© 2002 American Thoracic Society
Pulmonary Alveolar ProteinosisProgress in the First 44 YearsLudwig Institute for Cancer Research, Melbourne Tumour Biology Branch, and the Intensive Care Unit, The Royal Melbourne Hospital, Parkville, Australia 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: jseymour{at}petermac.unimelb.edu.au
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.
Key Words: pulmonary alveolar proteinosis • granulocyte-macrophage colony-stimulating factor • pulmonary surfactants • bronchoalveolar lavage • autoantibodies
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 (2–6). 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, 7–9), 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
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 x 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, 50–58).
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
Smoking
Age
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, 66–84) 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, 88–90), 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 (99–103), 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
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 (112–114). 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 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 ßc (ßc-/-) (117, 118). Surprisingly, these animals had no detectable abnormality of steady-state hematopoiesis but had impaired surfactant clearance by alveolar macrophages (119–121), 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 (119–121). 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 (122–125). 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 ßc-/- 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 ßc-/- 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 (131–133) 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 ßc-/- 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 ßc-/- 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 (138–140), a propensity to develop systemic infections (141, 142), reduced fertility and impaired ovarian follicle maturation (141, 143–145), 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 (153–155). Other investigators have confirmed these findings (156). No clear defects in either the GM-CSF ßc 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 (161–163). 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 (168–170). 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 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, 190–194), 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 ßc have been implicated in some of these cases (201). In a single report, four infants with congenital PAP were shown to have dramatically reduced ßc 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 ßc 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 ßc 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 ßc 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 The rare genetic disorder "lysinuric protein intolerance" is attributable to a mutation in the "y+L amino acid transporter-1" gene (204–206), 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 (207–210). 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 (228–231). 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, 232–234). 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 ßc 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 (243–245), 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, 248–250).
Application and Efficacy of Therapeutic Lavage
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). 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, 251–259).
Duration of Response Following Lavage
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
Improvement in Pulmonary Parameters Following Lavage
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  diffusion capacity for carbon monoxide (r2 = 0.011, p = 0.8) or vital capacity (r2 = 0.074, p = 0.3), nor was there a significant correlation between the vital capacity and 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
Additional Individual Institutional Reports
Harbour General Hospital, California
Mayo Clinic, Rochester
Cleveland Clinic, Cleveland
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ABSTRACT
Table of Contents
3 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 (
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).