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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of lipoproteinaceous material within the alveoli. Recent data suggest that granulocyte-macrophage colony- stimulating factor (GM-CSF) may be involved in the pathogenesis of PAP. To extend this understanding and clarify whether GM-CSF replacement confers benefit, we report the preliminary results for the first four patients in an open-label study of GM-CSF treatment for moderate exacerbation of PAP. All four patients had idiopathic PAP confirmed by open lung biopsy. Subcutaneous GM-CSF was self-administered once daily for 12 wk (dose escalation from 3 to 9 µg/kg/d). Response was assessed from symptom scores, arterial blood gas measurements, pulmonary function testing, and chest radiographs. Three of the four patients experienced symptomatic, physiologic, and radiographic improvement with GM-CSF. Responders experienced sufficient improvement in oxygenation as to eliminate the need for supplemental oxygen, and one patient was removed from the waiting list for lung transplantation. Improved oxygenation was not apparent until 8 to 12 wk after the start of therapy. Notably, expected increases in the peripheral white blood cell count did not occur, suggesting lack of a hematopoietic response to exogenous GM-CSF in PAP. We conclude that GM-CSF appears to benefit a subset of patients with adult PAP, and may represent an alternative to whole-lung lavage in treating the disease.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Pulmonary alveolar proteinosis (PAP) is an uncommon, idiopathic disease characterized by the deposition of extracellular granular lipoproteinaceous material within the alveoli of the lung. Although the true prevalence of PAP is unknown, the disease is considered rare, with current understanding based on fewer than 500 reported cases (1). PAP may exist in a primary or idiopathic form, or can result from a variety of conditions including infections, hematologic malignancies, and certain dust exposures (e.g., silica) (6). Patients with PAP may present with progressive cough and dyspnea along with alveolar infiltrates. The diagnosis can often be established by a characteristic milky-appearing bronchoalveolar lavage fluid (BALF), along with confirmatory findings by bronchoscopic biopsy or open lung biopsy. Sequential whole-lung lavage is currently the only established therapy for PAP, and has been shown to alleviate symptoms and improve oxygenation in adult patients with idiopathic PAP (7). The whole-lung lavage requires general anesthesia and intubation with a double-lumen endotracheal tube, which allows ventilation of one lung while the other lung is filled with saline and drained to "wash out" proteinaceous material from the alveolar spaces. Although whole-lung lavage is currently standard therapy for PAP, the clinical course of PAP is quite variable, and spontaneous improvement has been reported (3, 5). A variety of other treatments, including corticosteroids, have been largely unsuccessful.
Although there is persisting uncertainty about the pathogenesis of PAP, current thinking postulates an abnormality in
surfactant regulation, causing either increased surfactant production, decreased surfactant clearance, or both as the source
of the disease. Furthermore, recent murine gene-targeting
studies have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) is essential for normal surfactant clearance, and significant evidence is emerging that implicates lack
of stimulation by or responsiveness to GM-CSF in PAP. For example, genetically altered knockout mice, homozygous for a
disrupted GM-CSF gene develop a lung lesion histologically
resembling that in PAP, but with normal hematopoiesis (8, 9).
