American Journal of Respiratory and Critical Care Medicine

Pulmonary alveolar proteinosis is a rare clinical syndrome that was first described in 1958. Subsequently, over 240 case reports and small series have described at least 410 cases in the literature. Characterized by the alveolar accumulation of surfactant components with minimal interstitial inflammation or fibrosis, pulmonary alveolar proteinosis has a variable clinical course ranging from spontaneous resolution to death with pneumonia or respiratory failure. The most effective proven treatment—whole lung lavage—was described soon after the first recognition of this disease. In the last 8 years, there has been rapid progress toward elucidation of the molecular mechanisms underlying both the congenital and acquired forms of pulmonary alveolar proteinosis, following serendipitous discoveries in gene-targeted mice lacking granulocyte-macrophage colony-stimulating factor (GM-CSF). Impairment of surfactant clearance by alveolar macrophages as a result of inhibition of the action of GM-CSF by blocking autoantibodies may underlie many acquired cases, whereas congenital disease is most commonly attributable to mutations in surfactant protein genes but may also be caused by GM-CSF receptor defects. Therapy with GM-CSF has shown promise in approximately half of those acquired cases treated, but it is unsuccessful in congenital forms of the disease, consistent with the known differences in disease pathogenesis.

Description of a “New” Disease

Nature of the Accumulated Alveolar Material

Published Features of Patients with PAP

Presentation

Demographic Features

Smoking

Age

Arterial Oxygen Pressure

Serum LDH

Spirometric and Radiographic Features

Diagnostic Procedures

Histopathology

Pathogenesis and Classification

Acquired PAP

Congenital PAP

Secondary PAP

Development of Effective Treatment

Application and Efficacy of Therapeutic Lavage

Timing of Lavage

Repeat Lavage

Response to Therapeutic Lavage

Duration of Response Following Lavage

Predictors of Response to Lavage

Prognostic Impact of “Response” to Lavage

Improvement in Pulmonary Parameters Following Lavage

Additional Individual Institutional Reports

GM-CSF Therapy in Acquired PAP

Secondary Infections

Survival and Cause of Death

Potential Prognostic Factors for Survival

Spontaneous Resolution

Conclusion

Pulmonary alveolar proteinosis (PAP), also referred to as alveolar proteinosis, alveolar lipoproteinosis, alveolar phospholipidosis, pulmonary alveolar lipoproteinosis, and pulmonary alveolar phospholipoproteinosis, is a rare and enigmatic disorder that is characterized by abnormal intraalveolar surfactant accumulation and a variable natural history. With an estimated annual incidence and prevalence of 0.36 and 3.70 cases per million population, respectively (1), it is difficult for any one clinician or treatment center to accumulate significant experience with the disorder, and single case reports or small case series comprise more than 75% of all described instances of PAP. There are only five published series of 10 or more cases reported (26). Over the last 8 years, there has been a revolution in the understanding of the pathogenesis of PAP, which has led to the investigation of innovative treatment approaches. There are no randomized studies of any interventions yet available, and an interpretation of the outcome of uncontrolled studies would be improved by a better understanding of the natural history of the disease and the efficacy of current standard therapies. This review aims to provide an overview of aspects of this field in the light of these recent scientific advances and to describe management options for this puzzling disease. A number of excellent up-to-date and comprehensive reviews have discussed the clinical features (2, 79), diagnostic techniques (10, 11), and radiologic appearances (12, 13) of PAP and also the procedural aspects of therapeutic whole-lung lavage (7). The reader is referred to these publications for more detailed discussion of the important areas that are not addressed in detail here.

Throughout this article, we refer to data synthesized from reported cases of acquired PAP in the literature over the first 40 years following its initial description, up to 1998 when granulocyte-macrophage colony-stimulating factor (GM-CSF), a new biologic therapy potentially able to alter the natural history of the disease, emerged as a treatment option (14). The details of the methodology of the literature analysis used are provided (see online data supplement) and include information from 410 identifiably separate cases of PAP, described in 241 separate initial publications.

PAP has a relatively short history. Remarkably for what is now considered such a distinctive disorder, its existence was only recognized in 1958 through the seminal report of Rosen and colleagues (15). Dr. Benjamin Castleman of the Massachusetts General Hospital recognized the first case of this series in July 1953, and the remaining 26 cases were accumulated over the subsequent 4 years. The authors commented that the histologic appearance of the Periodic Acid Schiff (PAS)-positive proteinaceous alveolar deposits in the absence of a cellular infiltrate and normal interalveolar septa was “so characteristic and similar from one case to another that it seems highly unlikely that it could have escaped description previously” (15).

In retrospect, with interpretation sharpened by the clear description provided by Rosen and colleagues (15), there are at least two earlier publications of cases of probable PAP (16, 17). Linell and associates from Sweden described the case of a 57-year-old man who had been symptomatic since 1946 and died of disseminated cryptococcosis in June 1951 (17). At autopsy, pulmonary changes characteristic of PAP were found but were attributed to the cryptococcosis while noting that “no such observations are on record.” The true nature of the underlying condition in this case was subsequently acknowledged in 1961 (18). The other report predating that of Rosen and colleagues was the 1957 description of a woman with marked thrombocytosis caused by an underlying myeloproliferative disorder, where acellular eosinophilic “intra-alveolar coagulum” was found but erroneously attributed to platelet deposition (16, 19). Again, with the benefit of hindsight, these features were recognized as manifestations of PAP (20) and represent the first described case of PAP occurring as a “secondary” phenomenon to an underlying hematologic malignancy. Doyle and colleagues first postulated in 1963 that this association was not purely fortuitous (21) and rightly suggested that “careful hematologic studies would appear to be indicated in pulmonary alveolar proteinosis.” Mechanistic explanations for this association between PAP and hematologic disorders have only recently been forthcoming (see Pathogenesis and Classification subsequently here).

At the time of the initial characterization of PAP, the existence and physical characteristics of the normal alveolar lining fluid were newly established (22, 23). Using a series of special stains, histochemical processes, and direct chemical analysis, Rosen and colleagues skillfully demonstrated the high lipid content of the accumulated material and established that protein and carbohydrate were also present (15). They suggested that “exfoliated alveolar septal cells” (type II pneumocytes) could be the source of this material. In 1965, based on similarities of chemical composition, Larson and Gordinier first proposed that the material was surfactant (24) and commented that the abnormal accumulation could be due to “an overproduction … , impairment of removal, or [an] abnormal type of surfactant.” This “surfactant” hypothesis for PAP was temporarily weakened when the material obtained by lavage failed to demonstrate the expected surface-active properties (25, 26) and the hypothesis that it was derived primarily from the plasma transiently gained support (27). However, over the next 15 years, sequential reports have demonstrated the restoration of normal surface activity after ethyl alcohol extraction (28), consistent electron microscopic features (29, 30), and immunohistochemical confirmation of the presence of surfactant proteins (SPs) (31), cumulatively confirming the material as surfactant derived. The issue raised in 1965 of a potential structural abnormality of the accumulated surfactant material continues to be debated (32, 33), with most investigators now suggesting that the observed abnormalities are secondary to altered stoichiometric conditions, rather than representing the primary defect (34).

Presentation

Acquired PAP (the most common type, see Pathogenesis and Classification subsequently here) usually presents as progressive dyspnea of gradual onset, at times associated with a minimally productive cough or fatigue (2, 7). Other variably associated features may include weight loss and low-grade fever, although marked fever usually indicates the presence of a complicating infection. Physical examination is often normal or reveals relatively minor and nonspecific pulmonary findings, and digital clubbing is uncommon (9, 35). Described biochemical abnormalities may include elevated serum levels of lactate dehydrogenase (LDH), other protein products of pulmonary epithelial cells, including carcinoembryonic antigen (36), cytokeratin 19 (37), and the mucin KL-6 (38, 39), and levels of the SP-A, SP-B, and SP-D (40, 41), although none of these findings are specific for PAP.

