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©2014 MFMER | slide-1 Pulmonary Complications of Bone Marrow Transplantation: When infection isn’t the answer Shannon Piche, PharmD, BCPS PGY-2 Critical Care Resident

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Page 1: Pulmonary Complications of Bone Marrow Transplantation Complications... · Pulmonary Complications of Bone Marrow Transplantation: ... slide-5 Idiopathic Pneumonia Syndrome ... Down

©2014 MFMER | slide-1

Pulmonary Complications of Bone Marrow Transplantation:When infection isn’t the answer

Shannon Piche, PharmD, BCPSPGY-2 Critical Care Resident

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Objectives• List the American Thoracic Society diagnostic

criteria for idiopathic pneumonia syndrome• Identify key clinical differences between diffuse

alveolar hemorrhage, peri-engraftment respiratory distress syndrome, and non-cardiogenic capillary leak syndrome

• Determine the role of corticosteroid therapy in treatment of diffuse alveolar hemorrhage

DAH: diffuse alveolar hemorrhagePERDS: peri-engraftment respiratory distress syndromeCLS: capillary leak syndrome

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65 y/o M with respiratory distress• Past Medical History:

• Type II Diabetes Mellitus • Atrial fibrillation• Anxiety/depression• Myelodysplastic syndrome (MDS)

10/2011: Biopsy, MDS

7/2012:5-azacitidine

9/2014: Decitabine x7 cycles

7/2015:Cyclosporine + prednisone

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History of Present Illness

Day -6: • Conditioning regimen:

fludarabine, melphalan

Day 0: • Allogeneic, peripheral

blood stem cell transplant

Day +8:• Hospital admission• Mucositis• ANC: 0 cells/μL

Day +16: • Transferred to ICU• Increased WOB• ANC: 280 cells/μL

ANC: absolute neutrophil countWOB: work of breathing

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Idiopathic Pneumonia Syndrome

Peri-engraftment respiratory distress syndrome

Non-cardiogenic capillary leak syndrome

Diffuse alveolar hemorrhage

Cryptogenic organizing pneumonia

Delayed pulmonary toxicity syndrome

Bronchiolitis obliterans syndrome

Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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Pathophysiology

Conditioning chemotherapy

Previous infections

Total body irradiation

Inflammatory cytokines

T-cell activation

Alveolus

Capillary

Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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Pathophysiology, Example: DAH

Conditioning chemotherapy

Previous infections

Total body irradiation

Inflammatory cytokines

T-cell activation

Alveolus

Capillary

Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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Pathophysiology

Damage

Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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IPS: American Thoracic Society Definition 1. Evidence of widespread alveolar injury2. Absence of infection3. Absence of cardiac dysfunction, acute decline

in renal function as a sole explanation

Where do we go from here?

Panoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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Back to the Case• Vital signs

• T 39.0°C• SaO2: 88%• RR: 28

• Physical exam: notable for bilateral lower extremity edema

• Blood cultures, tracheal secretions pending• Chest x-ray

• HR: 112 bpm• BP: 151/72 mmHg

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Bilateral, Multi-lobar Pulmonary Infiltrates

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• HR: 112 bpm• BP: 151/72 mmHg

BAL: broncheoalveolar lavage

• Vital signs• T 39.0°C• SaO2: 88%• RR: 28

• Physical exam: notable for bilateral lower extremity edema

• Blood cultures, tracheal secretions pending• Chest x-ray• Considering CT chest, BAL

Back to the Case

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Respiratory distress in a BMT patient

Infection?

Days 1-30: • Diffuse alveolar hemorrhage• Peri-engraftment respiratory

distress syndrome• Non-cardiogenic capillary leak

syndrome

Timeline

• Work-up ongoing• Initiated on broad

spectrum antibiotics

Days 100+: • Delayed pulmonary toxicity

syndrome• Bronchiolitis obliterans

syndrome• Cryptogenic organizing

pneumoniaPanoskaltsis-Mortari A, et al. Am J Respir Crit Care Med. 2011;183:1262-79.