Mice defective in the GM-CSF/interleukin (IL)-3/IL-5-receptor
common 
c-chain demonstrate lung abnormalities resembling
those in PAP (10). Huffman and coworkers have reported that
local pulmonary epithelial cell expression of GM-CSF utilizing
the promoter gene from the human surfactant protein (SP)-C
gene, corrects alveolar proteinosis in GM-CSF-deficient mice
(11). Bone marrow transplantation and hematopoietic reconstitution of GM-CSF-deficient mice have been shown to reverse the lung disease in PAP (12, 13). Aerosolized GM-CSF,
administered daily over a period of 4 to 5 wk, appears to substantially mitigate PAP in GM-CSF-deficient mice (14). Additionally, Seymour and colleagues recently reported experience in a single adult patient with idiopathic PAP, in whom gas exchange improved significantly with administration of GM-CSF,
subsequently worsened with discontinuation of the drug, and
improved again with readministration of GM-CSF (15). Taken
together, these observations suggest that a relative deficiency
of or loss of responsiveness to GM-CSF may play a role in
PAP. To extend this understanding of the pathogenesis of
PAP, and to clarify whether GM-CSF replacement confers
benefit in PAP, we report the preliminary results of an open-label study of GM-CSF treatment for moderate exacerbation
of PAP.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The study was a prospective, open-label clinical trial of daily GM-CSF
therapy in a group of patients with idiopathic PAP. This study was approved by the institutional review board of The Cleveland Clinic
Foundation, and informed consent was obtained from all subjects
prior to enrollment. A diagnosis of idiopathic PAP was confirmed by
review of open lung biopsy results in all patients. Eligibility criteria included: (1) age 
18 yr; (2) primary idiopathic PAP; and (3) moderate
or severe disease as defined by the presence of symptoms attributable
to PAP (e.g., dyspnea, cough), the need for supplemental oxygen at
rest, and diffuse pulmonary infiltrates on chest radiography. The
study protocol included an initial screening evaluation consisting of a
history and physical examination, full pulmonary function testing (spirometry, lung volume measurements, diffusing capacity of carbon monoxide (DLCO), measurement of arterial blood gas tensions in room air, a 6-min walk test with pulse oximetry), assessment of dyspnea at baseline, using the Transitional Dyspnea Index, and a chest
radiograph (16). Baseline laboratory testing included a complete blood
count and assays of creatinine and liver enzymes.
Exclusion criteria included: (1) PAP resulting from another condition (e.g., myeloproliferative disorder or leukemia, occupational exposure to silica, human immunoeficiency virus disease, or respiratory infections); (2) increased risk of side effects with GM-CSF therapy (e.g., rheumatoid arthritis, immune thrombocytopenia, autoimmune thyroiditis); and (3) significant cardiac, renal (e.g., creatinine 2 mg/
dl), or liver disease (i.e., hepatocellular enzyme levels exceeding three
times normal). Eligible patients were treated with recombinant human, yeast-derived GM-CSF (Sargramostim; Immunex Corporation,
Seattle, WA) self-administered subcutaneously once daily.
The first dose of GM-CSF was administered in the clinic, after
which patients were observed for 2 to 4 h. Injection sites were rotated
between the anterior abdominal wall and upper thighs. During the 12-wk course of administration of the study drug, the dose was 250 µg
once daily for the first 4 wk, after which dose escalation was guided by
a preestablished algorithm. If the clinical response was suboptimal
(based on results of all clinical studies including evaluation of symptoms, blood gas analysis, 6-min walk distance, pulmonary function
studies, and extent of infiltrates on the chest radiograph), the dose of
GM-CSF was increased to 5 µg/kg/d for the second month of the
study, and to 7 to 9 µg/kg/d for the third month. After starting drug
administration, study subjects were seen at 2 wk and at 1, 2, 3, 4, and
6 mo. During this follow-up, a battery of studies were done including chest radiographs, full pulmonary function tests, arterial blood gas measurements, 6-min walk test, and dyspnea measurement with the Transitional Dyspnea Index (16). A dyspnea questionnaire was administered by a nurse at baseline and after 12 wk of GM-CSF therapy.
The index incorporated assessments of functional impairment, magnitude of task, and magnitude of effort. For the baseline index, each of
these categories was graded on a scale of from 0 to 4 (0 = very severe
impairment, 4 = no impairment). The Transitional Dyspnea Index
was graded on a scale of from 
3 (severe deterioration) to a +3 (major improvement).
