Pneumocystis pneumonia in everolimus therapy: An indistinguishable case from drug induced interstitial lung disease
A 66-year-old Japanese male with advanced renal cell carcinoma (RCC) visited our respiratory outpatient clinic complaining of progressive exertional dyspnea for 1 month after administration of everolimus. He had suffered from unresectable RCC with multiple bone metastases for 2 years (clear cell carcinoma. cT3cN0M1. stage IV). Previous therapy included sunitinib for 1 year, followed by axitinib for 2 months. This regimen failed to prevent disease progression. Thereafter, third-line therapy with everolimus was initiated. The patient was an exsmoker and had stopped smoking 35 years back. Annual check-ups had revealed that he was asymptomatic for any breathing problems, with no abnormalities in the pulmonary function tests or chest computed tomography (CT) scans. On his first visit to our clinic, he was afebrile but presented with general malaise and tachypnea accompanied by hypoxemia (SpO2, 96% after inhaling oxygen by mask at 4 L/min). He had slight systemic edema, probably caused by renal insufficiency and/or hypoalbuminemia. Cardiac pulmonary edema was excluded by echocardiography. On chest auscultation, no wheeze or crackle was audible. Chest radiograph revealed bilateral infiltration on both lungs, while chest CT revealed diffuse ground glass opacities in both lung fields (A and B). The laboratory findings on admission are presented in . In brief, we observed mild lymphocytosis, mild anemia, thrombocytopenia, slight liver dysfunction, and renal insufficiency. Lactate dehydrogenase (LDH) and CRP were elevated at 583 IU/L and 16.7 mg/dl, respectively. The serum level of Krebs von den Lungen-6 (KL-6): a sensitive marker for interstitial pneumonia, was also elevated at 735 U/mL (normal range; <500 U/mL), excluding the possibility of atypical pneumonia. On the basis of these findings, we suspected that the patient had everolimus-induced ILD. On the first hospital day, a bronchoalveolar lavage (BAL) was performed to determine the cellular fractionation in the BAL fluid (BALF) as well as to exclude respiratory infections. BALF recovered from right B3b revealed an increased total cell number (3.10 × 105 cells/mL) with lymphocytosis (macrophages, 65.4%; lymphocytes, 29.0%; neutrophils, 4.2%; eosinophils, 1.4%). The CD4/CD8 ratio was 0.9 (normal range in nonsmokers, 0.4−1.0). BALF cultures were negative for bacteria, acid-fast bacilli, and fungi. Unfortunately, we could not perform a transbronchial lung biopsy (TBLB) because of the patient's frequent cough and oxygen desaturation during the bronchoscopic procedure.\nBecause drug allergy for everolimus was strongly suspected, we performed a drug-induced lymphocyte stimulation test (DLST) using serum and BALF. Although DLST with serum revealed a negative reaction, the test with BALF was positive with a stimulation index of 204% compared with that in the control (368 cpm for everolimus and 179 cpm for control). Taken together, these clinical findings confirmed the diagnosis of everolimus-induced ILD. Therefore, everolimus therapy was discontinued, and intravenous methylprednisolone administration (1000 mg/day for 3 consecutive days) was initiated immediately after BAL. Oral prednisolone administration (50 mg/day) was followed by steroid pulse therapy. Despite this vigorous therapy, his respiratory distress and radiographic findings rapidly exacerbated day by day (). On the fifth hospital day, the presence of PCR for Pneumocystis jirovecii DNA in BALF was established. Moreover, serum (1–3) – β−D-glucan levels were markedly increased at 137.5 pg/mL (normal range; <20 pg/mL). Cytomegalovirus (CMV) pp65 antigenemia in the serum and CMV-DNA in BALF were negative. Therefore, a diagnosis of PCP was confirmed. Intravenous trimethoprim-sulfamethoxazole administration was initiated immediately, and his respiratory symptoms improved dramatically within a week, along with dissolution of the interstitial shadow on radiographs. Unfortunately, everolimus was discontinued even after recovery from PCP owing to intolerable adverse gastrointestinal effects, including nausea and anorexia. The patient was referred to the palliative care unit and died of cancer 5 months later.