1. Finding Cures. Saving Children. Saad Ghafoor, M.D. Division of Critical Care Medicine St. Jude Children’s Research Hospital Shaukat Khanum symposium November 29, 2013 Supportive Care in Allo-Transplant Patients The St. Jude Experience

2. Finding Cures. Saving Children. www.stjude.org

3. Finding Cures. Saving Children. The vision of Danny Thomas “No child should die in the dawn of life” ~Danny Thomas

4. Finding Cures. Saving Children. Consider then... and now Founded in 1962 Focus on pediatric cancer 125 employees Annual budget of $1M Acute lymphocytic leukemia (ALL) 4% survival Now in 2013 Focus remains pediatric cancer and catastrophic diseases 3,600 employees Annual budget of over $450M Acute lymphocytic leukemia (ALL) 94% survival

5. Finding Cures. Saving Children. “ The ABCs of Cancer ” “K” is for Kemo (chemo) “N” is for Needles “V” is for Vomit “Z” is for Zofran (ondansetron) “D” is for Dreams

6. Finding Cures. Saving Children. Our ICU patient population 350-390 ICU admissions each year Mix of medical and surgical patients (2/3 medical) 120-180 patients/year will require mechanical ventilation for respiratory failure Approximately half of our mechanically ventilated patients have previously undergone hematopoietic stem cell transplantation (HSCT) High incidence of multi-system organ failure

7. Finding Cures. Saving Children. Infectious pneumonia (bacterial, viral, fungal) Pulmonary fibrosis Bronchiolitis obliterans with organizing pneumonia (BOOP) Idiopathic pneumonia syndrome ARDS and/or acute lung injury Common themes: loss of alveolar air space (de-recruitment) atypically long courses of ventilator support multi-system organ failure Causes of respiratory failure

8. Finding Cures. Saving Children. Childhood cancer in general Data indicates that 84% of newly diagnosed children with cancer will require hospitalization, and 50% will require ICU services Childhood cancer accounts for approximately 3% of all pediatric ICU admissions 15-25% of pediatric HSCT patients will require mechanical ventilation Rosenman MB et al., J Pediatr Hematol Oncol (2005) Dalton HJ et al., Pediatr Hematol Oncol (2003) Rossi R et al., Crit Care Med (1999) Jacobe SJ et al., Crit Care Med (2003 ) Warwick AB et al., Bone Marrow Transplant (1998) Hayes C et al., Br J Haematol (1998) Diaz de Heredia C et al., Bone Marrow Transplant (1999 ) Diaz MA et al., Haematologica (2002 )

9. Finding Cures. Saving Children. Outcomes of HSCT patients after mechanical ventilation Survival rates for post-HSCT patients who require mechanical ventilation range from 9 to 46% with most reports comprising retrospective reviews at single institutions with small numbers of patients (average < 50 patients/publication) Great Ormond Street Hospital for Children, London: 15/31 ventilated HSCT patients survived to ICU discharge, 3+ organ system failure was associated with < 10% chance of survival Martin PL, Respir Care Clin (2006) Jacobe SJ et al., Crit Care Med (2003)

10. Finding Cures. Saving Children. Pediatric Critical Care Medicine - 2008

11. Finding Cures. Saving Children. Hypotheses to be tested 1) Outcomes of mechanical ventilation are more favorable for non-transplant oncology patients than for those undergoing HSCT 2) Outcomes of both populations are improving over time 3) There are factors available during the time of mechanical ventilation that will identify those patients with a lower likelihood of survival

12. Finding Cures. Saving Children. Materials and methods Comprehensive retrospective review of the St. Jude respiratory failure database to identify all intubated and mechanically ventilated patients from January 1996 through December 2004 Inclusion limited to patients with an established diagnosis of cancer or those who had undergone HSCT for any reason (non-malignant included) Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

13. Finding Cures. Saving Children. patient demographics and diagnoses use of and type of HSCT grade and presence of graft versus host disease (GVHD) primary reason for intubation pulmonary diseaseneuro changes/seizures hemodynamic compromiseairway obstruction abdominal distention post-operative CXR at the time of intubation (focal, diffuse, unilateral, bilateral) PaO2/FiO2 ratios 6-12 hours after intubation PRISM III score on the day of intubation number and type of organ system failure(s) duration of invasive mechanical ventilation survival to ICU discharge and 6-month survival era: 1996-1998, 1999-2001, 2002-2004 Abstracted data “ AIRWAY ” “ PULMONARY ” (early)(mid)(late)