Demographic Features

From an analysis of 410 published cases (Table 1)

TABLE 1. Demographic and disease features among published cases of acquired pap according to gender


Characteristic

All Patients
 (n = 410)

Male
 (n = 292)

Female
 (n = 110)

n
%
Median
 (I.Q. range)*
n
%
Median
 (I.Q. range)*
n
%
Median
 (I.Q. range)*
p Value
Age, years40839 (30–46)29239 (32–47)10935 (22–45) 0.001
Duration of symptoms/CXR changes, mo2887 (3–19)2167 (3–23)72 8 (3–14.5) 0.5
African American race14417111153324 0.2
Nonsmoker§16828114154661< 0.0001
Mode of diagnosis36026694 0.3
Autopsy111110
Open biopsy717072
Transbronchial biopsy101110
BAL437
Elevated hemoglobin972178191926 0.5
Elevated LDH**778253812483 0.8
PaO2, mm Hg15960 (46–70)11660 (48–69)4254 (41–72) 0.2
[A–a]Do2, mm Hg††13148 (34–60)9649 (33–60)3545 (37–61) 0.9
Therapeutic lavage,‡‡
312
54

214
52

90
56

 0.6

*Interquartile range is the range from the 25th to 75th percentiles of the distribution.

Values shown are calculated using the Mann-Whitney U-test or Kruskall-Wallis test for numeric data, and the χ2 test for categorical data, as appropriate.

Distribution of race applied only to those cases reported from the United States.

§At the time of onset of symptoms, patients 10 years of age or less at diagnosis were assumed to be nonsmokers.

Percentages do not total 100%, as 11 patients had the diagnosis established by other means (sputum examination in three and percutaneous needle biopsy in eight).

Eighteen or greater g/dl for males, ⩾ 17 g/dl for females.

**Serum level of lactate dehydrogenase above upper limit of cited reference range.

††Alveolar–arterial oxygen gradient; where the actual figure is not provided, this has been calculated assuming BTPS conditions.

‡‡As stated within the follow-up available at the date of most recent publication for those patients potentially eligible to receive such a procedure (cases published after 1963 and diagnosed ante-mortem).

Definition of abbreviations: BAL = bronchoalveolar lavage; CXR = chest x-ray; I.Q. = interquartile; LDH = lactate dehydrogenase; PAP = pulmonary alveolar proteinosis.

, the median duration of symptoms before diagnosis was 7 months. The median age at diagnosis was 39 years, but this differed significantly according to gender (39 years for males and 35 for females, p = 0.001). Most patients were men (male:female ratio = 2.65:1.0). As has been described repeatedly, most patients (72%) were smokers at the onset of symptoms, although this varied significantly according to gender (85% for males and 39% for females, p < 0.0001). There was no male predominance among nonsmokers (male:female ratio = 0.69:1.0), suggesting that the high proportion of males among PAP patients may be explained by their higher frequency of tobacco use in most societies. In addition, there are also seven patients reported (1.7%, two male and five female) who had co-existing autoimmune disorders or positive autoimmune serology (29, 4247). The autoimmune disorders comprised rheumatoid arthritis in two cases, positive smooth-muscle antibodies in two cases (with positive rheumatoid factor in the absence of clinical arthritis in one), and immunoglobulin A nephropathy, multiple sclerosis, and possible celiac disease in one case each. There are no available data on any possible human leukocyte antigen associations.

Serum immunoglobulin levels have been reported to be reduced in 4% of patients tested (44, 48, 49); however, two of these were siblings with immunoglobulin A deficiency (49), and there was also a single instance of a low-level immunoglobulin M paraprotein without proven hematologic malignancy (15). Elevated cholesterol levels have been described in 19% of the patients tested. There were 52 cases with data provided for absolute neutrophil counts, and all but one were normal; one patient had mild neutropenia of 1.04 × 109 per L (43). Bone marrow examinations were reported in 13 patients, and these showed no definite abnormalities other than erythroid hyperplasia attributable to chronic hypoxia (17, 43, 44, 5058).

A number of these clinical features resemble those seen among patients with another autoantibody-mediated systemic disease with pulmonary manifestations, Goodpasture's syndrome (antiglomerular basement membrane disease). In this disorder, there is also a marked male predominance (approximately 6:1) (59) and a high proportion of smokers (up to 80% [60, 61]). However, in contrast to PAP, there is a bimodal age peak seen in the incidence of Goodpasture's syndrome (59). In Goodpasture's syndrome, the target antigen is a domain of the α3 chain of type IV collagen, preferentially contained within glomerular and pulmonary alveolar basement membrane. The predominance of smokers suggests that inhaled toxins may either expose or lead to conformational alterations of the type IV collagen, rendering these immunogenic, or may alternatively increase the permeability of lung capillaries, allowing access of preformed antibodies to the alveolar basement membrane (60). Similar hypothetical models can be proposed for the role of smoking in the pathogenesis of PAP, but the anatomic localization of GM-CSF is far less restricted. These similarities between PAP and Goodpasture's syndrome suggest other possible areas for future investigation, including the possible HLA associations with the development of PAP (62), the role of antibody titers in prognosis and therapeutic monitoring (63), and the possible utility of plasmapheresis and immunosuppressive therapies targeting antibody production (59).

Smoking

Excluding patients younger than 10 years of age who were effectively nonsmokers by allocation, disease and demographic features have been reported for 121 smoking patients and 35 nonsmoking patients. Apart from the gender imbalance described previously here and a tendency for smokers to more often be reported from North America (66% of smokers versus 49% of nonsmokers, p = 0.08), there were no differences in age, duration of symptoms, hemoglobin, serum level of LDH, PaO2, or alveolar–arterial oxygen gradient ([A–a]Do2) evident between these two groups (each p ⩾ 0.2).

Age

Age at diagnosis is approximately normally distributed with a mean ± SD of 37.8 ± 13.3 years (Figure 1)

. There is a minor under-representation of patients 70 years of age or more, possibly attributable to less intensive investigation or reluctance to seek medical attention in this age group. Conversely, there is a small over-representation of cases below the age of 10 years. This may be due to a reporting or publication bias of cases occurring in this group, given the extreme rarity of this event. Alternatively, it may represent misclassification of truly congenital cases (see Pathogenesis and Classification subsequently here).

The distribution of age at diagnosis among males (mean ± SD, 39.6 ± 12.3 years) closely resembled that of the population as a whole. However, there were notable differences in the pattern of age at diagnosis for females (Figure 2)

. First, females were diagnosed an average of almost 6 years earlier than males (33.7 ± 14.8, p = 0.001 versus males). Also, the distribution among female cases was non-normal (D-score 0.093, p = 0.03), instead displaying a bimodal pattern with peak frequencies at the ages of approximately 25 and 40 years. This pattern may represent the agglomeration of cases with two distinct pathogenetic mechanisms affecting different age groups or alternatively a relative protection against a common mechanism during the 25- to 40-year age interval, which may relate to the peak reproductive period in Western societies (64). Consistent with this suggestion, there is just one reported case of a woman with PAP presenting during pregnancy (65). The only difference evident among female patients according to age was a higher frequency of smoking among women aged 35 years or more at diagnosis (56% versus 21%, p = 0.03).

Arterial Oxygen Pressure

The mean ± SD partial PaO2 at diagnosis was 58.6 ± 15.8 mm Hg (Figure 3)

, and this was approximately normally distributed, without any difference in level or distribution according to gender.

Serum LDH

Data on LDH values and applicable normal ranges were only reported in 36 cases (36, 43, 49, 56, 6684) and are expressed as a percentage of the upper limit of the applicable normal reference range. PAP patients had a mean ± SD LDH level that was 168 ± 66% of the upper limit of the normal range. There was no difference in LDH level according to gender (p = 0.91), nor was there any correlation between LDH and age at diagnosis (p = 0.75). Serial measurements of serum LDH levels in individual cases have suggested that the level of this enzyme may be useful as an indicator of disease severity (70, 85). There were 27 patients reported who had values for both serum LDH and concurrent PaO2 (in 24 cases the [A–a]Do2 was also known). LDH and PaO2 were moderately correlated (r2 = 0.372, p = 0.001), but the correlation between LDH and [A–a]Do2 was more significant (r2 = 0.489, p = 0.0001) (Figure 4)

.

