Not a bug?!

1. Not a bug?! Pulmonary Grand Rounds Cheryl Pirozzi, MD March 24, 2011

2. Case • CC: Shortness of breath • HPI: 41 yo man p/w increasing SOB and DOE x 1.5 week. • Now dyspnea with walking a few steps • Fevers to 106 °F • Nonproductive cough • Decreased appetite and PO intake, decreased UOP • “burning” pleuritic chest tightness

3. Case • Initially saw PCP 3d PTA → started on moxifloxacin with no improvement • Presented to ER due to progressive severe SOB • On presentation to ER SaO2 70%/RA

4. Case PMH • Psoriasis dx 15 y ago • Erosive inflammatory arthritis dx 9/2010 - Possible psoriatic arthritis • affecting bilat ankles, feet, hands, hips, shoulders • Started on MTX 9/2010 • Chronic neck/back pain 2/2 MVA, chronic narcotics • Hx childhood asthma, resolved in adulthood • Recurrent pancreatitis • GERD • Hyperlipidemia • Hypertension • Chronic fatigue

5. Case PSH: • Cholecystectomy. • Facial surgery after trauma as a child. • Knee surgeries. • Tonsillectomy.

6. Case SH: • H/o tobacco 1ppd x 19 y, quit 2007. • H/o heavy EtOH use, quit several years ago. No other substances. • Homosexual, one partner x 14 y. Lives in Magna. • Works at call center. Owns horses, dogs, 2 cats. No other signif exposures FH: • Sibling and father with psoriasis. • Mother- HTN, CAD • No known FH of lung disease ALLERGIES: ceftriaxone → hives

7. Case Home Meds: • MS Contin 30 mg t.i.d. • Norco 10/325 five times per day. • Methotrexate 20 mg PO q. week, started 9/2010. • Gabapentin 600 mg tid then 1200 qHS. • Bystolic 20 mg per day. • Hydrochlorothiazide 25 mg per day. • Trilipix 135 mg per day. • Voltaren gel 1% p.r.n. • Folic acid 1 to 2 mg daily. • Fish oil 4 g daily. • Flax seed oil 2 g daily.

8. Physical Exam- ER • VS: 39.1, p 87, 115/72 , R 15, 70%/RA → 96%/3 L • gen: NAD, slightly anxious, diaphoretic • HEENT: Mallampati I, PERRLA, EOMI, no oral lesions • CV: RRR no M/G/R, JVP ~ 2cm / SA • Lungs: subtle inspiratory bilateral crackles, no wheeze/rhonchi/ rub • Abd: soft, NT/ND • Ext: no clubbing, no edema

9. Labs • WBC 15, PMN 80%, L 10% E 1.7%, Hgb 13, Plt 294 • Na 132, K 3.7, Cl 96. CO2 26. BUN 24, Cr 1.5 (bl 1.0) • LFTs nl • LDH 1224

10. CXR

11. Hospital Course • Admitted to medicine 1/1/11 • Started on vancomycin, Zosyn, Bactrim, and Tamiflu • Methotrexate held • ID consulted • Infectious w/u: • Negative respir viral panel, sputum cx, sputum PCP, HIV, blood cx, Abs to C.pneumoniae, C.Psittaci, C.trachomatis, Legionella, Mycoplasma, Strep Pneumo, histo, PPD • Abx narrowed to Unasyn, azithro, bactrim • Pt not getting better • Pulm consulted

12. What next?

13. HRCT 1/3/11

14. HRCT 1/3/11

15. HRCT 1/3/11

16. Hospital Course • Bronch with BAL performed 1/4/11- uncomplicated • 1/4/11 evening MICU called for respiratory distress and hypoxia • PE: VS: 39.0, p 120, 113/60, R 40, 95%/Bipap 14/8/70% • Respiratory distress, diffuse bilateral crackles • ABG: (70%) 7.39/34/59, lact 1.1 • (100%) 7.44/31/75/21.

