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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3174-3175 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.7176
Granulocyte Colony-Stimulating Factor–Induced Pulmonary Hemorrhage in a Healthy Stem Cell DonorDepartment of Medical Oncology, Hematology, Immunology, Rheumatology, and Pulmology, Medical Center II, Eberhard-Karls-University, Tubingen, Germany
Department of Diagnostic Radiology, Eberhard-Karls-University, Tubingen, Germany
Department of Medical Oncology, Hematology, Immunology, Rheumatology, and Pulmology, Medical Center II, Eberhard-Karls-University, Tubingen, Germany
Children's University Hospital, Eberhard-Karls-University, Tubingen, Germany
Department of Medical Oncology, Hematology, Immunology, Rheumatology, and Pulmology, Medical Center II, Eberhard-Karls-University, Tubingen, Germany Herein, we report on a healthy 49-year-old male donor of haploidentical peripheral hematopoietic stem cells for his daughter, who had been diagnosed with acute myelogenic leukemia. Before stimulation with granulocyte colony-stimulating factor (G-CSF), this man was found to be in good health after physical examination, lung function testing, ECG as well as a chest x-ray. In addition, laboratory values were normal (Table 1). Being a cigarette smoker with a history of approximately 30 pack years, the only complaint at presentation was chronic nonproductive cough. There were no signs of infection or inflammation, and the patient was not taking any over-the-counter or prescribed drugs.
After 3 days of 10 µg/kg of subcutaneous G-CSF, divided in two doses, the donor developed cough, retrosternal discomfort, and hemoptysis. In our outpatient clinic he was found to have thickening of the peribronchovascular lung interstitium with ill-defined margins and associated patchy infiltrates distributed over both lower and middle pulmonary fields, consistent with pulmonary hemorrhage in a plain radiograph of the chest (Fig 1). In a nonenhanced high resolution computed tomography (CT) scan, there were patchy, ill-defined areas of ground-glass attenuation and even parenchymal consolidation acompanied by ill-defined centrilobular nodules. Due to the superimposition of these findings with mild thickening of intralobular septal lines, an unusual paving pattern was suggested (Fig 2). The opacities were found to involve the lower and dorsal aspects of both lungs. Additional infectious infiltrations could not be ruled out. There were no signs of pulmonary arterial embolism with contrast medium. Moreover, there was no growth of bacteria or fungi in sputum cultures. Immunopathologic examination of the patient's serum neither showed antialveolar basement nor any other autoantibodies. In contrast to the impressive imaging findings, repeated arterial blood gas analyses showed minor changes without respiratory failure. The patient was treated with high-dose prednisone (450 mg for 3 days) and with amoxycilline/clavulanic acid (2.2 g three times per day) because of concomitant fever and the aforementioned CT results suggesting additional pneumonic infiltrations. After 3 days, hemoptyses and temperature subsided. A CT scan showed remarkable improvements of hemorrhage. The patient could be discharged on an oral antibiotic regimen, which he completed 1 week later. G-CSF was discontinued, and the donor's wife was successfully substituted as a haploidentical donor for their daughter.
G-CSF induces mobilization of hematopoietic stem and progenitor cells by a variety of only partially known mechanisms, including disruption of SDF-1/CXCR-4 adhesive interaction in the bone marrow stem cell niche and liberation of soluble stem cell factor by directly or indirectly activated proteases, thereby allowing transendothelial passage of hematopoietic stem cells/hematopoietic progenitor cells into the bloodstream in a process that appears to be diametric to the phenomenon of homing.1 During G-CSF application in healthy adult humans, significant increases in polymorphonuclear granulocytes may contribute to some of the unwanted adverse effects. In animal models of lung injury, G-CSF-induced neutrophilia significantly increased the toxicity of intratracheal bleomycin.2 More data from the same group underscore the importance of G-CSF induced neutrophilia in the pathogenesis of toxic pulmonary lesions. However, when the author evaluated a large number of G-CSF treated human individuals developing lung pathology, only two of 1,801 cases had been treated with G-CSF alone.3 One more case has been published, where a healthy human donor of peripheral hematopoietic stem cells developed acute lung injury on day 4 of 10 µg/kg G-CSF.4 Due to these preclinical and clinical data, we suggest that pulmonary toxicity is a rare adverse effect of G-CSF application and may be especially important in patients with underlying pulmonary changes, in our case consistent with a history of cigarette smoke induced chronic obstructive pulmonary disease. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. Gazitt Y: Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: Circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies. Leukemia 18:1-10, 2004[CrossRef][Medline] 2. Azoulay E, Herigault S, Levame M, et al: Effect of granulocyte colony-stimulating factor on bleomycin-induced acute lung injury and pulmonary fibrosis. Crit Care Med 31:1442-1448, 2003[CrossRef][Medline] 3. Azoulay E, Attalah H, Harf A, et al: Granulocyte colony-stimulating factor or neutrophil-induced pulmonary toxicity: Myth or reality? Systematic review of clinical case reports and experimental data. Chest 120:1695-1701, 2001[CrossRef][Medline] 4. Arimura K, Inoue H, Kukita T, et al: Acute lung injury in a healthy donor during mobilization of peripheral blood stem cells using granulocyte-colony stimulating factor alone. Haematologica 90:ECR10, 2005
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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