Therapeutic Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Idiopathic Acquired Alveolar Proteinosis

Abstract

Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of GM-CSF in patients with idiopathic AP. Fourteen patients received 5 microg/kg/d GM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]DO2), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 microg/kg/d GM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for GM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 microg/kg/d GM- CSF, and one of four patients responded after dose escalation (20 microg/kg/d). The overall response rate was 43% (mean improvement in [A-a]DO2 = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. GM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was GM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM- CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.

Pulmonary Alveolar Proteinosis

“…Several reports found favorable response with systemic (subcutaneous) or localized (aerosol) GM-CSF. 10,132,136,142,[182][183][184][185][186][187][188][189][190][191] Prompt improvement with resumption of GM-CSF in patients who relapsed with GM-CSF therapy suggests that disease resolution was not attributable to spontaneous remission and that GM-CSF does have therapeutic activity. 183 Response is generally slow after GM-CSF therapy: the majority of patients show P (A-a)O 2 improvement of Ն 10 mm Hg only after 4 -6 weeks.…”

“…183 Response is generally slow after GM-CSF therapy: the majority of patients show P (A-a)O 2 improvement of Ն 10 mm Hg only after 4 -6 weeks. [181][182][183][184][185][186][187][188][189][190] Despite the slower improvement in oxygenation with GM-CSF, the magnitude of therapeutic effect achievable with GM-CSF or whole-lung lavage may be similar. 184 The observed delay in response is due to the time required for immature precursor cells to be recruited to the lung and stimulated by GM-CSF to differentiate into functional alveolar macrophages.…”

“…[181][182][183][184][185][186][187][188][189][190] Despite the slower improvement in oxygenation with GM-CSF, the magnitude of therapeutic effect achievable with GM-CSF or whole-lung lavage may be similar. 184 The observed delay in response is due to the time required for immature precursor cells to be recruited to the lung and stimulated by GM-CSF to differentiate into functional alveolar macrophages. The predictors of response with GM-CSF are yet to be determined, but one study found pre-treatment variables such as longer time from diagnosis, higher vital capacity, normal serum lactate dehydrogenase level, and higher plasma surfactant-protein-B level to be significantly associated with response to GM-CSF.…”

“…Similarly, peak eosinophil count following GM-CSF was the only treatmentrelated variable associated with response. 184 GM-CSF is generally well tolerated, but flushing, tachycardia, hypotension, musculoskeletal pain, dyspnea, nausea and vomiting, rigors, involuntary leg spasms, and syncope may occur following the first dose. These symptoms usually last for 10 min and do not recur with subsequent doses.…”

Proteinosis alveolar, un hallazgo incidental en un estudio preoperatorio con respuesta insuficiente al lavado pulmonar completo

“…Por otra parte, se han publicado casos de remisión espontánea sin tratamiento (10,15,16). De ser necesario algún tratamiento el LPC es el más seguro y efectivo (1), siendo la administración de GM-CSF una alternativa en casos seleccionados (17,18). Las infecciones oportunistas son la complicación más frecuente, y deben tratarse de forma específica.…”