Spirometric and Radiographic Features

On pulmonary function testing, the most common pattern seen is that of a restrictive defect, with a disproportionate reduction in diffusing capacity relative to modest impairment of vital capacity (2, 7, 9, 12). By plain chest radiograph, widespread bilateral patchy and asymmetrical airspace consolidation may be seen, without predilection for central or peripheral distributions, but many patterns are possible (9). The extent of radiologic abnormalities is frequently disproportionate to the relatively modest pulmonary symptoms and physical findings. High-resolution computed tomography scanning has a characteristic appearance of patchy or geographic air-space “ground-glass” opacities or consolidation with some thickening of the interlobular septa, resulting in a “crazy-paving” pattern (12, 13) (Figure 5)

, with the extent and severity of these changes showing correlations with the degree of impairment of spirometric function and pulmonary gas exchange (12). There is no definite lobar or zonal predominance. Although this pattern is characteristic for PAP, it is not specific (86, 87). In rare cases, a significant component of interstitial fibrosis can be present (75, 8890), more typically developing late in the clinical course of the disease.

Initially, most cases required open-lung biopsy for diagnosis, and this remains the “gold standard,” although false negatives are possible because of sampling error (11). Open-lung biopsy is less commonly required now (7, 10), as a diagnosis of PAP can be established in approximately 75% of clinically suspected cases by the classic findings of a “milky” effluent from bronchoalveolar lavage (BAL). This fluid contains large amounts of granular acellular eosinophilic proteinaceous material with morphologically abnormal “foamy” macrophages engorged with diastase-resistant PAS-positive intracellular inclusions (10, 11, 91) (Figure 6A)

, which also display characteristic features following Papanicolaou staining (92, 93). The presence of concentrically laminated phospholipid structures called lamellar bodies on electron microscopic examination of BAL fluid can be confirmatory (29, 94) (Figure 6B).

The characteristic features of PAP on light microscopy of lung biopsy specimens (Figure 7)

are the near-complete filling of the alveolar space and terminal bronchioles with PAS-positive acellular surfactant. There may be a mild interstitial lymphocytic infiltrate (15, 95); however, this is not a prominent feature, and the alveolar architecture is usually well preserved, except in those cases where pulmonary fibrosis has developed (96), typically late in the natural history of the disorder. Again, electron microscopic examination can be confirmatory in difficult cases (29, 94).

Novel insights over the last 8 years into the pathogenesis of PAP have lead to a greater understanding of the spectrum of disease processes that may lead to this clinical syndrome. For more than 30 years following the initial description of PAP, the pathogenesis remained unclear, with a commonly held view being that of enhanced surfactant secretion in response to an unknown inhaled irritant. Recognizing some histologic similarities with PAP, acute inhalation of silica (97, 98) and other particulate substances were suspected causes (30). Animal models were developed (99103), but these did not accurately reproduce the clinical features of PAP; lung biopsy specimens from patients rarely contained the quantities of particulate matter predicted (104, 105). An alternative hypothesis, which gained some support through the 1960s and 1970s, was that of an abnormal pulmonary response to an unusual infectious agent, such as Pneumocystis carinii (15, 20, 106) or Cryptococcus neoformans (18). However, the vast majority of lung lavage fluid samples are microbiologically sterile, and it is now recognized that most cases of infection encountered are a secondary event rather than the initiating process.

An important conceptual shift that facilitated advances in the understanding of the pathogenesis of PAP was the gradual recognition that there were three distinct classes of disease with a somewhat similar spectrum of histologic findings, namely acquired PAP, congenital PAP, and secondary PAP. Each of these is discussed in turn.

Acquired PAP

More than 90% of all cases of PAP occur as a primary acquired disorder of unknown etiology (2, 4, 15, 96), not associated with any familial predisposition. The first step toward understanding the possible pathogenesis came unexpectedly in 1994 from the field of experimental hematology through the development of gene-knockout mice lacking the hematopoietic growth factor GM-CSF (107, 108).

GM-CSF had been chemically purified in the late 1970s (109) and in 1984 was one of the first human cytokines to be cloned (110). GM-CSF became an intense focus of investigation through this period because of its potent capacity to stimulate the proliferation and differentiation of neutrophilic and monocyte/macrophage lineage hematopoietic cells in vitro, an action that had remained unexplained since its first recognition in 1964 (111). This capacity provides the basis for the clinical application of GM-CSF (112114). GM-CSF shares some, but not all, of its actions with granulocyte colony-stimulating factor, the other major neutrophilic hematopoietic regulator currently in clinical usage (112, 113). The pharmacologic administration of recombinant GM-CSF consistently leads to a dose-dependent stimulation of myeloid hematopoiesis resulting in peripheral blood neutrophilia, monocytosis, and eosinophilia (112). Each of these actions requires engagement of GM-CSF with its high-affinity receptor complex, which comprises a GM-CSF–specific α chain and a common β chain (βc). In both the human and the mouse, this βc is also a component of the receptor complexes for interleukin-3 and interleukin-5 (115) and is expressed on both alveolar macrophages and alveolar type II epithelial cells (116). Pulmonary epithelial cells also produce GM-CSF (34).

To explore the innate physiologic role of GM-CSF, investigators used gene-targeting methods to generate mice lacking either GM-CSF (GM−/−) (107, 108) or βcc−/−) (117, 118). Surprisingly, these animals had no detectable abnormality of steady-state hematopoiesis but had impaired surfactant clearance by alveolar macrophages (119121), leading to a condition that resembled human PAP, including a prominent lymphocytic infiltrate. In contrast to the diminished rate of surfactant clearance, the rates of synthesis of surfactant phospholipid and proteins were unperturbed (119121). This abnormality of surfactant clearance in GM−/− mice could be corrected by the local delivery of GM-CSF and did not require a systemic effect (122125). Although type II alveolar epithelial cells are responsible for synthesis, secretion, and recycling of all surfactant components (126, 127), surfactant catabolism involves approximately equal contributions from both type II cells and alveolar macrophages (34, 128). Although current evidence suggests that the primary defect in surfactant clearance in the absence of GM-CSF activity is alveolar macrophage dysfunction (119, 121, 129), alternative non-GM-CSF–dependent surfactant clearance pathways, perhaps involving type II cells, may explain the less severe surfactant accumulation in βc−/− compared with GM−/− mice (120). These conclusions are based on the demonstration of impaired surfactant catabolic capacity in isolated GM−/− alveolar macrophages (121) together with complete correction of the PAP phenotype in GM−/−, but not βc−/− mice, by bone marrow transplantation, which would not be expected to influence any type II cell defect (129, 130). Other incompletely investigated influences on surfactant homeostasis that may modulate the severity of PAP include the levels of alveolar SP-D (131133) and activity of the transcription factor PU.1, through which the GM-CSF signal is transduced (134). Thorough overviews of the metabolic profiles of GM−/− and βc−/− mice have been published recently (34, 120, 121, 135).

Although some naturally occurring immunodeficient mouse strains such as CB.17 scid/scid and the beige mouse have been reported to develop PAP (136, 137), in contrast to the GM−/− and βc−/− animals, the penetrance of this phenotype is low, and the lung abnormalities occur late in the animals' life. To date, the cellular mechanisms for these observations have not been elucidated, and their relevance to the human condition of PAP remains unclear.

In addition to the PAP, GM−/− mice manifest a number of more subtle, but important, extrapulmonary abnormalities. These include disturbed macrophage function (138140), a propensity to develop systemic infections (141, 142), reduced fertility and impaired ovarian follicle maturation (141, 143145), T-cell dysfunction (146, 147), a reduced number of cutaneous Langerhans cells (148), and ultimately reduced survival (141).

These observations provided an impetus to explore the possible existence of defects in either GM-CSF or its receptor and the potential therapeutic activity of exogenous GM-CSF in patients with PAP. A clinical study of GM-CSF therapy that began in August 1995 provided two important early observations (14). First, in contrast to expectations, GM-CSF administration did not result in any increase in peripheral blood neutrophil or monocyte counts, the only apparent hematopoietic response being a mild eosinophilia (149). Second, there was apparent improvement in the severity of PAP in the first treated patient (14). This attenuated hematopoietic response to GM-CSF has subsequently been observed in all patients with confirmed PAP treated by our own group (41), investigators at the Cleveland Clinic (150, 151), and other groups (152) (Ana Romero, personal communication, July 2001).