Complete blood counts were obtained weekly for the first month of the study and every 2 wk thereafter for 3 mo. Therapy was discontinued at 12 weeks in all patients.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Four adult patients with idiopathic PAP were evaluated in this study (Table 1), of whom three had previously been treated with repeated whole-lung lavage. Administration of GM-CSF was associated with clinical improvement in three of the four patients, as indicated by improvement in PaO2 during breathing of room air and narrowing of the alveolar-arterial oxygen gradient (A-a)O2 (Figure 1). More specifically, in the three responding subjects, mean baseline PaO2 increased from 51.5 ± 14.2 mm Hg (mean ± SD) to a zenith value of 70 ± 23.4 mm Hg (at Week 16; Figure 1). Similarly, the mean (A-a)O2 narrowed from 48.3 ± 20.1 mm Hg at baseline to a mean value of 18.3 ± 4.2 mm Hg at the nadir (noted at Week 16; Figure 1). The three patients who showed improvement had a reduction in baseline dyspnea with administration of GM-CSF (Figure 2). Serial pulmonary function data are summarized in Figure 3.
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A) are shown. Only FEV1 was available for Patient 4.
In contrast to the striking effects of GM-CSF on measures of oxygenation, the peripheral leukocyte count was unchanged from baseline to final values at 12 wk (Table 2).
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Individual case descriptions are presented in APPENDIX 1.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main finding of the study was that administration of GM-CSF conferred improved oxygenation and symptomatic benefit on three of four patients with idiopathic PAP. At the same time, GM-CSF did not elicit a leukocytosis. The four patients described in this report had well-characterized acquired PAP, proven by open lung biopsy to be idiopathic. All four patients had severe chronic disease requiring home oxygen therapy, and three of the four patients had previously required frequent whole-lung lavage under general anesthesia for symptom control. One patient was so debilitated by his disease that he was awaiting lung transplantation. GM-CSF therapy exerted a significant and dramatic clinical improvement in three of the four patients. All three responders were able to discontinue oxygen therapy. In addition to improvement in gas exchange, there was a clear improvement in symptom scores, lung volumes, DLCO, and infiltrates on chest radiography. One patient with very severe lung disease did not improve with the 12 wk of GM-CSF therapy, remained dependent on high-flow oxygen, and subsequently died within 3 mo from respiratory failure. The other three patients have not required therapy or oxygen as of the time of writing of this report.
Although caution is required in interpreting results of an open-label, uncontrolled observational study, several lines of evidence support the role of GM-CSF in the clinical improvement observed in this study (17). First, the magnitude of observed changes in oxygenation measures exceeded those expected from spontaneous variation. Second, among respondents, consistent improvements were seen in multiple related parameters including symptom scores, higher values of PaO2, clearing of pulmonary infiltrates on chest radiographs, and improvements in values of DLCO. In contrast, in the one nonresponding patient, no improvement was observed in any of the measured outcome variables. Third, the apparent responses to GM-CSF in the three responding patients represented a dramatic contrast to their prior clinical course, which had been characterized by recurrent exacerbations of alveolar proteinosis requiring frequent whole-lung lavage.
Patient 3 had open lung biopsy-proven idiopathic, primary PAP at age 12 yr, and was treated in our protocol at age 18 yr. We do not know whether the natural history of PAP in this patient was the same as or different than that in adults with idiopathic PAP. What we observed was that this patient had significant and active disease, and that during therapy with GM-CSF his disease improved as described. This observation does not permit us to conclude that pediatric PAP has the same pathogenesis or natural history as the adult disease.
Patients 1, 2, and 3 were active smokers, and continued to smoke despite smoking-cessation counseling through the course of the study protocol. The apparent clinical improvement in these three patients cannot be attributed to smoking cessation. Furthermore, the relationship between smoking and PAP is very poorly described in the published literature. Specifically, most of the studies of large series of patients with PAP do not comment on their smoking status (1). Davidson and associates (18) and Du Bois and colleagues (19) described a total of 13 patients who were either active or ex-smokers. In our own series, we noted that 18 of 24 patients were either current or former smokers (5). Therefore, the relationship between smoking and PAP remains poorly understood at this time.