17. CXR 1/4/11

18. Hospital Course • Intubated for hypoxic respiratory failure • Initial BAL studies neg for: PCP DFA, viral DFAs, gram stain • Abx broadened to meropenem, vanc, azithro • Steroids started for suspected MTX pneumonitis • IV Methylprednisolone

19. 1/5/11 • Significant improvement in oxygenation • Abx changed to levaquin • BAL results: • all micro neg • Diff: • 70% lymph, 12% macrophage, 13% bronchial lining cells, 5% PMN • of lymphs: 93% T-cells, 4% NK cells, 2% B-cells. • CD4:CD8 ratio = 9.2.

20. 1/6/11 • Extubated 1/6/11 • Hypoxia continued to improve • Discharged 1/8/11 • O2 sat 92%/RA with ambulation • Steroids decreased to prednisone 60 mg daily with decrease to 40 mg daily after 3 days • Abx d/c’d

21. CXR 1/7/11

22. Clinic f/u 1/11/11 • Continued decrease in SOB • PFTs • FEV1/FVC 78.5 • FEV1 2.64 L (67%) • FVC 3.36 L (68%) • DLCO 18.3 (51%)

23. Clinic f/u 1/11/11 • CXR

24. Diagnosis?

25. Methotrexate pulmonary toxicity • Potentially life-threatening adverse drug reaction • Several different clinical syndromes and findings: • Acute and subacute hypersensitivity pneumonitis • Interstitial fibrosis • Acute lung injury with noncardiogenic pulmonary edema • Organizing pneumonia • Pleuritis and pleural effusions • Pulmonary nodules • Bronchitis with airways hyperreactivity Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

26. Methotrexate pulmonary toxicity • Methotrexate (MTX) = folic acid antagonist, inhibits folate coenzymes → inhibits cellular proliferation • Pathogenesis - unclear • Hypersensitivity reaction • Suggested by fever, eosinophilia, increased CD4 T-cells on BAL, biopsy findings of mononuclear cell infiltration and granulomatous inflammation • Direct toxic effect of MTX on lung • suggested by the accumulation of methotrexate in lung tissue, biopsy findings of alveolar or bronchial epithelial cell atypia and lung injury pattern • Idiosyncratic reaction • Suggested by lack of correlation with dose and route of administration Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81

27. Methotrexate pneumonitis • Acute or subacute hypersensitivity pneumonitis • Most common form of methotrexate pulm toxicity • 0.3% to 11.6% of patients on MTX Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

28. Methotrexate pneumonitis • Risk Factors • Higher doses of MTX, daily administration • Preexisting lung disease • diabetes mellitus • hypoalbuminemia • previous use of disease-modifying antirheumatic drugs • older age • Decreased clearance (eg renal disease) Alarcon et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. Ann Intern Med 1997; 127:356. Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

29. Clinical presentation • Sxs: • Nonproductive cough • Progressive SOB • Pleuritic chest pain • Fever • Fatigue and malaise • Acute pneumonitis: over days-few weeks • Can be fulminant course • Subacute: slower course over several weeks • Most common presentation • approx 10% progress to pulmonary fibrosis Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

30. Clinical presentation • Timing of onset of toxicity very variable • Treatment duration 1 week – 18 years • Total MTX dose 7.5 mg to 3600 mg • Most common in 1st year Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

31. Clinical presentation • Exam • Fever, tachypnea, crackles, cyanosis • Lab findings • Hypoxemia • Mild leukocytosis, can have eosinophilia • Mild elevation of LDH Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

32. Clinical presentation • Imaging: • diffuse, dense, bilateral interstitial and alveolar opacities, GGOs, may be rapidly-progressive Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

33. Clinical presentation • Imaging: Kremer et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis. Arthritis Rheum. 1997;40(10):1829-37

