Not a bug?!
Pulmonary Grand Rounds
Cheryl Pirozzi, MD
March 24, 2011
Case
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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
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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
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
Case
PSH:
 Cholecystectomy.
 Facial surgery after trauma as a child.
 Knee surgeries.
 Tonsillectomy.
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
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.
Physical Exam- ER
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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
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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
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Admitted to medicine 1/1/11
Started on vancomycin, Zosyn, Bactrim, and Tamiflu
Methotrexate held
ID consulted
Infectious w/u:
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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
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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%
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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
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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
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IV Methylprednisolone
1/5/11
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Significant improvement in oxygenation
Abx changed to levaquin
BAL results:
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all micro neg
Diff:
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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
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Extubated 1/6/11
Hypoxia continued to improve
Discharged 1/8/11
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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
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Continued decrease in SOB
PFTs
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FEV1/FVC 78.5
FEV1 2.64 L (67%)
FVC 3.36 L (68%)
DLCO 18.3 (51%)
Clinic f/u 1/11/11
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CXR
 Diagnosis?
Methotrexate pulmonary toxicity
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Potentially life-threatening adverse drug reaction
Several different clinical syndromes and findings:
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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
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Methotrexate (MTX) = folic acid antagonist, inhibits folate
coenzymes → inhibits cellular proliferation
Pathogenesis - unclear
 Hypersensitivity reaction
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Direct toxic effect of MTX on lung
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Suggested by fever, eosinophilia, increased CD4 T-cells on BAL, biopsy
findings of mononuclear cell infiltration and granulomatous inflammation
suggested by the accumulation of methotrexate in lung tissue, biopsy
findings of alveolar or bronchial epithelial cell atypia and lung injury
pattern
Idiosyncratic reaction
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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
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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
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Risk Factors
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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
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Sxs:
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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
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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
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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
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Exam
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Fever, tachypnea, crackles, cyanosis
Lab findings
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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
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Imaging:
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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
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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
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Rule out opportunistic infection
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(MTX rx associated with PCP, CMV, cryptococcus, HSV,
Nocardia infections)
BAL
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negative for microorganisms
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lymphocytic alveolitis
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elevated CD4+ or CD8+ lymphocyte counts, typically
high CD4 : CD8
PFTs
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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
Diagnosis
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BAL
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elevated CD4+ or CD8+ lymphocyte, high CD4 : CD8
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Schnabel et al. BAL cell profile in methotrexate induced pneumonitis.
Thorax. 1997;52(4):377-9
Diagnosis
DIAGNOSTIC CRITERIA FOR METHOTREXATE-INDUCED
PNEUMONITIS (Searle et al)
1. Acute onset of shortness of breath
2. Fever >38.0°C
3. Tachypnea ≥ 28/min and nonproductive cough
4. Radiologic evidence of pulmonary interstitial or alveolar
infiltrates
5. WBC >15,000/mm3 (+/- eosinophilia)
6. Negative blood and sputum cultures (mandatory)
7. PFTs with restriction and decreased DLCO
8. PO2 <66 mm Hg/ RA at time of admission
9. 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
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Acute pneumonitis
 Alveolitis
 Granulomas
 Eosinophils
 Diffuse alveolar damage
Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81
Histopathology
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Subacute – chronic
 Interstitial inflammatory
infiltrate
 Granulomas
 fibrosis
Imokawa et al. Methotrexate pneumonitis. Eur Respir J. 2000;15(2):373-81
Treatment
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Stop MTX
High dose corticosteroids
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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
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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
f/u 2/11/11
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SOB improved, some DOE
PFTs
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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
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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
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Cannon GW. Methotrexate pulmonary toxicity. Rheum Dis Clin North Am. 1997
Nov;23(4):917-37.
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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.
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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.
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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.
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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
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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 methotrexateinduced pneumonitis. Am J Respir Crit Care Med. 2001 Oct 1;164(7):1186-91.