Everolimus associated interstitial pneumonitis: 3 Case reports

1.1. Case 1 

A 62-year-old patient was admitted for a dyspnea since 15 days. He had displayed an adenocarcinoma of the left kidney diagnosed in 2003, initially treated by widened nephrectomy. In 2005, pulmonary metastases were treated by surgery, and retroperitoneal localizations were treated with interferon alpha for 5 months. He received then the oral anti-angiogenic sunitinib because of pulmonary progression. From March 5th 2005, the patient was treated by 10mg/d of everolimus as a third line therapy in the frame of a clinical trial. Other treatments were: l-thyroxine, manidipine, and nadroparin calcium. After one month of treatment, a progressive dyspnea appeared, associated to a fever up to 40°C. Investigations attributed the fever to a purulent sinusitis with presence of Staphylococcus aureus and Streptococcus pneumoniae. Apyrexia was obtained with adapted antibiotic therapy and sinus drainage. Nevertheless the patient still displayed dyspnea.

A Sadoul scale stage II dyspnea was the only symptom detected. The blood oxygen saturation was of 86% at room air. The chest examination found bilateral fine crackles. White blood cell count revealed 7.6Giga/l elements (6.3Giga/l neutrophils, 0.15Giga/l lymphocytes and normal eosinophil, basophil and monocyte counts). Plasma fibrinogen concentration was of 9g/l. Liver enzymes were elevated (ASAT=2N, ALAT=2.5N), and a cholestasis was detected (gammaglutamyl transpeptidase and alkaline phosphatase elevated at 3N). The renal function was normal.

Chest radiograph showed bilateral interstitial infiltrate, and thoracic computed tomography confirmed by bilateral ground-glass opacities (Fig. 1). Pulmonary function tests revealed a moderate restrictive ventilatory defect (TLC 76.5%, RV 79.1% of predicted values, FEV1/FVC 94.2), and a severe alteration of lung diffusing capacity (DLCO 38.9% value, DLCO adjusted for alveolar volume DLCO/AV 64.1% of predicted value).

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Fig. 1 Case no. 1. Thoracic computed tomography: ground-glass aspect.

A bronchoscopy was performed and showed a haemorrhagic aspect of the bronchial mucosa at the entry of the lower right lobe bronchus without any other abnormality. The extensive microbial analysis of broncho-alveolar lavage (BAL) was negative. BAL fluid cytologic analysis revealed a profile compatible with hypersensitivity pneumonitis (31% macrophages, 40% lymphocytes with various activation stages, 29% granulocytes, mainly eosinophils). Transbronchial lung biopsies confirmed the hypersensitivity pneumonitis on alveolar lumen containing many macrophages, lymphocytic infiltrate in alveolar septa with a recent fibrosis including rare endoalveolar buds, and some granulomas.

The dyspnea being well tolerated, no corticosteroid therapy was required. Everolimus was stopped and the evolution was favourable with improvement of dyspnea and radiological abnormalities.

Diagnosis of everolimus-associated pneumonitis was retained on the absence of infectious disease, the chronology of the events and the presence of histological features of hypersensitivity pneumonitis.

1.2. Case 2 

A 51-year-old patient was referred to the pulmonary department because of an interstitial pneumonia, associated with asthenia, anorexia, weight loss, and fever. His main medical past was a renal adenocarcinoma with pulmonary metastases already present at diagnosis in March 2007. A treatment of 10mg/d of everolimus was started at that date. Other therapies included paracetamol, levocetirizine, and atorvastatine. One month later, progressive dyspnea with morning dry cough, fever up to 38.5°C, shivers, weight loss of 2kg, anorexia and asthenia developed. There was no thoracic pain, nor extrapulmonary sign to explain this fever. Chest examination was normal and blood oxygen saturation was of 98% at room air.

Chest radiograph revealed some discrete diffuse alveolar opacities confirmed by thoracic computed tomography, associated to bilateral ground-glass opacities. Pulmonary function tests showed a moderate alteration of carbon oxide diffusing capacity (90% of predicted values) without any ventilatory defect. Bronchoscopy was macroscopically normal. The extensive microbial analysis of BAL was negative. BAL fluid cytologic analysis showed again a profile compatible to hypersensitivity pneumonitis (15% macrophages, 77% lymphocytes with a polymorphic lymphoid population, 8% neutrophils). Transbronchial lung biopsies revealed a hypersensitivity pneumonitis with lymphocytic infiltrates on alveolar septa, eosinophilic granulocytes, a recent fibrosis and some granulomas.

Everolimus was stopped. After one month, pulmonary symptoms and fever had disappeared. Thoracic computed tomography showed the persistence of metastatic lesions but a disappearance of ground-glass opacities.

We concluded to an everolimus-associated hypersensitivity pneumonitis because of clinical, radiological and anatomopathological findings, and of the clinical evolution.

1.3. Case 3 

A 74-year-old patient was admitted in the nephrology department because of a feverish dyspnea. He was followed for a chronic glomerulonephritis since 1976. A first renal transplantation was performed in 1990 and a second in 2002 because of a chronic graft rejection. The treatment included tacrolimus and mycophenolate mofetil. This immunosuppressive therapy induced a cutaneous carcinoma. It was replaced by sirolimus in March 2006, then by everolimus in August 2006 because of anemia. Everolimus serum levels were in the therapeutic range, between 8 and 10mg/l.

In September 2007, the patient displayed cough with feverish (39°C) dyspnea. A probabilistic antibiotic therapy including a third-generation cephalosporin was started but failed. Chest examination found previously known systolic mitral murmur, diminution of breath sounds in the left pulmonary field associated with fine crackles, and ronchi in right pulmonary base. The blood oxygen saturation was of 94% under 2l/min of oxygen. White blood cell count was of 4.48Giga/l. There was an inflammatory anemia with hemoglobin at 7.7g/dL and a C reactive protein level of 151mg/L. The renal function was stable with a serum creatinine level of 146μmol/l. Liver enzymes were elevated (ASAT=2.5N, ALAT=2N), a cholestasis was detected (gammaglutamyl transferase at 1.8N, alkaline phosphatases at 1.5N).

Chest radiograph revealed alveolar opacities in upper and lower left lung lobes, and an interstitial syndrome of lower right lobe. Thoracic computed tomography showed ground-glass and alveolar opacities in the middle lobe and the upper right lobe, and ground-glass opacities of both lung bases (Fig. 2). Antibiotic therapy containing ceftriaxone and ofloxacin was started without success.

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Fig. 2 Case no. 2. Thoracic computed tomography: alveolar opacities and bilateral ground-glass aspect.

Bronchoscopy was macroscopically normal. The extensive microbial analysis of BAL and blood cultures was negative. BAL fluid cytologic analysis found 33% macrophages, 63% lymphocytes with various activation stages, 1.8% neutrophils and 1% eosinophils, a profile compatible with a hypersensitivity pneumonitis. Transbronchial lung biopsies confirmed this diagnosis with a recent fibrosis forming endoalveolar fibrous buds. Antibiotic therapy and everolimus were discontinued. A corticosteroid therapy at 1mg/kg per day was started. We observed a clinical improvement with apyrexia regression of chest symptoms and biological inflammatory syndrome.

Diagnosis of everolimus-associated hypersensitivity pneumonitis was retained on the clinical and biological evolution, the radiological and anatomopathological aspects and the absence of infectious disease.