A 52-year-old male was diagnosed with advanced colorectal cancer, with multiple metastases to the lungs, liver, and peritoneum. Histology revealed well-to-moderately differentiated adenocarcinoma, in which the KRAS and NRAS mutation tests were negative and microsatellite instability was stable, but the BRAF V600E mutation was positive. In his medical history, he had received an allogeneic BMT from his elder sister for severe aplastic anemia 33 years ago. As preparative therapy prior to BMT, the patient received total lymph node irradiation (7.5 Gy) and cyclosporine at 50 mg/kg for four days. Only the bilateral lung apices were involved in the irradiated field, but no pulmonary changes suggestive of radiation pneumonitis were noted thereafter. He experienced a grade 1 skin rash as an acute graft-versus-host disease (GVHD) symptom after BMT, which disappeared clinically without treatment; however, a skin biopsy performed several months later showed pathological findings suspicious of chronic GVHD. During follow-up, there was no worsening of GVHD at the skin or other sites, including interstitial pneumonia, and the patient received no immunosuppressive agents at the time of diagnosis of colon cancer. He had no history of smoking or known allergies. The patient had received two doses of COVID-19 vaccine manufactured by Moderna 9 and 10 months prior to the diagnosis of colorectal cancer and polymerase chain reaction (PCR) test for COVID-19 was negative multiple times during the DILD treatment. The vaccination history other than COVID-19 was unknown. He had type 2 diabetes and used long-acting insulin. Because the sigmoid colon tumor invaded the left ureter and lower gastrointestinal endoscope could not pass through the primary site, the patient underwent transverse colostomy for colon obstruction due to the tumor. Before receiving chemotherapy, the patient experienced a severe cough due to lung metastasis but had no respiratory distress, with a pulse oxygen saturation (SpO2) of 95% in room air. Chest computed tomography (CT) showed multiple pulmonary nodules, but no abnormal findings suggesting accumulative lung damage such as fibrosis ( Figure 1 ). All screening tests including blood cultures for bacterial infections and serological examinations for viral infections were negative. One month after surgery, 1st-line chemotherapy with FOLFIRI (5-fluorouracil [FU] bolus 400 mg/m2 + leucovorin 400 mg/m2 + irinotecan 150 mg/m2 followed by 5-FU 2400 mg/m2 in a 46-hour infusion) + bevacizumab (5 mg/kg) with palonosetron hydrochloride and dexamethasone as prophylactic anti-emetic therapy was started. He developed a fever without myelosuppression on day 6; however, the bacterial culture was negative, and there was no new lung infiltration on chest radiography. Naproxen (600 mg/day) was administered for the noninfectious fever, which quickly resolved. He was discharged from the hospital in a good general condition and received a second course of chemotherapy at our outpatient clinic with no severe adverse events. On day 15 of the second course of chemotherapy, the patient had no dyspnea. However, because his SpO2 was 92% in room air, the patient was admitted for oxygen demand. A CT scan showed no apparent tumor growth, but there were slight bilateral ground-glass shadows ( Figure 2 ). A bronchoscopy was performed on the same day. There were no abnormalities in the endotracheal lumen such as apparent redness, edema, or neoplastic lesions; bronchoalveolar lavage (BAL) was performed in the middle lobe, and a biopsy of the peripheral lung was performed in the lower lobe of the right lung. The pathology showed that there was only fibrosis around the tumor as a tumor environment, and there was no obvious fibrosis in the background lungs consistent with the CT findings ( Supplementary Figure 1 ). Bacterial and fungal cultures and PCR tests for pneumocystis jirovecii DNA and cytomegalovirus (CMV) DNA of the BAL fluid were negative. Pathology of the lung biopsy showed pulmonary metastasis of the colon cancer and no apparent findings of inflammation. Serum lactate dehydrogenase (LDH) and KL-6 levels were within the normal ranges, and the betaD-glucan test was negative. The white blood cell count was 2,740/muL, neutrophil count 1,140/muL, and lymphocyte count 880/muL. The interferon-gamma release assay for tuberculosis was negative. Differential diagnoses were interstitial pneumonitis or atypical pneumonia. The clinical course after onset of DILD is summarized in the  Supplementary Figure 2 . There were no apparent clinical manifestations of chronic GVHD around the time of DILD. As his respiratory status was stable, the antimicrobial agent levofloxacin was initiated. Four days after admission, the patient's respiratory status was stable. However, at night on day 5, the cough and dyspnea worsened and the oxygen demand increased. CT examination revealed expanded bilateral interstitial infiltrations ( Figure 3 ). The white blood cell count was 6,260/muL, neutrophil count 5,440/muL, and lymphocyte count 720/muL, and the KL-6 level was mildly elevated (531 U/ml). On day 6, methylprednisolone (1 g/day) and piperacillin-tazobactam (4.5 g q6hr) were administered. Thereafter, the patient's respiratory condition improved rapidly, and the shadows in the bilateral lung fields disappeared on day 21 after starting steroid therapy ( Figure 4 ). The steroid dose was gradually decreased and steroid administration was switched to oral prednisolone 30 mg/day after day 22. The prednisolone dose was reduced to 20 mg/day on day 33 after starting steroid treatment, and the patient was scheduled to be discharged. Immediately before discharge on day 39, the patient complained of abdominal pain. Abdominal CT revealed a retroperitoneal hematoma and pseudoaneurysm in the anterior superior pancreatic duodenal artery. Because bleeding from the metastasis near the pancreatic head was suspected, the patient was transferred to a tertiary hospital, where intra-arterial embolization was performed. During the intervention, oral prednisolone was maintained at the same dose, and the patient returned to our hospital immediately after the intervention. On day 43, the lung infiltration reappeared. On day 44, steroid pulse therapy with methylprednisolone (500 mg/day) and piperacillin-tazobactam (4.5 g q6hr) was resumed. The methylprednisolone dose was tapered to 125 mg/day on day 47. On day 49, nasal high-flow therapy was initiated because oxygen demand increased. On the same day, intravenous cyclosporine (150 mg/day) was started after consultation with a hematologist, and methylprednisolone (500 mg/day) was retried. On day 51, laboratory tests reported the levels of aspartate aminotransferase (32 U/L), alanine transaminase (53 U/L), alkaline phosphatase (351 U/L), gamma-glutamyl transpeptidase (236 U/L), and total bilirubin (3.0 mg/dL). Considering the possibility of exacerbation of sepsis, an antifungal agent, micafungin (100 mg/day), was administered to treat all infectious diseases. On day 53, because serum CMV antigenemia tested on day 51 was positive (Cytomegalovirus antigen positive cell count was 200-206 positive cells per two slides, CMV IgG was > 250 AU/mL, CMV IgM INDEX was 1.04, absolute lymphocyte count was 280/muL), ganciclovir (500 mg/day) was added in combination with other antibiotics. The measurements of the same blood sample showed that the white blood cell count was 22,740/muL, neutrophil count 22,060/muL, lymphocyte count 280/muL, LDH 654 U/L, creatinine kinase 22 U/L, CRP 3.89 mg/dL, and betaD-glucan test was negative. Unfortunately, the patient eventually died of respiratory and hepatic failure 56 days after starting the steroid therapy.
Chest CT showing the improvement in bilateral lung interstitial infiltrate shadows on day 21 of steroid treatment.