A series of experiments performed by Nakata and colleagues in Tokyo provided the likely explanation for this attenuated hematopoietic response to GM-CSF. They identified a GM-CSF–neutralizing autoantibody in the serum and BAL fluid of patients with acquired PAP that was not present in patients with congenital or secondary PAP (153155). Other investigators have confirmed these findings (156). No clear defects in either the GM-CSF βc receptor (41, 157) or GM-CSF gene sequence itself (157) have yet been identified in patients with acquired PAP. Although a study of two patients suggested normal basal GM-CSF secretion by alveolar macrophages (158), there have been some in vitro observations of impaired responsiveness to GM-CSF (41) or reduced GM-CSF secretion in response to various agonists (156, 159, 160), but these results are difficult to interpret in light of the likely presence of neutralizing GM-CSF antibody and the use of antigenic assays such as enzyme-linked immunosorbent assay rather than functional assays specific for biologically active GM-CSF. On present evidence, it is likely that the anti–GM-CSF antibody is pathogenic in the development of the disease through its ability to inhibit the activity of endogenous GM-CSF, leading to a state of functional GM-CSF deficiency, recapitulating the findings in the GM−/− mouse.

Antibodies capable of binding, and in some cases neutralizing, GM-CSF have been reported to occur in low titer in some immunocompetent patients treated with recombinant GM-CSF (161163). The period of persistence of these therapy-induced antibodies and any possible in vivo activity remains unclear. In the absence of exposure to recombinant GM-CSF, spontaneous GM-CSF binding antibodies are far less common, being detected in only 4 of 1258 (0.3%) healthy volunteers (164, 165). There is a case report of the association of a GM-CSF–neutralizing immunoglobulin G antibody in a patient with acquired amegakaryocytic thrombocytopenia (166), but the causal relationship originally suggested is called into doubt by our current understanding of the redundancy of GM-CSF in steady-state hematopoiesis (107, 108). However, there does appear to be a higher frequency of GM-CSF–neutralizing antibodies among patients with autoimmune disorders (0.7%), specifically myasthenia gravis (1.9%), with at least one patient followed for more than 2 years without any pulmonary symptoms manifest (167).

This important discovery of GM-CSF–neutralizing antibodies in patients with PAP potentially also explains a number of earlier observations. It had been shown 20 years ago that the BAL fluid and serum from patients with PAP had “immunoinhibitory” activity in vitro, blocking the response of mononuclear cells to mitogens (168170). Similarly, although high concentrations of surfactant are inhibitory to a number of macrophage functions (92), the observations of impaired phagocytic function (171, 172), chemotaxis (173), and microbial killing (174, 175) by alveolar macrophages derived from patients with PAP may be partly attributable to the actions of the anti–GM-CSF antibody. Furthermore, the systemic production of the antibody now provides an explanation for the recurrence of PAP following double-lung transplantation (176).

Congenital PAP

Although cases of PAP in infants had been sporadically reported in the 1950s and 1960s (15, 177179), including cases in families with multiple affected siblings (177, 180), they were not considered initially to represent a process distinct from adult cases. Following the recognition of PAP as a rare cause of immediate-onset neonatal respiratory distress (181183), the description in 1981 of a consanguineous family with four affected siblings (184) established “congenital” PAP as a distinct familial and likely genetic disorder.

It has been shown subsequently that most cases of congenital PAP are transmitted in an autosomal recessive manner (184, 185), most often caused by homozygosity for a frame shift mutation (121ins2) in the SP-B gene (186, 187), which leads to an unstable SP-B mRNA, reduced protein levels, and secondary disturbances of SP-C processing (188). The estimated gene frequency of the 121ins2 mutation is one per 1,000 to 3,000 persons in the United States (189). However, there is increasing recognition of molecular genetic heterogeneity among infants with congenital SP-B deficiency (187, 190194), which may have phenotypic and prognostic correlations (195). Importantly, heterozygotes for the most commonly recognized SP-B mutation (121ins2) appear to have normal respiratory function into their 4th decade of life (196). If the mouse model of this condition is an accurate predictor of the human condition, such heterozygotes may be at risk for the development of reduced lung compliance and gas trapping with aging (197) and could be at increased risk of hyperoxic lung injury (198). It also has been recognized recently that mutations in SP-C can lead to similar forms of neonatal respiratory distress (199). In animal models, the deletion of SP-D also leads to accumulation of alveolar macrophages and increased surfactant pool size (131), but in both of these settings, the histopathology is distinct from that seen in congenital SP-B deficiency (200). Also, the SP-C processing defect of SP-B deficiency is not manifest in mice with SP-D deficiency (132).

There are a proportion of infants with the syndrome of neonatal onset PAP who do not have any recognized disturbance of SP-B expression, and abnormalities of the GM-CSF receptor βc have been implicated in some of these cases (201). In a single report, four infants with congenital PAP were shown to have dramatically reduced βc expression on peripheral blood mononuclear cells, greatly reduced binding of GM-CSF and impaired in vitro responsiveness to both GM-CSF and interleukin-3 (201). In one of these patients, a putative mutation in the GM-CSF βc gene, which would lead to an amino acid substitution, was identified (201). To date, other investigators have been unable to identify any similar cases of βc mutations (149, 202, 203), and five infants with congenital PAP in the absence of SP-B mutations have been treated with GM-CSF, all manifesting a normal hematopoietic response, which excludes the possibility of such a receptor defect (149). Conversely, preliminary findings from a British group have identified high levels of expression of a novel truncated form of βc lacking the usual transmembrane domain, suggesting that this may function as a soluble inhibitory receptor (202). It is too early to be sure what proportion of otherwise unexplained cases of congenital PAP is due to defects in GM-CSF receptor expression, but these results clearly demonstrate that defects in this pathway can be associated with human disease states.

Secondary PAP

Although uncommon among adult PAP patients, there exist a number of recognized underlying causes for the secondary development of PAP. These conditions include lysinuric protein intolerance, acute silicosis and other inhalational syndromes, immunodeficiency disorders, and malignancies and hematopoietic disorders.

The rare genetic disorder “lysinuric protein intolerance” is attributable to a mutation in the “y+L amino acid transporter-1” gene (204206), resulting in defective plasma membrane transport of dibasic amino acids and multisystem manifestations, including hematopoietic abnormalities leading eventually to PAP in a high proportion of the cases (207210).

A rare acute-onset form of silicosis recognized in the 1930s (97, 211) was subsequently called “acute silico-proteinosis” to emphasize the histologic resemblance to PAP (98, 212, 213). This was associated with heavy short-term exposure to high concentrations of respirable free silica. With improved occupational health and safety standards, this condition has been reported rarely since the 1980s (42, 214, 215), except for cases of intentional inhalation of domestic scouring products (216). Very rarely, other inhaled environmental or industrial materials such as cement dust (217), cellulose fibers (218), aluminum dust (78), or titanium dioxide (219) have been associated with the development of PAP. Whether such associations are truly causal is not entirely clear in each of these circumstances.

Alveolar proteinosis also develops rarely as a complication of either underlying immunodeficiency disorders, such as thymic alymphoplasia (220), severe combined immunodeficiency disorder (221), or immunoglobulin A deficiency (49), or in the context of iatrogenic immunosuppression such as following solid-organ transplantation (222, 223). One patient has been reported to develop PAP in the setting of dermatomyositis, but this patient also had received prolonged steroid therapy (224). A single study has suggested that patients with the acquired immunodeficiency syndrome complicated by P. carinii pneumonia may have some features of PAP (225), although this observation has not been reproduced, and described cases of PAP associated with acquired immunodeficiency syndrome remain extremely rare (226, 227).

PAP also occurs in association with underlying malignancies, almost exclusively of hematopoietic origin (228231). In these cases, the development of secondary PAP probably reflects numerical deficiency and/or functional impairment of alveolar macrophages, which are derived from blood monocytes (228, 232234). In the myeloid leukemias and myelodysplastic syndromes, where secondary PAP is most commonly encountered, alveolar macrophages may be derived from the malignant clone itself and in some circumstances have been shown to carry specific defects that may explain the observed functional impairment of surfactant clearance (234). This suggestion is supported by resolution of the pulmonary process following restoration of normal hematopoietic function (230, 234). Similarly, there is some evidence implicating defects in GM-CSF signaling in patients with secondary PAP complicating acute myeloid leukemia. Three patients have been described where their leukemic cells lacked expression of βc and were unresponsive to GM-CSF, with similar defects shown to be present in BAL-derived cells (234). These defects, together with the underlying PAP, were corrected in each of two cases where normal hematopoiesis was successfully re-established, suggesting that the leukemic clone with its impaired responsiveness to GM-CSF was responsible for replacing/displacing the functionally normal alveolar macrophages and potentially contributing to the manifestations of secondary PAP (234).

