Not a bug?!

Pulmonary Grand RoundsCheryl Pirozzi, MD

March 24, 2011

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

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

CasePMH 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

CasePSH: Cholecystectomy. Facial surgery after trauma as a child. Knee surgeries. Tonsillectomy.

CaseSH: 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

CaseHome 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.

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

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

CXR

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

What next?

HRCT 1/3/11

HRCT 1/3/11

HRCT 1/3/11

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.

CXR 1/4/11

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

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.

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

CXR 1/7/11

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%)

Clinic f/u 1/11/11 CXR

Diagnosis?

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

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

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

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

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

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

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

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

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

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

Schnabel et al. BAL cell profile in methotrexate induced pneumonitis. Thorax. 1997;52(4):377-9

Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

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

DiagnosisDIAGNOSTIC 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

Lung biopsy - Histologic findings

Histopathology Acute pneumonitis

Alveolitis Granulomas Eosinophils Diffuse alveolar

damage

Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81

Histopathology Subacute – chronic

Interstitial inflammatory infiltrate

Granulomas fibrosis

Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81

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

Prognosis Mortality 15% Most have a complete recovery of

pulmonary function Some have permanent lung impairment

Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997 Nov;23(4):917-37Camus et al. Drug-induced and iatrogenic infiltrative lung disease. Clin Chest Med 25 (2004) 479–519

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

CXR 2/11/11

CTA 2/11/11

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

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.