Not a bug?!
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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.