Without knowing the source, nature, or cause of the accumulated material in PAP, initial therapies were empirical. These included antibiotics, corticosteroids, and attempts at physical dissolution through the administration of potassium iodide, streptokinase, trypsin, heparin, and acetylcysteine (30, 106), all without manifest benefit. Following recognition of the nature of the accumulated material as surfactant, pharmacological manipulation of the surfactant system was attempted (235), again without reproducible benefit.

The first advance in the treatment of PAP came in November 1960, when Dr. José Ramirez-Rivera at the Veterans' Administration Hospital in Baltimore applied repeated “segmental flooding” as a means of physically removing the accumulated alveolar material (52, 66, 85, 236). Following 30 mg of oral codeine, and without other sedation or anesthesia, a percutaneous transtracheal endobronchial catheter of 1.17-mm external diameter was positioned “blindly.” Through this catheter, aliquots of 100 ml of warmed saline were instilled at a rate of 50–60 drops per minute. This usually initiated a bout of “45 to 70 minutes of violent coughing,” which typically produced “30–40 ml of white viscid material,” and was repeated four times a day for 2–3 weeks using physical positioning to direct the saline sequentially into different lung segments (237). The procedure was prolonged, distressing for patients, and burdensome but provided the first therapy with reproducible and functionally significant improvements in symptoms and pulmonary function. In the early 1960s, the application of such a procedure was truly radical and on the basis of available animal experimental data (238) was viewed as potentially harmful (237) even though Garcia-Vincente had initially proposed the concept of pulmonary lavage in 1929 (239).

Such “segmental flooding” provided proof that physical removal of adequate amounts of the material provided functional improvement, but as initially described, this was clearly an impractical therapy for broad application. Although a number of influential colleagues were reportedly “not very encouraging” of the concept (237), in July 1964, Ramírez-Rivera proceeded with a trial of whole-lung lavage, using up to 3 L of saline with added heparin or acetylcysteine, initially under local anesthesia (240). This human trial built on the earlier physiologic studies of lung degassing of Coryllos and Birnbaum (241) and the smaller scale canine experimental work of Kylstra (242), suggesting such a procedure was potentially feasible and safe. Over the next 4 decades, this original procedure has been sequentially refined through the routine use of general anesthesia (67, 240), increased lavage volumes (67, 68), the use of saline alone (243245), the addition of concomitant chest percussion (244, 246), and the successful completion of bilateral sequential whole lung lavage in the same treatment session (7). If required by the severity of hypoxia, this procedure can be performed with the assistance of partial extracorporeal membrane oxygenation (247). Whole-lung lavage remains the current standard of care for PAP (5, 96), and the physiologic changes associated with this procedure have been thoroughly reviewed elsewhere (6, 248250).

Application and Efficacy of Therapeutic Lavage

In the absence of a randomized trial or even a formal prospective study, the true impact of the advent of therapeutic lavage on the natural history of acquired PAP is difficult to ascertain. Furthermore, any comparison of survival rates for those patients who did, or did not, undergo lavage makes no allowance for the relative severity of the disease process itself, although it seems likely that those patients with more severe disease would have been more likely to undergo lavage. Nevertheless, from the analyzed literature, those patients who underwent lavage at any time during the course of their disease had a superior survival, with a 5-year actuarial survival rate ± SE from diagnosis of 94 ± 2% compared with 85 ± 5% for those not receiving such treatment (p = 0.04) (Figure 8)

.

Patients who were treated with lavage were more likely to have been reported after 1969, reflecting increasing use of the newly described therapeutic procedure (Table 2)

TABLE 2. Demographic and disease features at diagnosis among published cases of acquired pulmonary alveolar proteinosis, according to reported treatment with therapeutic lavage


Feature

Lavage
 (n = 146)

No Lavage
 (n = 85)


n
%
Median
 (I.Q. Range)*
No.
%
Median
 (I.Q. Range)*
p Value
Age, years14639 (30–45)8537 (29–46) 0.7
Male, sex140698578 0.2
Smoker59763882 0.6
Duration of symptoms, mo111 7 (3–15)39 4 (3–27) 0.7
Publication 1970 or later146858560< 0.0001
Elevated LDH§42931560 0.007
North American source146738569 0.7
[A–a]Do2, mm Hg
60

54 (4–68)
34

42 (34–55)
 0.006

*Interquartile range is the range from the 25th to 75th centiles of the distribution.

Values shown are calculated using the Mann-Whitney U-test or Kruskall-Wallis test for numeric data and the χ2 test for categorical data, as appropriate.

At the time of onset of symptoms, patients 10 years of age or younger at diagnosis were assumed to be nonsmokers.

§Serum level of lactate dehydrogenase above upper limit of cited reference range.

Alveolar–arterial oxygen gradient; where the actual figure is not provided, this has been calculated assuming BTPS conditions.

Definition of abbreviations: BTPS = body temperature, ambient pressure, and saturated with water vapor; I.Q. = interquartile; LDH = lactate dehydrogenase.

. They were also more likely to have an elevated serum LDH at diagnosis and a higher [A–a]Do2, findings that are closely correlated in PAP patients.

Timing of Lavage

In the literature cases, the interval between the diagnosis of PAP and the first application of therapeutic whole-lung lavage ranged from 0 (immediate lavage) to 210 months, with a median of 2 months (n = 92). The majority of patients who underwent lavage did so within 12 months of diagnosis (79%), but there was a continuing increase in the proportion of patients having received such therapy. In the era of availability of lavage after 1964, the likelihood of a patient with PAP remaining free from therapeutic lavage was only 37% at 5 years (Figure 9)

.

Repeat Lavage

Among patients who had undergone therapeutic lavage, the median total number of procedures performed was two (range, 1 to 22), and the number of procedures performed was proportional to the duration of follow-up, such that 66% of patients followed for more than 1 year from diagnosis (median, 37 months) had required more than one lavage.

Although there are no established response criteria for therapeutic lavage, significant clinical, physiologic, and radiologic improvements were claimed following the first therapeutic lavage in 84% of the evaluable published cases (5, 29, 66, 69, 72, 77, 249, 251259).

Duration of Response Following Lavage

In 55 instances of reported response to lavage, there was information provided on the duration of benefit. The definition of disease recurrence varied between reports but included any of the following: the recurrence, or significant progression of respiratory symptoms attributable to PAP, or the application of further therapeutic interventions such as repeated lavage. Episodes of infection were not considered to represent disease recurrence. The median duration of clinical benefit from lavage was 15 months, with less than 20% of those patients followed beyond 3 years remaining free of recurrent PAP manifestations (Figure 10)

.

Predictors of Response to Lavage

Comparing the demographic and disease-related features of patients who did (n = 92) or did not (n = 18) respond to therapeutic lavage, there were no differences seen in gender, region of origin, duration of symptoms, smoking status, time from diagnosis to lavage, [A–a]Do2, serum LDH, or year of publication (each p ⩾ 0.3). There was a tendency for nonresponding patients to be younger (median 35 versus 39 years, p = 0.1). When response rates to lavage were calculated within cohorts for age at diagnosis (20 years or less, 21–39 years, and 40 years or more), there was a significant difference observed: 58% (7 of 12), 84% (42 of 50), and 90% (43 of 48), respectively (p = 0.03).

Prognostic Impact of “Response” to Lavage

To reduce “lead-time bias” associated with those patients who survived long enough to undergo therapeutic lavage many years after diagnosis, patients who underwent lavage more than 12 months after diagnosis were excluded from this analysis. Although there was a greater early mortality among the nonresponders (survival at 6 months was 87 ± 9% versus 97 ± 2%), overall survival did not differ significantly (actuarial 5-year survival rate 87 ± 9% versus 92 ± 4%, p = 0.3).