Our results extend the findings in the case reported by Seymour and colleagues in which administration of GM-CSF to an individual with adult PAP caused the (A-a)O2 gradient to narrow initially, widen again when the treatment was suspended, and narrow again when GM-CSF was readministered (15). The results of our study also contribute to available evidence that a blunted hematopoietic proliferative response to GM-CSF is at least a characteristic of PAP, if not an important pathogenetic step in its development. A delayed alleviation of lung disease in response to GM-CSF has been consistently noted. Improvement in gas exchange was only first apparent after 8 to 12 wk of treatment in the three responders in our study. In a recent trial of aerosolized GM-CSF in GM-CSF- deficient mice, improvement was first evident only after 4 to 5 wk (14). These observed delays in response are consistent with the hypothesis that GM-CSF is required for immature precursor cells to be recruited to the lung and stimulated to differentiate into functional alveolar macrophages.
Recent animal data strongly suggest that GM-CSF is essential for pulmonary homeostasis and surfactant clearance (8-
13). Although a specific molecular defect has not been identified in most cases of PAP, current observations implicate
GM-CSF in the pathogenesis of human PAP. Specifically:
(1) In congenital PAP, Dirksen and coworkers have described
four patients with a c-chain defect in the GM-CSF receptor
on peripheral blood mononuclear cells (PBMCs) (20). (2) A
patient with adult PAP has been observed to have a mutation
at position 382 of GM-CSF complementary DNA (21). In this
patient, lipopolysaccharide stimulation of cultured PBMCs failed
to elicit GM-CSF in the supernatant. (3) A patient with PAP
was observed to have a funtional deficiency of GM-CSF that was reversed by neutralization of the inhibitory cytokine IL-10 with an antibody in a culture system (22). (4) BALF from the lungs of patients with idiopathic PAP expressed a neutralizing antibody that inhibits GM-CSF (23). (5) Patients with PAP
have shown a blunted responsiveness to GM-CSF and to IL-3,
both of which utilize a common c chain on the GM-CSF receptor complex (24). These observations suggest that adult idiopathic PAP is a heterogeneous disease that involves a relative deficiency of or loss of responsiveness to GM-CSF.
Although our results and those of Seymour and colleagues suggest that GM-CSF administration confers benefit in PAP, important reservations and questions remain. First, in the absence of a randomized, blinded controlled trial, the observed effects of GM-CSF in mitigating the lung disease in PAP, however suggestive our data may be in this regard, remain unconfirmed. Second, several studies of acquired PAP have not shown a deficiency of serum or BALF GM-CSF levels (25, 26). Third, a patient with PAP who underwent bilateral lung transplantation developed recurrent PAP in the transplanted lungs (25). Although this suggests a defect in the monocyte- macrophage lineage, the patient's GM-CSF protein level and messenger RNA and gene for GM-CSF were noted to be normal. Fourth, a recent preliminary study compared GM-CSF levels measured in plasma and BALF in 10 adult PAP patients with those in 10 healthy volunteers (26). Both the blood and BALF GM-CSF levels of patients with PAP were significantly higher than those of the normal controls. Also, although baseline GM-CSF production by BALF cells from PAP patients in culture over a period of 24 h was substantially greater than that of the controls, the response of GM-CSF level to lipopolysaccharide stimulation of BALF cells at 24 h was equivalent in the two groups. The investigators who conducted this study concluded that GM-CSF is not etiologic in patients with acquired PAP. However, differential cell counts in BALF were not performed, and previous studies showed a much lower percentage of macrophages in patients with PAP than in healthy subjects. Therefore, comparisons between unfractionated BALF cells from PAP patients and healthy controls are suspect. Furthermore, the functional integrity of the GM-CSF ligand or receptor, or the presence of a neutralizing antibody to GM-CSF, should be assessed.
Even with the assumption that GM-CSF has benefit for PAP, many important questions remain, including that of the optimal dose of GM-CSF, the optimal duration of therapy, and the optimal route of GM-CSF administration, and of whether there is a daily cumulative dose threshold beyond which effects are foreseen and a risk of rebound worsening after an initial response. In view of the finding that not all of our study subjects responded, what features predict responsiveness to GM-CSF? Additionally, although GM-CSF was well tolerated in both the present study and in that of Seymour and colleagues, is there long-term risk associated with chronic GM-CSF administration (e.g., bone marrow or lung toxicity)?
