Correspondence
Efficacy of Granulocyte–Macrophage Colony-Stimulating Factor in Acquired Alveolar Proteinosis
N Engl J Med 1996; 335:1924-1925December 19, 1996
- Article
To the Editor:
Acquired alveolar proteinosis is a rare lung disease of adults characterized by excessive accumulation of surfactant.1 Standard therapy is whole-lung lavage, which usually provides temporary symptomatic benefit.1 In mice lacking the hematopoietic regulator granulocyte–macrophage colony-stimulating factor (GM-CSF), a pulmonary abnormality develops that resembles alveolar proteinosis.2,3 Therefore, we initiated a trial of recombinant human GM-CSF therapy in a patient with this disease after obtaining the approval of the institutional ethics committee and written informed consent from the patient.
A 49-year-old man was given a diagnosis of alveolar proteinosis after open-lung biopsy in 1993. He subsequently underwent three therapeutic lavages, with transient improvement each time. When GM-CSF therapy began, he had extensive alveolar infiltrates and could walk only 400 m on level ground or climb one flight of stairs. There was no evidence of pulmonary infection. During treatment with GM-CSF, his exercise capacity progressively increased and arterial oxygenation improved (Figure 1Figure 1
Serial Measurements of the Alveolar–Arterial Oxygen Gradient in a Patient with Acquired Alveolar Proteinosis during GM-CSF Therapy.). By day 35 he could walk an unlimited distance on level ground or climb four flights of stairs without resting. Treatment with GM-CSF was discontinued on day 70, at which time his activity was not limited and the alveolar infiltrates had partially cleared. However, by day 84 exertional dyspnea had recurred. Resumption of GM-CSF therapy on day 252 was followed by a similar pattern of improvement. There was no deterioration in oxygenation after GM-CSF was resumed, but vomiting and fever developed on day 1. Thereafter, the only side effects were mild erythema at injection sites and headache, which was relieved by acetaminophen. The patient's maximal neutrophil count was 6.65×109 per liter.Although the condition of some patients with alveolar proteinosis improves spontaneously, this patient's previous pattern of disease and the clinical, physiologic, and radiographic changes in response to the initiation, withdrawal, and reintroduction of GM-CSF therapy all support a causal role for GM-CSF in the response and are consistent with an underlying impairment of GM-CSF production or responsiveness in the pathogenesis of this patient's disease. On the basis of the pulmonary changes that characterize GM-CSF–deficient mice and the demonstrated impairment of surfactant clearance in these animals,5 it is likely that administered GM-CSF activates alveolar macrophages and increases their rate of surfactant clearance.
5 ReferencesJohn F. Seymour, M.B., B.S.
Ashley R. Dunn, Ph.D.
Ludwig Institute for Cancer Research, Parkville 3050, AustraliaJanette M. Vincent, M.B., B.S.
Jeffrey J. Presneill, M.B., B.S.
Michael C. Pain, M.D.
Royal Melbourne Hospital, Parkville 3050, Australia1
Wasserman K, Mason GR. Pulmonary alveolar proteinosis. In: Murray JF, Nadel JA, eds. Textbook of respiratory medicine. 2nd ed. Vol 2. Philadelphia: W.B. Saunders, 1994:1933-46.
2
Stanley E ,Lieschke GJ ,Grail D , et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no major perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci U S A 1994;91:5592-5596
CrossRef | Web of Science | Medline3
Dranoff G ,Crawford AD ,Sadelain M , et al. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994;264:713-716
CrossRef | Web of Science | Medline4
Harris EA ,Kenyon AM ,Nisbet HD ,Seelye ER ,Whitlock RM . The normal alveolar-arterial oxygen-tension gradient in man. Clin Sci Mol Med 1974;46:89-104
Medline5
Ikegami M ,Ueda T ,Hull W , et al. Surfactant metabolism in transgenic mice after granulocyte-macrophage colony stimulating factor ablation. Am J Physiol 1996;270:L650-L658
Web of Science | Medline
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