Improvement in Pulmonary Parameters Following Lavage

There were 47 patients reported with paired data prelavage and postlavage for PaO2, [A–a]Do2, FEV1.0, vital capacity, or diffusion capacity for carbon monoxide. A favorable therapeutic response was claimed for 85% of these patients. Overall, following therapeutic lavage there was a clear and significant improvement in all parameters analyzed (Figure 11

and Table 3)

TABLE 3. Prelavage and postlavage pulmonary parameters for patients with acquired pap


Parameter

n

Mean Change
 (SD)

95% CI
 of the Mean

p Value*
Arterial Po2, mm Hg41 20.1 (14.3) 15.6 to 24.6< 0.0001
[A–a]Do2, mm Hg21−30.6 (18.0)−38.8 to −22.4< 0.0001
FEV1.0, L33 0.26 (0.47) 0.09 to 0.42 0.0034
Vital capacity, L40 0.50 (0.54) 0.33 to 0.67< 0.0001
DlCO, mL/mm Hg · min
25
 4.4 (4.5)
 2.6 to 6.3
< 0.0001

*p Value is for the comparison of prelavage versus postlavage data for individual patients for each parameter for only those patients with available data using a two-sample t test.

Definition of abbreviations: CI = confidence interval; DlCO = diffusing capacity for carbon monoxide; PAP = pulmonary alveolar proteinosis.

when the best result reported within 3 months following lavage was considered. There was no correlation between the magnitude of change of any of these parameters and gender, age, region of origin, or year of publication. There were too few nonsmokers to explore the influence of cigarette use on responses obtained with lavage. When compared with males, females had both a lower prelavage vital capacity, despite the lack of difference in other parameters (1.61 versus 3.16 L, p < 0.0001), and a smaller mean absolute increment in vital capacity (0.22 versus 0.54 L, p = 0.02). However, there was no difference in the magnitude of response according to gender, when change in vital capacity was standardized by expression as a percentage of baseline values (mean change 13.0% versus 15.5%, p = 0.1).

The degree of change of each of the previously mentioned lung function parameters following lavage was not closely correlated. For example, there was no significant correlation between the increment in [A–a]Do2 and either Δ diffusion capacity for carbon monoxide (r2 = 0.011, p = 0.8) or Δ vital capacity (r2 = 0.074, p = 0.3), nor was there a significant correlation between the Δvital capacity and Δ diffusion capacity for carbon monoxide (r2 = 0.059, p = 0.2). One report also measured changes in pulmonary shunt fraction following lavage in 14 patients, and this improved from a mean ± SE of 20 ± 1% to 11 ± 1% (p < 0.001) (249).

Although the number of patients evaluable for some parameters was very small, those patients described in the original reports as “responders” had numerically greater improvements in each of the parameters analyzed than “nonresponders,” supporting the validity of the self-reported response categories (each p ⩽ 0.08). The median changes for “responding” patients were PaO2 +20.5 mm Hg (n = 34), [A–a]Do2 −33.0 mm Hg (n = 17), FEV1.0 +0.21 L (n = 27), vital capacity +0.52 L (n = 33), and diffusion capacity for carbon monoxide +4.5 ml/min·mm Hg (n = 20).

Additional Individual Institutional Reports

In addition to the previously mentioned efficacy data derived from published reports with individual patient data, there are a small number of single institutional reports that have evaluated the efficacy of lavage without providing individual patient data.

Harbour General Hospital, California

Through the period 1966 to 1976, Dr. Wasserman had performed therapeutic lavage on 19 patients, with efficacy data available from 11 of these (6). Reporting all results as median values for the evaluable patients, vital capacity improved from 78 to 89% of predicted normal values, diffusion capacity for carbon monoxide from 44% of predicted to 71%, and PaO2 from 66 to 85 mm Hg (each p ⩽ 0.005). In a subsequent publication from the same institution evaluating 21 patients (96), the median time to repeated lavage was 22 months, and after 5 years, 62% (13%) of patients had required a repeated procedure.

Mayo Clinic, Rochester

Through the period 1957 to 1983, a total of 29 patients with acquired PAP were seen, and 21 of these underwent some form of lavage procedure (8 transtracheal and 13 using more recent isolated whole-lung procedures) (4). Only three of these 21 patients (14%) were described as not obtaining any response to the lavage (type not specified). A major weakness in this report is that “postlavage” studies were performed many months after the lavage procedure, such that the mean interval between preprocedure and postprocedure tests was 30 ± 21 months (range, 2–135).

Cleveland Clinic, Cleveland

A review of 24 patients was recently published (2), 13 (54%) of whom underwent lavage on a median of two occasions (range, 1–8). There were limited objective response data presented for the first lavage, with the median vital capacity for three evaluable patients being unimproved, 71% and 66% of predicted, prelavage, and postlavage, respectively.

There are two published prospective phase II studies of subcutaneous GM-CSF treatment of patients with acquired PAP (41, 150). In an American study, which commenced accrual in March 1998 using 5–9 μg/kg/day, formal response criteria were not specified, but three of four treated patients (75%) attained “symptomatic, physiologic, and radiographic improvement” (150) with their mean ± SD [A–a]Do2 improving from 48.3 ± 20.1 mm Hg at baseline to 18.3 ± 4.2 mm Hg at Week 16 of treatment. A subsequent abstract has updated this study (151), with a cumulative response rate of 71% (five of seven patients). In a larger multinational study conducted between August 1995 and September 1998, 5 of 14 patients (36%) showed a response to initial therapy with 5 μg/kg/day (41), despite pre-existing GM-CSF–neutralizing antibodies (41, 155). Among these five responding patients, the mean improvement in [A–a]Do2 was 23.2 mm Hg (range 13.1 to 46.2 mm Hg). One further patient responded after dose escalation to 20 μg/kg/day (improvement in [A–a]Do2 from 52.0 to 28.8 mm Hg). Taken together, these studies demonstrate an overall response rate of 10/21 (48%; 95% CI, 26–70%) to GM-CSF at 5–9 μg/kg/day; however, there are clearly some additional patients who respond only to higher doses. Two other case reports also support a therapeutic effect of subcutaneous GM-CSF (152) (Ana Romero, personal communication, July 2001). This frequency of apparent response to GM-CSF is clearly lower than that obtained with therapeutic lavage and needs to be interpreted in the context of the known variability in the natural history of the disorder and the reported occurrence of apparent “spontaneous” remissions in approximately 10% of patients (see later here).

It is important to note that the duration of follow-up of patients treated with GM-CSF to date is less than 5 years, although there have not been reports of any late toxicity (41, 150, 151). Patients with PAP infrequently develop late pulmonary fibrosis (96), and the development of pulmonary fibrosis in an adenovirus-mediated GM-CSF transgenic mouse model (260) raises the concern that GM-CSF therapy may enhance this risk. However, the fibrosis in this transgenic model is likely due to the vector used, as other GM-CSF transgenic animals have no such propensity (124, 125, 260, 261).

From early studies among cancer patients with pulmonary metastases, it is known that GM-CSF can be delivered safely as an aerosol (262), and the successful use of this form of GM-CSF delivery has been described in a single PAP patient (263). However, such a route of delivery may not correct any systemic manifestations of GM-CSF deficiency in PAP patients.

It has long been recognized that patients with PAP are at risk of secondary infections with a variety of organisms. Although certainly reported, the common bacteria responsible for many respiratory infections in community and hospital patients, such as Streptococcus (257, 264267), Klebsiella (257), Haemophilus (257, 268), Staphylococcus (268, 269), Pseudomonas (269), Serratia (71), Proteus (270272), and Escherichia coli (273), do not predominate. Although there is likely to be some degree of publication bias favoring the reporting of “unusual” organisms, opportunistic pathogens are over-represented among patients with acquired PAP, being reported in 13% of patients overall (Table 4)

TABLE 4. Overview of opportunistic pathogens reported in patients with acquired pap


Opportunistic Pathogen

References

n

Comments
Mycobacterium tuberculosis(25, 287, 303, 306–308)6No cases reported since 1987; one case of tuberculous meningitis
MAIC(309)1
Streptomyces spp.(310)1
Cryptococcus spp.(15, 17, 71, 264, 311)4Two patients had received corticosteroids
Nocardia spp.(15, 42, 49, 53, 168, 276–281, 288, 289, 312–324)34Twenty-nine cases from North America; prior corticosteroids in four cases;
   Cerebral involvement in seven; Infection fatal in five instances; Nocardia
   preceded diagnosis of PAP by 4 years in one case
Mucorales(30)1No prior steroids reported
Histoplasma spp.(325)3All three cases from endemic region of Venezuela
Coccidiodies immitis(254)1From nonendemic region of United States
Aspergillus spp.(275, 326, 327)3Prior steroids in one, and one case of fatal cerebral involvement
Blastomyces dermatitidis(328)1From endemic region of United States
Acinetobacter spp.
(329)
1

Definition of abbreviations: MAIC = mycobacterium avium-intracellulare complex; PAP = pulmonary alveolar proteinosis.

