Interstitial Pneumonitis after Treatment with Pemetrexed for Non-small Cell Lung Cancer
A 69-year-old male was admitted with fever and dyspnea. Seven months before admission, he was diagnosed with stage IV lung adenocarcinoma (cT3N2M1 for metastases of bone). He was an ex-smoker (45 packs/yr), and his performance status was Eastern Cooperative Oncology Group (ECOG) 1. He had no history of drug allergies. He was treated with first-line chemotherapy, including gemcitabine (1,000 mg/m2, days 1 and 8) and carboplatin (area under the curve, 5.5), every three weeks for six cycles. After four weeks from the last gemcitabine and carboplatin administration, disease progression was noted. The patient started second-line treatment with pemetrexed (500 mg/m2, day 1, every three weeks) with vitamin supplementation and steroid pre-medication. On admission, his vital signs were as follows: blood pressure, 110/70 mm Hg; pulse rate, 74/min; respiration rate, 24/min; and body temperature, 36.8℃. No abnormal heart sounds were detected on chest auscultation; however, fine crackles were detected in the bilateral lower lung fields. Results of arterial blood gas analysis showed severe hypoxia (pH, 7.470; pCO2, 28.2 mm Hg; pO2, 39.5 mm Hg; HCO3-, 20.7 mM; and O2 saturation, 84.6%); thus, the patient received 4 L/min oxygen through a nasal cannula. Peripheral blood tests showed the following: white blood cells, 7,600/µL; hemoglobin, 11.0 g/dL; and platelets, 170,000/µL. The patient's C-reactive protein concentration increased to 3.991 mg/dL, and routine chemistry showed the following: Na, 135 mM; K, 4.1 mM; Cl, 103 mM; aspartate transaminase, 26 IU/L; alanine aminotransferase, 17 IU/L; alkaline phosphatase, 113 IU/L; gamma glutamyl transferase, 29 IU/L; total bilirubin, 0.8 mg/dL; blood urea nitrogen, 8.8 mg/dL; and creatinine, 0.6 mg/dL. Lactic dehydrogenase increased to 1,094 IU/L. Findings on chest radiography revealed interstitial infiltration in both lung fields. Findings on computed tomography (CT) revealed diffuse ground glass opacities (). Pneumococcal antigenuria and serology against Mycoplasma were negative. Due to the patient's immunocompromised status, treatment with broad-spectrum antibiotics (levofloxacin) and trimethoprim-sulfamethoxazole against Pneumocystis jiroveci was started. Bronchoscopy showed only anthracotic pigmentation and no endobronchial lesions. A microbiological culture obtained from bronchoalveolar lavage fluid showed no evidence of bacterial, viral, or fungal pathogens. Sputum cultures, acid-fast staining for bacilli, blood cultures, and P. jiroveci pneumonia polymerase chain reaction all showed negative results. An extensive microbiological investigation, including bronchoscopy, excluded the possibility of infection, including opportunistic infections. Treatment with pemetrexed, which was suspected as the cause of the drug-induced pneumonitis, was stopped, and high-dose prednisolone was administered. We performed a tissue biopsy via video-assisted thoracoscopic surgery in order to confirm interstitial pneumonitis. Markedly distorted lung architecture with interstitial collagenous fibrosis was observed on microscopic examination. Focal honeycomb changes were observed (). The alveolar spaces were filled with luminal mucoid secretions and inflammatory cells. Chronic interstitial inflammation with interstitial fibroblastic activity was also observed (). The pathological findings were compatible with nonspecific interstitial pneumonia. A diagnosis of drug-induced interstitial pneumonitis caused by pemetrexed was ultimately made; in response, antibiotic therapy was discontinued, and high-dose prednisolone therapy was continued for two weeks. Treatment with oral prednisolone resulted in improvement of the patient's clinical presentation and interstitial infiltration in both lung fields (). The patient received third-line erlotinib therapy following his recovery from interstitial pneumonitis.