To the Editor:
We enjoyed the comprehensive review of alveolar proteinosis by Seymour and Presneill (1). Recent murine models have implicated a role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in surfactant homeostasis (2). Therapeutic whole-lung lavage under anesthesia has emerged as the standard therapy for symptomatic pulmonary alveolar proteinosis (PAP) with hypoxemia (3). Preliminary observations indicate that GM-CSF therapy may benefit some patients with idiopathic PAP (4, 5). The human disease differs from the murine model since patients have neutralizing antibodies against GM-CSF, both in the sera and lung lavage fluid (6). Whether the anti–GM-CSF antibody is an epiphenomenon or is involved in the pathogenesis of PAP remains unknown.
We describe the case of a 41-year old nonsmoker with a 5-year history of non-resolving pulmonary infiltrates. Open-lung biopsy showed typical pathologic features of idiopathic pulmonary alveolar proteinosis (i.e., air spaces filled with eosinophilic proteinaceous material without significant inflammation or tissue destruction). She underwent whole-lung lavage on three occasions with a modest benefit only. She was treated with subcutaneous GM-CSF at 18 mcg/kg/day for 6 months without objective improvement. After experimental therapy with GM-CSF, she continued to require oxygen between 3 and 6 liters at rest, underwent five additional whole-lung lavages over 18 months without improvement, and was evaluated for possible lung transplantation. The circulating anti–GM-CSF antibody titer was 1:6,400 on multiple occasions. On a compassionate basis, she was treated with plasmapheresis, 1.5 plasma volume exchanges on ten separate sessions over a 2-month period. One of these episodes was complicated by gram-negative sepsis and respiratory failure. She subsequently recovered from this, and her anti–GM-CSF antibody titer was reduced to 1:400. This reduction in the anti–GM-CSF antibody titer with plasmapheresis was associated with improvement in symptoms, oxygenation, and radiographs. She continues to be off oxygen with a room air PaO2 of 75.
This observation of a dramatic reduction in circulating antibody titer in PAP with plasmapheresis, along with improvement of the lung disease, is the first reported case. These data represent strong evidence that the circulating anti–GM-CSF antibody is involved in the pathogenesis of idiopathic PAP, and that measures to lower the circulating antibody level should be considered as an alternative therapeutic measure.
| 1. | Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002;166:215–235. |
| 2. | Dranoff G, Crawford AD, Sadelain M, Ream B, Mulligan RC. Involvement of granulocyte-macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994;264:713–716. |
| 3. | Ramirez RJ, Kieffer RF, Ball WC. Bronchopulmonary lavage in man. Ann Intern Med 1965;63:819–828. |
| 4. | Kavuru MS, Sullivan EJ, Piccin R, Thomassen MJ, Stoller JK. Exogenous granulocyte-macrophage colony-stimulating factor administration for pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000;161:1143–1148. |
| 5. | Seymour JF, Presneill JJ, Schoch OD, Downie GH, Moore PE, Doyle IR, Vincent JM, Nakata K, Kitamura T, Langton D, et al. Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis. Am J Respir Crit Care Med 2001;163:524–531. |
| 6. | Kitamura T, Tanaka N, Watanabe J, Uchida K, Kanegasaki S, Yamada Y, Nakata K. Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte-macrophage colony-stimulating factor. J Exp Med 1999;190:875–880. |
From the Authors:
We thank Dr. Kavuru and colleagues for their interest in our review of pulmonary alveolar proteinosis (PAP) where we discussed the features shared with antiglomerular basement membrane antibody disease (AGBMAD) (1). They describe an illustrative case of PAP, where, as expected, serum anti–GM-CSF antibody was detected (2). Therapy with relatively low-intensity plasmapheresis for 2 months was associated with clinical improvement and a reduction in the titre of anti–GM-CSF antibody. This case suggests further similarities between PAP and AGBMAD, where anti-GBM antibodies have been directly shown to be pathogenetic in experimental animals (3). The described correlation between improved clinical parameters and reductions in serum anti–GM-CSF antibody levels, which has also been observed in a patient treated with GM-CSF (4), does not formally establish the pathogenetic role for anti–GM-CSF antibodies in PAP, although on present evidence this is likely (1). Direct experimental confirmation of this pathogenetic role may be problematic due to inter-species variability in GM-CSF sequence and incomplete knowledge of the reactivity of the antibody. The case described by Kavuru and colleagues suggests that there may be a relationship between the serum concentration of anti–GM-CSF antibody and the activity of the disease process. However, by conventional measures of disease severity, we have not been able to demonstrate this relationship (5). This could relate to a “compartmentalisation” phenomenon, where marked differences may exist between BAL and serum anti–GM-CSF antibody concentrations (4). It is likely that the level of antibody within the alveolar fluid is the primary determinant of alveolar macrophage exposure to bioactive GM-CSF.
In any case, the likely pathogenetic role of the IgG anti–GM-CSF antibody in PAP provides a rationale for the investigation of plasmapheresis to reduce antibody levels. IgG antibodies are relatively inefficiently cleared by plasmapheresis, as more than 50% are distributed within the extravascular space and there is rapid re-equilibration. Clinically, plasmapheresis at less than 3-day intervals is most effective at sustaining reduced IgG levels (6), and a more effective program may consist of 5 or more exchanges over 7–14 days, together with measures to concomitantly reduce further antibody production, as has been shown to be effective in AGBMAD (7). However, the corticosteroids and cylophosphamide used in AGBMAD may have deleterious effects upon alveolar macrophage function and number, respectively. Properly conducted clinical trials of plasmapheresis and immunosuppression in PAP should provide further insight into the pathogenesis of this fascinating disease, and may expand our current choice of effective therapies.
| 1. | Seymour JF, Presneill JJ. Pulmonary alveolar proteinosis: progress in the first 44 years. Am J Respir Crit Care Med 2002;166:215–235. |
| 2. | Kitamura T. Uchida K, Tanaka N, Tsuchiya T, Watanabe J, Yamada Y, Hanaoka K, Seymour JF, Schoch OD, Doyle I, et al. Serological diagnosis of idiopathic pulmonary alveolar proteinosis. Am J Respir Crit Care Med 2000;162:658–662. |
| 3. | Lerner RA. Glassock RJ, Dixon FJ. The role of anti-glomerular basement membrane antibody in the pathogenesis of human glomerulonephritis. J Exp Med 1967;126:989–1004. |
| 4. | Schoch OD. Schanz U, Koller M, Nakata K, Seymour JF, Boehler A. BAL findings in a patient with pulmonary alveolar proteinosis successfully treated with GM-CSF. Thorax 2002;57:277–280. |
| 5. | Seymour JF, Doyle IR, Nakata K, Presneill JJ, Schoch OD, Hamano E, Uchida K, Fisher R, Dunn AR. Relationship of anti–GM-CSF antibody concentration, surfactant protein A and B levels, and serum LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis. Thorax 2003;58:252–257. |
| 6. | Keller AJ, Urbaniak SJ. Intensive plasma exchange on the cell separator: effects on serum immunoglobulins and complement components. Br J Haematol 1978;3:531–540. |
| 7. | Levy JB. Turner AN, Rees AJ, Pusey CD. Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosuppression. Ann Intern Med 2001;134:1033–1042. |