. One institutional series reported the isolation of atypical Mycobacteria from the lavage material of 42% of patients who underwent therapeutic lavage between 1984 and 1992; however, five of these eight instances were in very low colony numbers of dubious clinical significance, and clinical infection was not felt to be present in any of these patients (274).

Notably, a number of infections among patients with PAP were disseminated, particularly involving the central nervous system, either caused by Aspergillus spp. (275) or Nocardia spp. (251, 276281). This phenomenon suggests that the predisposition to infection among patients with acquired PAP is systemic in nature, rather than simply reflecting local environmental changes in the lung. This may be important in light of the suggested pathogenetic role of the systemic neutralization of GM-CSF activity.

No disease- or patient-related factors could be identified that were associated with the occurrence of opportunistic infection. There was no difference in reported neutrophil counts (median 6.7 versus 5.2 × 109 per L, p = 0.3). Patients with opportunistic infections had a shorter duration of symptoms before the diagnosis of PAP (median 5 versus 8 months, p = 0.05), perhaps consistent with their presentation being precipitated by the development of the infection itself, and were more likely to be diagnosed at autopsy (21% versus 9%, p = 0.01). Patients who developed opportunistic infections had not been treated with corticosteroids more frequently (16% versus 18%, p = 0.6) and were no more likely to be smokers (75% versus 73%, p = 1.0). This does not support the earlier contention that clinically significant exposure to organisms such as Mycobacterium avium-intracellulare may be acquired from cigarettes (274, 282). The frequency of opportunistic infections in published cases has not changed over time.

Data on duration of survival from the date of diagnosis of PAP, including those diagnosed at autopsy, were available for 343 patients. The median period of observation for patients still alive at last reported follow-up is 18 months, with the longest follow-up available being 26 years (25, 66, 85, 236, 283). The actuarial survival rates ± SE at 2, 5, and 10 years are 78.9 ± 8.2%, 74.7 ± 8.1%, and 68.3 ± 8.6%, respectively (Figure 12)

.

There were a total of 69 deaths reported, 65 of which were attributable to PAP. The cause of death was directly due to respiratory failure resulting from PAP in 47 cases (72%). In an additional 13 cases (20%), the cause of death was indirectly related to PAP through uncontrolled infection in 12 (including predominantly cerebral foci in four) (15, 24, 271, 275, 281289) and cardiac arrest during lavage in one case (253). In the remaining five cases (8%), the deaths were attributable to unrelated causes, including one case each of bladder cancer (290), bowel cancer (291), acute myocardial infarction (101), pancreatitis (273), and gastrointestinal bleeding (50). These incidental causes of death account for two of the seven deaths observed beyond 2 years from diagnosis.

Disease-specific survival of those patients diagnosed during life was assessed to reduce potential biases introduced by cases diagnosed at autopsy and intercurrent events (Figure 13)

. The actuarial 5-year disease-specific survival rate was 88 ± 4%. More than 80% of the loss of life attributable to PAP seen during the first 5 years of observation occurs during the first 12 months following diagnosis. The risk of death declined significantly beyond 12 months from diagnosis. When data from those patients diagnosed at autopsy were included, by calculating survival from the first recorded onset of symptoms or radiographic changes, the 5-year actuarial survival rate was 70% (n = 254).

Gender and Age

There was no difference in overall survival from the date of diagnosis according to gender (5-year survival rate 74% for males and 76% for females, p > 0.5). Also, there was no difference among women according to age, with a 5-year survival rate of 80 ± 6% for those aged above the median for women of 34 years and 71 ± 9% for those aged 34 years or less (p = 0.4).

However, within the entire cohort, using the median age of the entire group (39 years) as a cut point, there was evidence of inferior outcome for older patients (p = 0.006), attributable to both a greater direct mortality from PAP and a greater incidence of death from incidental causes. The risk of death from opportunistic infections did not differ appreciably between the two age groups. Excluding incidental causes of death, the magnitude of the survival difference (actuarial rates of 84 ± 3% versus 70 ± 5% at 5 years, p = 0.055) was reduced.

Given the higher than expected incidence of cases among young children less than 5 years of age, this subgroup was examined, revealing a poor outlook. The actuarial 5-year survival rate was 14 ± 13%, with just one of the seven patients surviving beyond 10 months.

Cases Less Than 5 Years of Age

There were just seven patients diagnosed at less than 5 years of age in the period before 1998. The adverse outlook in this age group appeared to be attributable in part to the reduced efficacy of therapeutic lavage. There were five such children diagnosed during the era of lavage availability (44, 177, 201, 292, 293), and three were treated (one repeatedly) without any evident benefit (44, 177, 293). Recent reports confirm this adverse experience (294, 295). This diminished effectiveness of therapeutic lavage mirrors that reported for patients with congenital disease where lavage also has limited efficacy (181, 185, 201, 296, 297) and suggests that some of these cases may have been misdiagnosed forms of congenital PAP. Some of these infants were also treated with corticosteroids, N-acetylcysteine, and ambroxol without any evidence of benefit.

Within the limitations of the small number of patients available in published case reports, there are similarities in the clinical presentation of apparent PAP in children below the age of 5 years with those of congenital disease. Four of the reported cases described prominent gastrointestinal symptoms at presentation (food intolerance, failure to thrive, progressive weight loss, and vomiting) (44, 177, 287, 293). Also, one infant presenting at the age of 4 years had a sibling who died at the age of 2 and a half months from a respiratory illness labeled as “viral pneumonia” without a lung biopsy or autopsy being performed, and another family had two affected children, suggesting a possible familial basis (293, 295). The majority of these cases were reported before the recognition of SP-B deficiency as a cause of congenital PAP, although in one instance, this diagnosis was excluded by the finding of SP-B in BAL fluid (201) and another by normal polymerase chain reaction for SP-B mRNA (295).

Smoking

There were 103 patients with available survival data who were smokers at the time of onset of symptoms (including three who then ceased prior to the confirmation of the diagnosis) and 24 who were nonsmokers at the first onset of symptoms (including six who had ceased between 1 and 10 years earlier). The actuarial 5-year survival rate from the time of diagnosis was identical at 82% for these two groups. There are insufficient data available to comment on any possible influence of continued smoking on infection risk or survival.

Arterial Oxygenation

In the 159 patients where arterial oxygenation data were reported, PaO2 at presentation, using either the median of the cohort (58 mm Hg) or quartiles, was not associated with any differences in disease-specific survival (p ⩾ 0.2). However, there was a trend for an improved outcome among patients with an [A–a]Do2 below the median of 50 mm Hg, where 5-year actuarial survival rates were 98 ± 2% compared with 90 ± 4% for those 50 mm Hg or more (p = 0.09).

LDH Level

Serum LDH was not predictive of survival, whether expressed as a percentage of the upper limit of normal or simply as elevated compared with normal.

Year of Publication

Grouping patients in 10-year cohorts by year of initial publication, there has been a dramatic and consistent improvement in survival with time (trend p < 0.0001). The 5-year actuarial survival rates for patients reported in the years 1958–1967, 1968–1977, 1978–1987, and 1988–1997 are 52%, 72%, 93%, and 100%, respectively. This improvement, at least in part, is due to a major reduction in the number of patients diagnosed at autopsy. However, the same trend is evident using disease-specific survival and restricting the analysis to patients diagnosed antemortem, with 5-year actuarial survival rates of 77 ± 6%, 91 ± 4%, 96 ± 3%, and 100%, respectively (trend p = 0.0002).

Geographic Region

There was no statistically significant difference observed between cases reported from North America (n = 140), Europe (n = 41), or Asia (n = 15); 5-year actuarial survival rates were 89 ± 3%, 87 ± 5%, and 100%, respectively (p = 0.4).