In summary, the results of this open-label study of four patients with idiopathic PAP show that GM-CSF administration confers benefit to some but not all recipients. Both animal data and human studies of acquired PAP support the notion that GM-CSF is necessary for normal pulmonary homeostasis and surfactant clearance, and that its exogenous administration has a biologic effect. Acquired PAP can occur despite an intact GM-CSF gene and increased GM-CSF levels in the serum and BALF. Although a specific molecular defect has not been identified in the majority of patients with adult PAP, patients with PAP appear to have a blunted hematopoietic response to exogenous GM-CSF therapy despite well documented reports of its alleviation of the lung disease in PAP. These observations suggest an abnormality at the GM-CSF receptor or the GM-CSF ligand, or the presence of a neutralizing antibody. Pending more definitive information from larger observational studies, or even possibly from randomized trials, these data provide a subset of patients with adult PAP with a possible therapeutic option that represents a novel alternative to repeated whole-lung lavage.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Mani S. Kavuru, M.D., Director, Pulmonary Function Laboratory, Cleveland Clinic Foundation, 9500 Euclid Avenue Desk A90, Cleveland, OH 44195. E-mail: Kavurum{at}ccf.org
(Received in original form June 9, 1999 and in revised form September 21, 1999).
Acknowledgments: The authors wish to acknowledge Dr. Carol Farver for reviewing all biopsies, Susan Biello and Valerie Hawkins for manuscript preparation, Drs. Ann Hayes and Mark Gilbert of Immunex for kindly supplying Sargramostin, and several referring physicians as well as the four patients who participated in this study.
Supported by grant IND No. BB-7134 from the Immunex Corporation, Seattle, WA.
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References |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. Rosen, S. H., B. Castleman, and A. A. Liebow. 1958. Pulmonary alveolar proteinosis. N. Engl. J. Med. 258: 1123-1142 .
2. Kariman, K., J. A. Kylstra, and A. Spock. 1984. Pulmonary alveolar proteinosis: prospective clinical experience in 23 patients for 15 years. Lung 162: 223-231 [Medline].
3. Prakash, U. B. S., S. S. Barhan, H. A. Carpenter, D. E. Dines, and H. M. Marsh. 1987. Pulmonary alveolar proteinosis: experience with 34 cases and a review. Mayo Clin. Proc. 62: 499-518 [Medline].
4. Asamoto, H., M. Kitaichi, K. Nishimura, H. Itoh, and T. Izumi. 1995. Primary pulmonary alveolar proteinosis-clinical observations of 68 patients in Japan. Jpn. J. Thorac. Dis. 33: 35-45 .
5.
Goldstein, L. S.,
M. S. Kavuru,
P. Curtis-McCarthy,
H. A. Christie,
C. Farver, and
J. K. Stoller.
1998.
Pulmonary alveolar proteinosis: clinical
features and outcomes.
Chest
114:
1357-1362
6. Blanc, P. D., and J. A. Golden. 1992. Unusual occupationally related disorders of the lung: case reports and a literature review. Occup. Med. 7: 403-422 .
7. Ramirez, R. J., R. B. Schultz, and R. E. Dutton. 1963. Pulmonary alveolar proteinosis: a new technique and rationale for treatment. Arch. Intern. Med. 112: 419-431 .
8.
Stanley, E.,
G. J. Lieschke,
D. Grail,
D. Metcalf,
G. Hodgson,
J. A. M. Gall,
D. W. Maher,
J. Cebon,
V. Sinickas, and
A. R. Dunn.
1994.
Granulocyte/macrophage colony-stimulating factor-deficient mice
show no perturbation of hematopoiesis but develop a characteristic
pulmonary pathology.
Proc. Natl. Acad. Sci. U.S.A.
91:
5592-5596
9.
Dranoff, G.,
A. D. Crawford,
M. Sadelain,
B. Ream,
A. Rashid,
R. T. Bronson,
G. R. Dickersin,
C. J. Backurski,
E. L. Mark,
J. A. Whitsett, and
R. C. Mulligan.
1994.
