Kremer et al proposed criteria for the diagnosis of pulmonary injury associated with methotrexate therapy. The authors are from multiple hospitals in the United States.


Major criteria:

(1) hypersensitivity pneumonitis by histopathology without evidence of pathogenic organisms.

(2) radiologic evidence of pulmonary interstitial or alveolar infiltrates

(3) blood cultures (if febrile) and initial sputum cultures (if sputum is productive) negative for pathogenic organisms. Also includes patients who are afebrile and who do not produce sputum, even if no blood or sputum cultures were done.


Minor criteria:

(1) shortness of breath for < 8 weeks

(2) nonproductive cough

(3) oxygen saturation <= 90% at the time of initial evaluation on room air

(4) diffusing capacity of the lung for carbon monoxide (DLco) <= 70% of that predicted for age

(5) leukocyte count <= 15,000 per µL


Original interpretation (Table 2, page 1831)


Definite case - one of the following:

(1) all 3 major criteria

(2) (major criteria 1 and 2) AND (2 or more minor criteria)

(3) (major criteria 2 and 3) AND (3 or more minor criteria)


Probable cause:

(1) (major criteria 2 and 3) AND (2 minor criteria)


Modified interpretation in Alarcon et al (page 357):


Definite case - both of the following:

(1) major criterion 1 OR (major criteria 2 and 3), AND

(2) 3 of the 5 minor criteria


Probable case - both of the following:

(1) major criteria 2 and 3, AND

(2) 2 of the 5 minor criteria


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