The concept of possible “spontaneous resolution” of the manifestations of acquired PAP was initially proposed in the series of Rosen and colleagues (15). While acknowledging the brief period of follow-up since diagnosis for their patients, they described the patients as either having stable persistent symptoms, progressive deterioration in their disease process, or spontaneous improvement. A total of 26 patients were so classified: 19%, 31%, and 50% in these three categories, respectively. Although five patients were claimed to have “shown definite improvement,” in only one instance was this accompanied by clearance of all previous radiological abnormalities (Case 19).

Other authors also have made similar observations. Kariman and colleagues described “spontaneous remission” of the disease process occurring 1 to 3 years after diagnosis in 24% of a series of 23 patients (5). In the retrospective review of the Mayo clinic experience (4), 29% of patients showed apparently spontaneous resolution after an unspecified period of observation.

Overall, from all available individual patient reports collected, 24 of 303 (7.9%) were described as manifesting a significant degree of spontaneous improvement (5, 15, 24, 30, 53, 82, 257, 267, 298305). The features of these patients are compared in Table 5

TABLE 5. Features of patients with acquired pap who claimed to have manifest “spontaneous resolution”


Characteristic

Spontaneous remitters (n = 24)

Nonremitters (n = 279)

p Value

n
%
Median
 (I.Q. range)*
n
%
Median
 (I.Q. range)*

Age at diagnosis2438 (25–45)27838 (30–45)0.6
Gender, % male2471273730.8
Publication date, % pre-19652433279200.1
Duration of symptoms204 (3–14)1788 (3–24)0.1
Smoker, %1788105730.2
Serum LDH, % elevated§56056800.3
Arterial PaO2, mm Hg1262 (52–69)12360 (48–70)0.9
[A–a]Do2, mm Hg1147 (33–57)10247 (33–57)0.8
Duration of follow-up, mo
24

33 (12–76)
218

22 (10–48)
0.1

*Interquartile range is the range from the 25th to 75th centiles of the distribution.

p Values shown are calculated using the Mann-Whitney U-test or Kruskall-Wallis test for numeric data and the χ2 test for categorical data, as appropriate.

At the time of onset of symptoms, patients 10 years of age or less at diagnosis were assumed to be nonsmokers.

§Serum level of lactate dehydrogenase above upper limit of cited reference range.

Alveolar–arterial oxygen gradient; where the actual figure is not provided, this has been calculated assuming BTPS conditions.

Definition of abbreviations: BTPS = body temperature, ambient pressure, and saturated with water vapor; I.Q. = interquartile; LDH = lactate dehydrogenase; PAP = pulmonary alveolar proteinosis.

with those of patients not claimed to have manifest such spontaneous improvement. There were no features able to identify clearly those patients who would subsequently manifest “spontaneous resolution,” although such patients tended to have a shorter duration of symptoms before diagnosis, and had been followed for a longer period of time. Interestingly, 33% of all claimed cases of “spontaneous resolution” had been published before 1965. In their retrospective review, Kariman and colleagues suggested that spontaneous remitters had higher PaO2 levels (72 ± 5 versus 57 ± 4 mm Hg, p < 0.05) and lower [A–a]Do2 (38 ± 3 versus 51 ± 3 mm Hg, p < 0.05) at diagnosis than those patients who eventually required therapeutic lavage (5). However, in this comparison, they did not account for the lead-time bias necessary to allow the manifestation of such spontaneous resolution (19 patients underwent lavage 3 months or less after initial assessment) nor compensate for the fact that low PaO2 levels were one of the criteria for the institution of therapeutic lavage.

Among the 24 claimed cases of spontaneous resolution, the median time from diagnosis to resolution was 20 months (range, 3 to 61 months; n = 19) and from the onset of symptoms was 24 months (range, 10 to 76 months; n = 19). None of the reported patients had subsequently manifest deterioration, or recurrence, and none of these patients had died. At the time of most recent reporting the median duration of these ongoing remissions was 14 months (range, 1 to 144 months; n = 20).

Although such reports have clearly established that the severity of symptoms, radiographic abnormalities, and functional defects may diminish over time in a minority of patients with acquired PAP, it is not clear that this represents complete resolution of the disease process and restoration of entirely normal lung function and surfactant homeostasis. Closer examination of the details of the individual cases discloses that comprehensive objective studies to document disease resolution (such as radiographic studies, spirometry, and arterial blood gases) were either not repeated (15, 30, 257, 298, 300302) or when repeated documented persisting abnormalities (15, 24, 53, 82, 299301, 303, 304). The cases from the large series of Kariman and colleagues were classified as spontaneous remitters if “diffuse pulmonary infiltrates cleared and pulmonary function returned to normal levels” without providing individual patient data to confirm this assessment (5).

Although it is clear that the disease process of PAP eventually enters a quiescent state in most surviving patients, either without therapeutic intervention, or following a period of variable duration where therapeutic lavage is required, it is unclear whether the underlying pathophysiologic process is reversed, or simply reduced in severity to such a degree that clinical, radiographic, and functional consequences are minimized. Without a simple, dichotomous, noninvasive diagnostic test, it has not been possible yet to distinguish definitively between a true pathophysiologic “cure” and the persistence of subclinical disease.

Conclusion

Analysis of 241 published articles describing over 400 separate individual cases of PAP has revealed a number of important features of this rare lung condition. The great majority of PAP cases are of the acquired variety occurring in adults. From these reports, a “typical patient” was a male smoker aged 30 to 50 years, and females aged 25–40 are under-represented. PAP is also a congenital disorder in a minority of cases, whereas other cases are secondary to other conditions, notably hematologic malignancy.

A number of important milestones mark the key advances of medical insight into PAP. Early among these was the 1965 description of whole-lung lavage, which remains today's standard therapy. Within 5 years from diagnosis, almost two-thirds of PAP patients had received such lavage, with more than 80% attaining significant, but transient, benefit.

More recently, major advances since 1994 have resulted in the discovery of animal models of PAP based on deletion of genes for GM-CSF itself or the GM-CSF receptor. Thus deficiency of GM-CSF has become a strongly suspected pathogenetic mechanism for adult acquired PAP, and GM-CSF administration with therapeutic intent has been evaluated in several small studies with benefit in approximately 50% of all patients so far treated. In the last 2 years, the demonstration of neutralizing anti–GM-CSF antibodies in all cases of acquired PAP has suggested that the disease may have an autoimmune pathogenesis, with the pulmonary disease resulting from a blockade of endogenous GM-CSF action. That GM-CSF therapy may reverse both pulmonary and extrapulmonary abnormalities found to be present in PAP suggests that these blocking antibodies, even if pathogenic, may in some cases be overcome or circumvented by pharmacologic administration of GM-CSF.

Spontaneous clinical resolution clearly occurs in a small minority of adult PAP patients, although the available evidence makes the existence of spontaneous cure less certain. There are no simple biochemical or clinical parameters so far described that are of use as prognostic variables applicable to most patients, although serum LDH levels correlate with the degree of impairment in oxygenation. Fortunately, only 10–15% of PAP patients may die directly from PAP-induced pulmonary failure. This mortality risk is perhaps less among those diagnosed in the last decade, probably because the prognosis of PAP patients with respiratory impairment is improved by whole-lung lavage. Those rare children aged less than 5 years diagnosed with apparently acquired PAP have a very adverse prognosis, and these cases may represent atypical manifestations of congenital PAP.

Much remains to be learned about this fascinating disease, and it is likely that we are on the threshold of a new era in the understanding of PAP. With the recent recognition of its possible autoimmune nature, it is to be hoped that improved pathophysiologic insights will translate rapidly into targeted therapeutic strategies, which may render redundant the physical removal by lung lavage of accumulated surfactant.

The authors express sincere thanks to Professor Ashley Dunn who supervised this project from its initiation, the library staff of the Melbourne Tumour Biology Branch of the Ludwig Institute for Cancer Research for their skill and persistence in sourcing many publications; they also thank the numerous colleagues who contributed so greatly to both the laboratory and clinical research projects underpinning this work.

Supported in part by a National Health and Medical Research Council Postgraduate Research Fellowship (J. F. S.)

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Correspondence and requests for reprints should be addressed to Dr. John F. Seymour, Division of Hematology/Medical Oncology, Peter MacCallum Cancer Institute, St. Andrew's Place, East Melbourne, Victoria, 3002, Australia. E-mail:

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