Involvement of granulocyte-macrophage
colony-stimulating factor in pulmonary homeostasis. 1994.
Science
264:
713-716
10.
Nishinakamura, R.,
N. Nakayama,
Y. Hirabayashi,
T. Inoue,
D. Aud,
T. McNeil,
S. Azuma,
S. Yoshida,
Y. Toyoda,
K. Arai,
A. Miyajima, and
R. Murray.
1995.
Mice deficient for the IL-3/GM-CSF/IL-5 c receptor exhibit lung pathology and impaired immune response, while IL-3 receptor-deficient mice are normal.
Immunity
2:
211-222
[Medline].
11. Huffman, J. A., W. M. Hull, G. Dranoff, R. C. Mulligan, and J. A. Whitsett. 1996. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF deficient mice. J. Clin. Invest. 97: 649-655 [Medline].
12.
Nishinakamura, R.,
R. Wiler,
U. Dirksen,
Y. Morikawa,
K. Arai,
A. Miyajima,
S. Burdach, and
R. Murray.
1996.
The pulmonary alveolar
proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 c receptor-deficient mice is reversed by bone marrow
transplantation.
J. Exp. Med.
183:
2657-2662
13.
Cooke, K. R.,
R. Nishinakamura,
T. R. Martin,
L. Kobzik,
J. Brewer,
J. A. Whitsett,
D. Bungard,
R. Murray, and
J. L. M. Ferrara.
1997.
Persistence of pulmonary pathology and abnormal lung function in
IL-3/GM-CSF/IL-5 c reporter-deficient mice despite correction of
alveolar proteinosis after BMT.
Bone Marrow Transplant.
20:
657-662
[Medline].
14. Reed, J. A., M. Ikegami, E. R. Cianciolo, W. Lu, P. S. Cho, W. Hull, A. H. Jobe, and J. A. Whitsett. 1999. Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice. Am. J. Physiol. (Lung Cell Mol. Physiol. 20) 276:L556-L563.
15.
Seymour, J. F.,
A. R. Dunn,
J. M. Vincent,
J. J. Presneill, and
M. C. Pain.
1996.
Efficacy of granulocyte-macrophage colony-stimulating factor in
acquired alveolar proteinosis.
N. Engl. J. Med.
335:
1924-1925
16.
Mahler, D. A.,
D. H. Weinberg,
C. K. Wells, and
A. R. Feinstein.
1984.
The measurement of dyspnea: contents, interobserver agreement, and
physiologic correlates of 2 new clinical indexes.
Chest
85:
751-758
17. Goldstein, L. S., M. S. Kavuru, and J. K. Stoller. 1999. Pulmonary alveolar proteinosis: a review. Clin. Pulm. Med. 6: 102-109 .
18. Davidson, J. M., and W. M. Macleod. 1969. Pulmonary alveolar proteinosis. Br. J. Dis. Chest 63: 13-28 [Medline].
19.
Du Bois, R. M.,
W. A. C. McAllister, and
M. A. Branthwaite.
1983.
Alveolar proteinosis: diagnosis and treatment over a 10-year period.
Thorax
38:
360-363
20.
Dirksen, U.,
R. Nishinakamura,
P. Groneck,
U. Hattenhorst,
L. Nogee,
R. Murray, and
S. Burdach.
1997.
Human pulmonary alveolar proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common
chain expression.
J. Clin. Invest.
100:
2211-2217
[Medline].
21. Bewig, B., H. Schaffer, A. Bastian, D. Kirsten, K. Dahlhof, and X. Wang. 1999. Human alveolar proteinosis associated with GM-CSF cDNA mutation (abstract). Am. J. Respir. Crit. Care Med. 159: A706 .
22.
Tchou-Wong, K.-M.,
T. J. Harkin,
C. Chi,
M. Bodkin, and
W. N. Rom.
1997.
GM-CSF gene expression is normal but protein release is absent
in a patient with pulmonary alveolar proteinosis.
Am. J. Respir. Crit.
Care Med.
156:
1999-2002
23.
