Abstract
Pneumocystis jirovecii (formerly carinii) pneumonia (PJP) is an opportunistic infection well-recognized in patients with profound T cell immunodeficiency. It is much less common in patients with solid tumors unless they have other major predisposing factors such as prolonged treatment with corticosteroids or T4 lymphocyte counts of less than 200 cells/mm3. We present a previously unreported case of fatal PJP in a breast cancer patient with bone metastases who was receiving a first-line treatment with weekly paclitaxel, trastuzumab, and dexamethasone as premedication for paclitaxel. She had received eight doses of paclitaxel at 80 mg/m2, trastuzumab 2 mg/m2, and dexamethasone 10 mg for just over 7 weeks when she was diagnosed with PJP. While the patient’s granulocyte counts were normal throughout her treatment, the total lymphocyte counts reached the nadir of 400 cells/mm3 a few days after the eighth dose of chemotherapy – around the time of PJP diagnosis. Both dexamethasone and the total lymphocyte nadir predisposed this patient to PJP.
Keywords
Introduction
Pneumocystis jirovecii pneumonia (PJP), formerly Pneumocystis carinii pneumonia, is an opportunistic infection well-recognized in patients with profound T cell immunodeficiency. It is much less common in patients with solid tumors unless they have other major predisposing factors. A few cases have been reported in breast cancer patients who had received high-dose chemotherapy followed by autologous stem cell transplantation, multiple cycles of chemotherapy spanning more than a year, and multiple cycles of dose-dense chemotherapy. 1 – 3
Trastuzumab is a humanized monoclonal antibody targeting the human epidermal growth factor receptor type-2 protein that is overexpressed in some breast tumors. There have been no reports of PJP in patients receiving trastuzumab as a single agent or in combination with chemotherapy. 4
Paclitaxel is a taxane chemotherapy drug widely used to treat many types of solid tumors. There have been reports of PJP in patients treated with ‘intensive’ taxane treatment. 5 Here we describe a previously unreported case of PJP in a patient with metastatic breast cancer treated with weekly paclitaxel and trastuzumab, with dexamethasone as part of premedications for paclitaxel.
Case report
A 62-year old woman was diagnosed with hormone receptor-negative and Her2/neu receptor-positive breast cancer with multiple bone metastases in early 2007. First-line treatment with weekly paclitaxel (Apotex Inc., Weston, Ontario, Canada) at 80 mg/m2 and trastuzumab (Hoffman-La Roche Limited, Mississauga, Ontario, Canada) at 2 mg/kg was initiated on 1 April 2007, with dexamethasone (Sandoz Canada Inc., Boucherville, Quebec City, Canada) 10 mg IV as one of premedications for paclitaxel.
On 1 June she presented to the hospital for her eighth dose of paclitaxel and trastuzumab. She complained of fatigue for the past one week and a nonproductive cough for the past 2–5 days but did not have fever. After paclitaxel and trastuzumab were administered, the oxygen saturation dropped from 93% to 84%.
On auscultation, there were a few crackles in both lungs, but good air entry bilaterally. She was sent for an urgent computed tomography (CT) scan of the thorax, which showed extensive ground-glass opacities and some reticular changes extending from the perihilar region to the lung periphery and to the apex in the right upper lobe as well as to the basal segments in both lower lobes. There was some evidence of fibrosis with mild bronchiolectasis, but no nodularity or interlobular septal thickening. There was no evidence of pulmonary embolism.
She was admitted to the hospital and treatment with ceftriaxone (Sandoz Canada Inc., Boucherville, Quebec City, Canada), azithromycin (Pfizer Canada Inc., Kirkland, Quebec City, Canada) and various doses of prednisone (Apotex Inc., Weston, Ontario, Canada), equivalent to approximately 1 mg/kg daily, was initiated. Blood, urine, and sputum cultures were all negative. Total lymphocyte count was 400 cells/mm3 on 3June. Bronchoalveolar lavage was performed on 4June and was negative for virus, fungus, Legionella, and acid-fast bacilli. However, Pneumocystis jirovecii was detected by immunofluorescence. On 6 June the arterial blood gas pH was 7.54, pCO2 30 mmHg (normal, 35–45 mmHg), pO2 36 mmHg (normal, 80–100 mmHg) and oxygen saturation of 74%.
Sulfamethoxazole/trimethoprim (SMZ/TMP) (GlaxoSmithKline Inc., Mississauga, Ontario, Canada) was added to the antibiotic regimen, but the patient deteriorated and died 17 days after admission to the hospital. The admission diagnosis was changed from pneumonitis to PJP once Pneumocystis jirovecii was detected in BAL, and the cause of death was stated as pneumonia. The human immunodeficiency virus (HIV) status was never tested in this patient as it was felt that she did not have the risk factors for it.
Discussion
Two important predisposing factors for PJP include prolonged treatment with corticosteroids and T4 lymphocyte counts of <200 cells/mm3. 1 –3,5– 11 Prednisone equivalent doses of 16 mg daily for 8 weeks or 20 mg daily for 1 month were reported as significant risk factors for PJP in patients who did not have acquired immune deficiency syndrome (AIDS).7,11 Sepkowitz and colleagues categorized pulse corticosteroid dose given as part of chemotherapy treatment as corticosteroid taper. 6 They observed that more than half of the PJP cases were diagnosed during the corticosteroid taper, with prednisone equivalent doses ranging between 15 and 480 mg given over 1–48 months. 6
Our patient received dexamethasone 10 mg (equivalent to about 67 mg of prednisone) once weekly over seven weeks before the diagnosis of PJP. Tolaney and colleagues reported two cases of PJP in breast cancer patients who received four cycles of dose-dense chemotherapy over a six-week period. 3 One patient received dexamethasone 24 mg (approximately 160 mg of prednisone) every two weeks over six weeks. 3 The dexamethasone dose was not specified for the second patient. 3
Mackall and colleagues reported slower recovery of lymphocytes compared to granulocytes with each successive cycle of dose-intensive chemotherapy. 12 Our patient also had normal granulocyte counts throughout paclitaxel treatment, while total lymphocyte counts trended downward with the nadir reaching 400 cells/mm3 after seven weekly doses of paclitaxel, and just prior to the diagnosis of PJP. The two cases of PJP reported by Tolaney and colleagues also occurred around the time of lymphocyte nadir. 13
Seven weeks of dexamethasone and severe lymphocytopenia likely predisposed our patient to PJP. While the incidence of PJP among breast cancer patients receiving taxane chemotherapy is low, the mortality rate among cancer patients is high at approximately 50%.9,10,14 Some centers, such as Memorial Sloan-Kettering Cancer Centre, treat cancer patients receiving an equivalent of prednisone 20 mg or more for one month or more with prophylactic SMZ/TMP, which is continued for one month after the corticosteroid is discontinued.7,9 For many other centers, PJP prophylaxis is not a standard among solid tumor patients. Consideration may need to be given to those patients receiving prolonged corticosteroid treatment, including both continuous and interrupted,6,7,9– 11 especially during periods of severe lymphocytopenia.
Footnotes
Acknowledgments
Authors would like to thank Ms Kimberley Stefaniuk and DrSrikala Sridhar for the editing of this manuscript. Sophie Kim would also like to thank Mr Jack Seki for his counsel and support. All authors confirm no conflict of interest in the write-up of this manuscript.