381 (59.5%)<0.0001 Secondary ARDS # 225 (22.4%) 55 (15.1%)170 (26.6%)<0.0001 Fungal infection & 293 (30.7%) 83 (23.2%) 210 (35.1%)0.0001 Pneumocystis 64 (6.4%) 30 (8.2%) 34 (5.3%)0.07 No definite diagnosis § 41 (5.7%) 12 (4.5%) 29 (6.4%)0.29 Organ Support NIV NIV failure 387 (38.6%) 276 (27.5%) 174 (47.8%) 103 (28.3%) 213 (33.3%) 173 (27.0%) <0.0001 0.67 Endotracheal MV 893 (88.9%)293 (80.5%)600 (93.8%)<0.0001 Vasopressors 731 (72.8%)241 (66.2%)490 (76.6%)0.0004 Renal replacement therapy 306 (30.5%) 99 (27.2%)207 (32.3%)0.09

41. Berlin definition

42. 1990-2001: trends in outcomes

43. Determinants of hospital mortality OR95%CIP value Solid tumor 0.51(0.34-0.77)0.002 Need for emergency surgery 0.61(0.35-1.05)0.07 Allogeneic BMT/HSCT 1.71(1.07-2.71)0.04 mSOFA (per point) 1.11(1.06-1.16)<0.001 Cause of respiratory involvement No definite diagnosis 1(Reference)- Primary ARDS 0.41(0.20-0.88)0.02 Secondary ARDS 0.90(0.41-2.01)0.80 Invasive fungal infection 1.72(1.25-2.37)0.001 Ventilation NIV 1(Reference)- NIV failure 2.93(1.80-4.79)<0.001 Endotracheal MV 3.24(2.02-5.24)<0.001 ARDS severity Mild 1(Reference)- Moderate 1.25(0.88-1.78)0.22 Severe 1.61(1.10-2.36)0.01

44. ARDS and Aspergillus Monocyte de-activation Copland, AJRCCM, 03 T cells switch to TH2/TH3 PLötz et al, Crit Care Med, 04 Increase anti-inflammatory CK (IL-10, TNF  -r1, IL-1ra) Park et al, AJRCCM, 01 In a case-control study, ARDS was independently associated with positive Aspergillus in the LRT OR= 2,36 [1,14- 4,89] (p=0,02) Vandewoude, Crit Care, 06

45. 8/64 patients with IPA

46. Invasive fungal infection and ARDS Need for additional descriptive data Need for better understanding of the risk factors Differences across IFI IPA Zygo Other mould / fungi Pneumocystis Towards primary preventive strategies? Noninvasive fungal diagnostic kit

47. Second confirmatory data set First study to be launched in the European group Observational data EORTC criteria (customized) Relationship between ARDS etiology and outcomes Prophylaxis

48. Three major advances: -Leukemic infiltrates -Non invasive diagnostic strategy -ARDS