Kitamura, T.,
N. Tanaka,
J. Watanabe,
S. Kanegasaki,
Y. Yamada, and
K. Nakata.
1999.
Idiopathic pulmonary alveolar proteinosis as an autoimmune disease with neutralizing antibody against granulocyte macrophage colony-stimulating factor.
J. Exp. Med.
190:
1-6
24.
Seymour, J. F.,
C. G. Begley,
U. Dirksen,
J. J. Presneill,
N. A. Nicola,
P. E. Moore,
O. D. Schoch,
P. V. Asperen,
B. Roth,
S. Burdach, and
A. R. Dunn.
1998.
Attenuated hematopoietic response to granulocyte-macrophage colony-stimulating factor in patients with acquired
pulmonary alveolar proteinosis.
Blood
92:
2657-2667
25. Johnson, J. G., R. Aris, Z. Zhou, M. Verghese, M. R. Knowles, and R. C. Boucher. 1998. Granulocyte-macrophage colony stimulating factor (GM-CSF) and alveolar proteinosis (abstract). Am. J. Respir. Crit. Care Med. 157: A805 .
26. Carraway, M. S., A. J. Ohio, and C. A. Piantadosi. 1999. GM-CSF in alveolar macrophages in pulmonary alveolar proteinosis (abstract). Am. J. Respir. Crit. Care Med. 160: A705 .
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APPENDIX 1 |
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Patient 1
This patient was a 43-yr smoker who presented to The Cleveland Clinic in March 1998. In 1994 he had noted progressive dyspnea with exertion over several months, and a chest radiograph showed pulmonary infiltrates. He subsequently underwent a right open lung biopsy, which showed the typical findings of alveolar proteinosis. After this, he had required frequent whole-lung lavages every 2 to 4 mo. Some of the lavages had been bilateral and some had been right-sided only. In general, he responded quite well to these lavages. Significant dyspnea on exertion was present prior to the lavage, and after-lavage he was largely symptom-free and able to walk for miles. The most recent lavage procedures had been in October 1997, December 1997, and January 1998. On his initial study visit, the patient had dyspnea on exertion with walking up one flight of stairs, and had a dry cough. His occupational history was significant for factory work in the rubber industry, and he had previously been a truck driver. A review of his symptoms was otherwise unremarkable. Pulmonary function studies showed a moderate restrictive abnormality with a diffusion impairment. The patient's PaO2 in room air was between 60 and 66 mm Hg. Upon treatment with 2-L of oxygen with exertion, his oxygen saturation (SaO2) dropped to 88%. He was started on therapy with 250 µg GM-CSF daily. At 4 wk, the dose was increased to 500 µg/d. At 8 wk the patient returned with significant reduction in his dyspnea. His PaO2 had increased significantly, to 80 mm Hg, and there was no significant oxygen desaturation with walking. There was also improvement in the chest radiograph. Four weeks after completion of therapy, the patient's PaO2 in room air increased to 83 mm Hg.
