A 73-year-old Japanese woman complained of a fever >=38C and exertional dyspnea at her regular clinic visit in the middle of July 2014. In May 2014, she had started fifth-line systemic chemotherapy of weekly irinotecan monotherapy (60 mg/m2, Days 1, 8 and 15, every 4 weeks) for her metastatic thymic carcinoma (squamous cell carcinoma type). These symptoms appeared on the 23rd day of the second cycle in the middle of July 2014. We found these symptoms on the 29th day of the second cycle. Chest X-ray suggested light ground-glass shadow, especially in the right upper lung field. Computed tomography (CT) showed diffuse ground-glass shadow spreading in all of the lung fields, in addition to shrinkage of the lung metastases (Fig. 1). The differential diagnoses based on her clinical course and these chest image findings included congestive heart failure, drug-induced pneumonia and pneumocystis pneumonia. We discontinued the chemotherapy and recommended her immediate hospitalization. However, she declined immediate admission at that time. During the four days she waited until ultimately allowing admission, her symptoms, respiratory conditions and abnormal shadow on chest X-ray did not change remarkably.
Since April 2007, she had undergone thymectomy, left upper lung partial resection, left lower lobe resection, stereotactic radiation therapy to the right lung metastases and systemic chemotherapies, including the administration of carboplatin plus paclitaxel twice, cisplatin plus etoposide and gemcitabine. Except for febrile neutropenia, she did not experience severe toxicities during her previous treatment. Her medical, family and social histories were unremarkable. Her current medication included loxoprofen sodium, rebamipide and pregabalin. These medications had been administered for years. Except for anti-tumor drugs, she had not started any new regular drugs for more than three years. She was not using any anticoagulants or antiplatelet agents.
Her vital signs on admission were as follows: heart rate 68 beats/min with a regular rhythm, SpO2 95% (on room air) and blood pressure 124/60 mmHg. A physical examination revealed neither murmur in her heart sound nor rale in her breath sounds. Her blood cell counts were as follows: hemoglobin 9.6 g/dL, hematocrit 28.6%, white blood cells 6,300/mm3 (neutrophils 50.7%, lymphocyte 30.6%, eosinophils 2.2%), platelets 288,000/mm3. Her C-reactive protein and lactate dehydrogenase were slightly elevated to 1.91 mg/dL and 311 U/L, respectively. Pneumocystis pneumonia and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis were unlikely because beta-D-glucan, proteinase-3 and myeloperoxidase ANCA were undetectable. Congestive heart failure was also doubtful because her brain natriuretic peptide levels were slightly elevated to 46.7 pg/mL (<18.4 pg/mL). Coagulation was also within the normal range. Her uridine diphosphate glucoronosyltransferase (UGT1A1)*28 and *6 gene polymorphisms were wild-type.
We performed bronchoscopy on the 33rd day of the second course, in late July 2014. This examination did not find any apparent bleeding in the airway, trachea and bronchus. Bronchoalveolar lavage fluid (BALF) recovered from B4 in the right middle lobe, with a recovery rate of 40% (60 mL/150 mL of saline), gradually became bloody (Fig. 2). The routine microbiology culture of BALF did not detect bacterial or fungal infection. The cell count analysis (total cell count 5.1x105 cells/mL) of BALF indicated the following: alveolar macrophages 58%, neutrophils 3%, lymphocytes 38% and eosinophils 1%. BALF contained macrophages with positive staining of iron (Berlin blue) but no atypical cells suspected of malignancy (Fig. 3). We also performed a transbronchial lung biopsy (TBLB) from the right B2, B8 and B9. Although a small number of lymphocytes were scattered in the alveolar interstitium and immunochemical staining for Pneumonositis jirovecii was negative, we could not detect hemosiderin-laden macrophages in the TBLB specimens. Based on these bronchoscopic findings, we diagnosed the patient with drug-induced DAH and discontinued irinotecan and started oral prednisolone (0.5 mg/kg/day). Prednisolone was gradually tapered and discontinued two months later. CT in late August 2014 showed disappearance of the ground-glass shadows (Fig. 1).
We did not try a challenge re-administration of irinotecan. Thereafter, she received docetaxel in September 2014 and S-1 in November 2015 but did not suffer from alveolar hemorrhage from these drugs. She died due to a worsening of thymic carcinoma in March 2016 at another hospital.