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• i.e., pulmonary edema

• Weight gain• Peripheral edema• Responsive to

diuresis

• Fever• Cutaneous rash• Days surrounding

engraftment

• Fever +/-• Hemoptysis (~60%)• Diagnosis: BAL

- Progressively bloody return

- >20% Hemosiderin-laden macrophages

DAH:

PERDS: CLS:

Respiratory distress

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Back to the Case: What’s the Verdict?• PERDS

Previous day, first detectable ANCNo rash on physical exam

• CLSDown 2kg from admissionPeripheral edema on physical exam

• DAHProgressively bloody return on BAL26% hemosiderin-laden macrophages

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Diffuse Alveolar Hemorrhage • Epidemiology:

• Median onset day +19 (range, day +5-34)• 5-12% incidence in BMT population• Reported 21-day mortality 60-100%

• Risk factors:• Age >40 years• Full-intensity conditioning regimen, total body

irradiation• Underlying acute leukemia or MDS• Type of transplant?

• PT/PTT, thrombocytopenia are NOT risk factorsAfessa B, et al. Am J Respir Crit Care Med. 2002;166:641-45

Wanko SO, et al. Biol Blood Marrow Transplant. 2006;12:949-53Lewis ID, et al. Bone Marrow Transplant. 2000;26:539-43.

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Diffuse Alveolar Hemorrhage Use of Corticosteroids in Bone Marrow Transplant Patients

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Treatment Outline1. Steroids2. Steroids3. Steroids

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Diffuse Alveolar Hemorrhage

Immune Mediated• ANCA-associated vasculitis• Systemic lupus erythematosus• Rheumatoid arthritis• Antiphospholipid antibody

syndrome

Non-Immune Mediated• Infection• Acute respiratory distress

syndrome• Coagulopathy• Left ventricular dysfunction

Bone Marrow Transplantation

Krause ML, et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.

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Pathophysiology

Alveolus

Capillary

Krause ML, et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.

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Treatment Outline1. Steroids2. Steroids3. Steroids4. Others?

• Management of coagulopathy• rVIIa• Etanercept

Let’s take a walk down memory lane…

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Metcalf, et al. • Retrospective cohort, descriptive analysis • Patient population

• January 3, 1985 – November 9, 1990• 603 BMT patients reviewed for DAH diagnosis

• Treatment (N = 63; 3 groups)• No steroids• Low-dose: ≤ 30mg methylprednisolone or equivalent• High-dose: > 30mg methylprednisolone or

equivalent (125-250mg q6h)

Metcalf JP, et al. Am J Med. 1994;96:327-34.

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Mortality

No steroids (N = 12)

Low-dose(N = 10)

High-dose(N = 43)

P-value

Death priorto discharge 11 9 29 P <0.05

#1

90% 67%

Metcalf JP, et al. Am J Med. 1994;96:327-34.

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Mortality

No steroids (N = 12)

Low-dose(N = 10)

High-dose(N = 43)

P-value

Death priorto discharge 11 9 29 P <0.05

No steroids (N = 12)

Low-dose(N = 10)

High-dose(N = 43)

P-value

Death (at studyconclusion?) 11 9 35 Not evaluated

#1

#2

90% 81%Metcalf JP, et al. Am J Med.

1994;96:327-34.

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Mortality: Kaplan-Meier Curve

#3

P <0.01

Metcalf JP, et al. Am J Med. 1994;96:327-34.

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Study Conclusions• Three different representations of mortality

• Somewhat contradicting, confusing• Statistical methods unclear

• Difficult to interpret• Only available data• Doesn’t seem harmful? – ADE not well reported• Let’s go with it…

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Raptis, et al. • Retrospective case-series• Patient population

• September 1993 – January 1998• 74 BMT patients evaluated, 4 with DAH

• Treatment

Case #1 #2 #3 #4Methylprednisoloneregimen 1g daily 1g daily 2g x1, 1g

daily 0.5g daily

Raptis P, et al. Bone Marrow Transplant. 1999;24:879-83.

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Study Conclusions• 50% mortality due to DAH-related complications• Authors’ perspective:

• DAH is life-threatening• Potentially reversible with high-dose steroid

treatment

• Even smaller population• Again, doesn’t seem harmful?

Raptis P, et al. Bone Marrow Transplant. 1999;24:879-83.

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Rathi, et al. • Retrospective cohort, descriptive analysis• Inclusion:

• October 2007 – June 2011• BMT patients w/ DAH that received steroids +/-

aminocaproic acid

• Exclusion: • Age <18 years• Steroids +/- aminocaproic acid for non-DAH

illnesses

ACA: aminocaproic acid Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.