34. Diagnosis • Rule out opportunistic infection • (MTX rx associated with PCP, CMV, cryptococcus, HSV, Nocardia infections) • BAL • negative for microorganisms • lymphocytic alveolitis • elevated CD4+ or CD8+ lymphocyte counts, typically high CD4 : CD8 • PFTs • Restrictive pattern, decreased DLCO Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519 Schnabel et al. BAL cell profile in methotrexate induced pneumonitis. Thorax. 1997;52(4):377-9

35. Diagnosis • BAL • elevated CD4+ or CD8+ lymphocyte, high CD4 : CD8 • Schnabel et al. BAL cell profile in methotrexate induced pneumonitis. Thorax. 1997;52(4):377-9

36. Diagnosis DIAGNOSTIC CRITERIA FOR METHOTREXATE-INDUCED PNEUMONITIS (Searle et al) 1. Acute onset of shortness of breath2. Fever >38.0°C3. Tachypnea ≥ 28/min and nonproductive cough4. Radiologic evidence of pulmonary interstitial or alveolar infiltrates5. WBC >15,000/mm3 (+/- eosinophilia)6. Negative blood and sputum cultures (mandatory)7. PFTs with restriction and decreased DLCO8. PO2 <66 mm Hg/ RA at time of admission9. Histopathology consistent with bronchiolitis or interstitial pneumonitis with giant cells and without evidence of infection Definite: ≥ 6 criteria; Probable: 5 of 9 criteria; Possible: 4 of 9 criteria Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

37. Lung biopsy - Histologic findings

38. Histopathology • Acute pneumonitis • Alveolitis • Granulomas • Eosinophils • Diffuse alveolar damage Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81

39. Histopathology • Subacute – chronic • Interstitial inflammatory infiltrate • Granulomas • fibrosis Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81

40. Treatment • Stop MTX • High dose corticosteroids • If pt is severely ill or does not improve with d/c MTX • Taper depending on clinical response • Supportive care • Do not re-treat with MTX (50-80% recur) Kremer et al. Arthritis Rheum. 1997;40(10):1829-37 Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

41. Prognosis • Mortality 15% • Most have a complete recovery of pulmonary function • Some have permanent lung impairment Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519 Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37

42. f/u 2/11/11 • SOB improved, some DOE • PFTs • FEV1/FVC 78.7 • FEV1 2.97 L (75%) • FVC 3.78 L (76%) • DLCO 28.5 (79%) • Prednisone tapered to 30 mg x 2 week, 20 mg x 2 wk, 10mg

43. CXR 2/11/11

44. CTA 2/11/11

45. Conclusions • Methotrexate pneumonitis is a potentially life-threatening complication of MTX rx • Acute – subacute presentation • Rule out infection • BAL helpful for diagnosis, characteristically shows lymphocytic alveolitis with high CD4 / CD8 • Rx with withdrawal of MTX and steroids

47. References • Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37. • Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J. 2000;15(2):373-81. • Camus P, Bonniaud P, Fanton A, Camus C, Baudaun N, Pascal Foucher P. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479– 519. • Schnabel A, Richter C, Bauerfeind S, Gross WL. Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis. Thorax. 1997;52(4):377-9 • Alarcon, GS, Kremer, JM, Macaluso, M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis: A multicenter, case-control study. Ann Intern Med 1997; 127:356. • Kremer JM, Alarcon GS, Weinblatt ME, Kaymakcian MV, Macaluso M, Cannon GW, Palmer WR, Sundy JS, St Clair EW, Alexander RW, Smith GJ, Axiotis CA. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review. Arthritis Rheum. 1997;40(10):1829-37 • Fuhrman C, Parrot A, Wislez M, Prigent H, Boussaud V, Bernaudin JF, Mayaud C, Cadranel J. Spectrum of CD4 to CD8 T-cell ratios in lymphocytic alveolitis associated with methotrexate-induced pneumonitis. Am J Respir Crit Care Med. 2001 Oct 1;164(7):1186-91.