14. Finding Cures. Saving Children. An exhausting project

15. Finding Cures. Saving Children. Demographics and disease Between January 1996 and December 2004 there were 401 courses of mechanical ventilation Average age of admission was 9.5 years 64% of cohort was white, 56% of cohort was male Underlying diagnoses: 206 admissions for HSCT (161 allo, 13 auto) Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine leukemia/lymphoma n=237 (59% of admissions) solid tumors n=85 (21% of admissions) brain tumors n=42 (11% of admissions ) non-malignant processes n=37 (9% of admissions)

16. Finding Cures. Saving Children. Overview of outcomes 146 out of 195 (75%) of non-HSCT admissions were extubated and discharged from the ICU 92 out of 206 (45%) of HSCT admissions extubated and were discharged from the ICU Overall 6-month survival after mechanical ventilation was 60% for non-HSCT patients compared to 25% for HSCT patients Total of 163 deaths while on mechanical ventilation Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

17. Finding Cures. Saving Children. PULMONARY 25948% (125/259)34% (73/218) AIRWAY 14280% (113/142)61% (76/125) Pulm. Disease 214 48% (102/214) 33% (59/179) Reference Hemodynamic 32 41% (13/32) 26% (7/27) 1.33 Abdominal 13 77% (10/13) 58% (7/12) 0.27 Airway 29 62% (18/29) 52% (13/25) 0.56 Neurological 66 76% (50/66) 53% (30/57) 0.29 Post-op 47 96% (45/47) 77% (33/43) 0.04 Comparing reason for intubation Categoryn PICU survival 6-month survival Odds ratio of dying 4.18 ** Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

18. Finding Cures. Saving Children. Odds ratios of mortality VariableOdds ratio of dying (95% CI) PULMONARY reason for intubation4.18 (2.63, 6.81) Allogeneic HSCT(versus non-HSCT)4.52 (2.89, 7.14 ) Prior intubation within 6 months1.99 (1.14, 3.52) Anti-neoplastic therapy > 12 months 5.55 (2.73, 12.30 ) Cardiovascular failure8.04 (4.81, 14.03) Neurological failure5.73 (2.97, 11.81) Renal failure5.04 (3.20, 8.05 ) Hepatic failure6.37 (3.67, 11.49) Organ system failure Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

19. Finding Cures. Saving Children. Improving outcomes over time HSCT Non-HSCT Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine Survival is improving in both general oncologic and post-HSCT patients Rate of improvement is greater for non-HSCT population Importantly, the survival rate for HSCT patients requiring mechanical ventilation remains 50%

20. Finding Cures. Saving Children. Cumulative outcomes by duration of mech. ventilation CUMULATIVE FREQUENCY DAYS AFTER INTUBATION HSCT patients Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

21. Finding Cures. Saving Children. 260 hours probability of survival is 50% by 11 days for survivors, average duration of mechanical ventilation is 230 hours Survival probability by duration Greatest opportunity to improve survival is in the first several days of mechanical ventilation

22. Finding Cures. Saving Children. Conclusions from this review HSCT patients who require mechanical ventilation have worse outcomes than non-HSCT oncology patients (45% v. 75% survival to ICU discharge) Outcomes following mechanical ventilation are improving for both HSCT and non-HSCT oncology patients The need for repeated courses of mechanical ventilation, allogeneic transplant and concomitant organ system dysfunction increase risk of death Changes in Outcomes (1996-2004) for Pediatric Oncology and HSCT Patients Requiring Mechanical Ventilation. Pediatric Critical Care Medicine

23. Finding Cures. Saving Children. Complications following HSCT Soubani AO, Crit Care Med (2006 ) 55% ICU mortality in our pediatric HSCT patients who require mech. ventilation

24. Finding Cures. Saving Children. Engraftment syndrome Onset of fever, skin rash, noncardiogenic pulmonary edema within the peri-engraftment period; absence of microbiologic cause Hypoxemia is the predominant clinical challenge (66%), but frequently associated with hepatic dysfunction (23%) and renal insufficiency (20%) Mostly observed with autologous transplants, incidence of 7-35%, mortality of 7-25% Lee CK et al., Bone Marrow Transplant (1995 ) Madero L et al., Bone Marrow Transplant (2002) Gonzalez-Vincent M et al., Bone Marrow Transplant (2004)

25. Finding Cures. Saving Children. Engraftment syndrome 13 y/o recurrent T cell ALL with fever, rash, hypoxia on day +20 after MUD BMT; bronch ruled out infectious pathogen and alveolar hemorrhage... bilateral interstitial infiltrates, required mech. vent support