Patient 2
This patient was a 40-yr-old white male and active smoker working as a cook in a hospital in Springfield, Ohio. He presented on May 8, 1998 with a 2-mo history of cough and dyspnea. An initial chest radiograph showed bilateral alveolar infiltrates. His history was negative for heart disease, occupational exposures, or known malignant disorders. A computed tomographic (CT) scan of the patient's chest confirmed bilateral, fluffy alveolar infiltrates with ground-glass changes. Pulmonary function studies showed a moderate restrictive abnormality with a TLC of 4.28 L (60% predicted) and a severe diffusion abnormality with a DLCO of 11.6 (44% predicted). The patient's PaO2 was 58 mm Hg and his PaCO2 was 41 mm Hg in room air. With exertion there was severe oxygen desaturation, with the patient's SaO2 falling from 94 to 73%. The patient required 3 L/ min of oxygen via nasal cannula to maintain an SaO2 above 94% predicted with exertion. Bronchoscopy with bronchoalveolar lavage revealed cloudy fluid, and a transbronchial biopsy was suggestive of alveolar proteinosis. The patient subsequently underwent a right thoracoscopic lung biopsy, which showed alveoli to have extensive filling with periodic acid- schiff-positive proteinaceous material; all cultures were negative for organisms. The diagnosis was made of idopathic PAP with a moderate to severe exacerbation requiring oxygen therapy. The patient was started on subcutaneous GM-CSF at a dose of 250 µg/d. At 4 wk there was no significant change in respiratory status. The dose of GM-CSF was increased to 500 µg/d. At 8 wk the patient's PaO2 increased to 64 mm Hg in room air; with exertion the SaO2 remained above 91%. When the dose of GM-CSF was increased to 750 µg/d for 16 d, the patient experienced nausea and emesis, and the dose was reduced to 500 µg/d. At 12 wk there was no major symptomatic change, although the PaO2 increased to 72 mm Hg with increased walk distance. GM-CSF was discontinued and the patient was followed at 4 wk after the end of therapy, at which time he reported noting a substantial reduction in his respiratory symptoms. His PaO2 continued to increase, to 78 mm Hg in room air, and his DLCO also improved. The patient was seen in a follow-up visit at 5 mo after the end of therapy and had remained without O2 and with a stable chest radiograph.
Patient 3
This patient was an 18-yr-old black male smoker with a diagnosis of idiopathic PAP by open lung biopsy at age 12 yr. He had severe disease with marked dyspnea, which made him largely homebound and dependent on home oxygen therapy. He had severely restricted pulmonary function with a severe diffusion impairment. He had required 33 whole-lung lavages for symptomatic improvement, conducted at intervals of 6 wk for the 2 yr before his enrollment in the study. He was listed as a candidate for lung transplantation elsewhere. His chest radiograph and a CT scan of the chest showed the typical, extensive bilateral alveolar infiltrates of PAP. The patient showed no significant clinical response for the first 8 wk after the start of therapy. Between 8 and 12 wk, with a dose of 375 to 500 µg/d GM-CSF, he noted substantial symptomatic improvement. He began taking long walks without oxygen, and began playing half-court basketball. His PaO2 in room air increased to 81 mm Hg and his SaO2 remained above 91% with walking. Over the 4 wk following the conclusion of therapy the patient's PaO2 in room air showed continued improvement, to a level of 89 mm Hg. His SaO2 remained above 97% with walking. There was a significant increase in lung volumes and DLCO, although there was persistent moderate restrictive abnormality. The chest radiograph showed gradual progressive improvement, with near normalization by 12 wk. Overall, improvement persisted at 8 wk after the cessation of therapy. The patient was removed from the lung transplant list and at the time of this writing no longer required oxygen therapy.
Patient 4
This patient was a 36-yr-old black nonsmoker from Georgia who had been in good health until 1996, when he noted a gradual onset of fatigue and reduced exercise tolerance. In February 1997, a chest radiograph showed unresolving bilateral lung infiltrates. The patient was evaluated bronchoscopically, with transbronchial biopsy as well as an open lung biopsy, which confirmed idiopathic PAP. He had undergone 13 whole-lung lavages over the 15 mo before his evaluation in our study on September 9, 1998. Initial lavages had given him some symptomatic benefit, but less so with the passage of time. He was markedly limited by dyspnea upon walking less than 25 ft. He had a daily cough and sputum production, and had lost 50 lb over the year preceeding the study. His occupational history was remarkable for work as a heating and air-conditioning repairman. Chest radiographs upon the patient's entry into our study showed diffuse interstitial infiltrates. Pulmonary function studies showed very severe restriction and the patient's baseline PaO2 in room air was 28 mm Hg. He was dependent on home O2 at 8 L/min taken via a simple mask. GM-CSF was started at 250 µg/d and the dose was escalated to 500 µg/d over the 12 wk treatment period. There was no significant symptomatic or physiologic improvement. The PaO2 in room air was 25 mm Hg at the end of the study. The patient was subsequently hospitalized in Georgia with an exacerbation of PAP requiring mechanical ventilation. He expired on February 20, 1999. The family denied an autopsy request.
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