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Treatment

BMT + DAHn = 119

Steroids onlyn = 37

High dose: ≥1 g/dayn = 23

Low dose: <0.25 g/dn = 19

Medium dose: 0.25-<1 g/dn = 50

High dose: ≥1 g/dayn = 8

Low dose: <0.25 g/dn = 18

Medium dose: 0.25-<1 g/dn = 11

Steroids + ACAn = 82

Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.

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Mortality

Outcomes Low-dose Medium-dose High-dose P-valueSteroids only n = 18 n = 11 n = 23Mortality – n (%)

ICU 4 (22.4) 7 (63.6) 6 (75) 0.02Hospital 9 (50) 9 (81.8) 8 (100) 0.02

Steroids + ACA n = 19 n = 40 n = 23Mortality – n (%)

ICU 6 (31.6) 23 (57.5) 15 (65.2) 0.07Hospital 13 (68.4) 33 (82.5) 18 (78.3) 0.45

*No difference when evaluating 30-d, 60-d, and 100-d mortality between steroid doses

Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.

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A Closer Look…

Variables ICU Mortality Hospital MortalityOR 95% CI P-value OR 95% CI P-value

Steroids + ACA vs. steroids alone 0.81 0.29-2.27 0.69 1.02 0.38-2.75 0.96

Medium-dose vs. low-dose steroids 3.93 1.31-11.77 0.01 2.91 1.03-8.21 0.04

High-dose vs. low-dose steroids 4.79 1.45-15.90 0.01 2.99 0.87-10.34 0.08

*No difference when evaluating 30-d, 60-d, and 100-d mortality between groups

Rathi NK, et al. Bone Marrow Transplant. 2015;50:420-26.

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Study Conclusions• Strongest study published – both size, design

• Limitations still exist

• No benefit conferred with ACA• Makes sense, DAH not thought to be a result of

coagulopathy

• Medium-, high-dose steroids potentially harmful• No benefit in any group beyond hospital stay

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Mortality: Kaplan-Meier Curve

P <0.01

Metcalf JP, et al. Am J Med. 1994;96:327-34.

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Study Conclusions• Strongest study published – both size, design• No benefit conferred with ACA

• Makes sense, DAH not thought to be a result of coagulopathy

• Medium-, high-dose steroids potentially harmful• No benefit in any group beyond hospital stay

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Harmful Effects of Steroids• Not well described in aforementioned literature• Infection• Blood glucose control• Delirium• Myopathy• Concurrent use of paralytic

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Clinical Practice• Clinicians recognize high risk for mortality• Data scarce, conflicting• Mayo Clinic – Rochester practice

• Supportive cares + steroids • Methylprednisolone 250mg q6h x4-5 days followed

by taper• Monitor for ADE, check in the ‘con’ column for

considering short course

• Should practice shift away from the use of high-dose steroids?

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ConclusionList the American Thoracic Society diagnostic

criteria for idiopathic pneumonia syndromeIdentify key clinical differences between diffuse

alveolar hemorrhage, peri-engraftment respiratory distress syndrome, and non-cardiogenic capillary leak syndrome Determine the role of corticosteroid therapy in

treatment of diffuse alveolar hemorrhage

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Which of the following is true?A. Use of aminocaproic acid

for the treatment of DAH is the standard of care as it has been shown to significantly reduce 60-d mortality

B. Mortality associated with DAH s/p BMT is reported to be <10%

C. Treatment of DAH with steroids is controversial as studies have shown both positive and negative results

D. None of the above are true

A. B. C. D.

0% 0%0%0%

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JW is a 38y/o M s/p allogeneic PBSCT in the setting of ALL. He presents to the ICU day +14 with acute respiratory distress, a fever, and a diffuse cutaneous rash. What non-infectious pulmonary complication s/p BMT might JW be experiencing?

A. Diffuse alveolar hemorrhage

B. Cryptogenic organizing pneumonia

C. Non-cardiogenic capillary leak syndrome

D. Peri-engraftment respiratory distress syndrome

A. B. C. D.

0% 0%0%0%

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RM is a 66 y/o F s/p autologous PBSCT in the setting of MDS. She presents to the ICU day +20 with acute respiratory distress and was found to have DAH requiring intubation and subsequent paralysis. Which of the following would be a reason to consider avoiding use of steroids?

A. Advanced ageB. Use of paralyticC. BMT associated

DAH is a non-immune mediated process

D. Timing of DAH onsetA. B. C. D.

0% 0%0%0%

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Questions & Discussion