26. Finding Cures. Saving Children. Engraftment syndrome early use of corticosteroids surfactant administration within 4 hours of starting mechanical ventilation 9 day course of ventilation currently doing well

27. Finding Cures. Saving Children. Diffuse alveolar hemorrhage Non-infectious onset of dyspnea, hypoxia, diffuse bilateral pulmonary infiltrates and progressive return of bloody fluid on bronchoalveolar lavage Incidence in pediatric post-HSCT population is 5% but mortality is as high at 83% Equal incidence in autologous and allogeneic HSCT and most common cause of death is multiple system organ failure (MSOF) Ben-Abraham et al., Chest (2003) Heggen J et al., Pediatrics (2002) Soubani AO, Crit Care Med (2010 ) Ben-Abraham et al., Chest (2003)

28. Finding Cures. Saving Children. Diffuse alveolar hemorrhage 16 y/o with AML M1 who had allogeneic HSCT developed severe respiratory distress on day +39, nearly immediate need for mech. ventilation BAL ruled out infection, but demonstrated bilateral pulmonary hemorrhage high-dose steroids and PEEP were primary support

29. Finding Cures. Saving Children. Diffuse alveolar hemorrhage Diffuse bilateral dense alveolar infiltrates with massive pulmonary consolidation BAL cytospin 400X

30. Finding Cures. Saving Children. Bronchiolitis obliterans organizing pneumonia (BOOP) Onset of dyspnea, dry cough, fever, and absence of identifiable infectious etiology Incidence in pediatric HSCT population is difficult to determine but adult reviews suggest 1-10%; carries an association with both aGVHD and cGVHD Proliferative inflammatory bronchiolar infiltrate associated with organizing pneumonia; indolent course; mortality ~ 15-25% Yoshihara S et al., Biol Blood Marrow Transplant (2007) Soubani AO, Crit Care Med (2010 ) Yoshihara S et al., Biol Blood Marrow Transplant (2007 )

31. Finding Cures. Saving Children. Bronchiolitis obliterans organizing pneumonia (BOOP) 18 y/o s/p allogeneic HSCT for recurrent AML multiple episodes of diffuse alveolar hemorrhage and mechanical ventilation high resolution CT images obtained at day +107 showed lobular pattern consistent with broncho- pneumonia and ground glass appearance c/w BOOP

32. Finding Cures. Saving Children. Idiopathic pneumonia syndrome (IPS) Syndrome of diffuse alveolar injury characterized by multi-lobar infiltrates in the absence of identifiable infectious cause; progressive hypoxemia Incidence approximates 10-12% in both adult and pediatric HSCT patients; risk factors include +CMV status, aGVHD, unrelated donor, TBI, advanced age Immune mediated lung injury associated with increased TNFα and other cytokines Keates-Baleeiro J et al., Bone Marrow Transplant (2006) Soubani AO, Crit Care Med (2010 ) Cooke KR, Transplantation (2000) Keates-Baleeiro J et al., Bone Marrow Transplant (2006 )

33. Finding Cures. Saving Children. Idiopathic pneumonia syndrome (IPS) 9 y/o with MDS, 6 / 6 URD BMT, IPS day +12 Standard treatment would include broad inflammatory suppression with steroids... alternative includes Etanercept, soluble Fc fragment anti-TNFα antibody

34. Finding Cures. Saving Children. Overloaded ?

35. Finding Cures. Saving Children.

36. We are making progress February 2, 1974

37. Finding Cures. Saving Children. What’s the bottom line? There is an expanding list of indications for HSCT Mortality of respiratory failure in pediatric HSCT patients remains greater than 50% A key underlying feature of the most common causes of post-HSCT respiratory failure is alveolar de-recruitment Interventions aimed at preventing distal airway loss are most likely to succeed if directed at the earliest phase of mechanical ventilation (in the first several days) We have sufficient single-institution, retrospective data... it’s time for multi-center prospective trials

38. Finding Cures. Saving Children. Future directions Network of clinical researchers from 48 PICUs across North America Link to the PALISI site at PedSCCM.org Sponsoring network of several multi-center randomized clinical trials including: –exogenous surfactant in post-HSCT acute lung injury –Etanercept in pediatric idiopathic pneumonia syndrome –early use of continuous renal replacement therapy –approach to transfusion threshold in HSCT patients –beginning to examine biomarkers of acute lung injury

39. Finding Cures. Saving Children. Collaboration = innovation

40. Finding Cures. Saving Children.