Introduction

Occupational respiratory exposures contribute to a significant burden of non-malignant respiratory disorders worldwide. The spectrum of respiratory disorders includes pneumoconioses such as asbestosis, coal workers’ pneumoconiosis and silicosis, asthma, COPD, bronchiolitis, hypersensitivity pneumonitis, pulmonary fibrosis, sarcoidosis, and certain infections. Pulmonary alveolar proteinosis (PAP) is a rare lung disorder marked by deposition of lipoproteinaceous material in the alveoli and alveolar macrophages due to abnormal surfactant homeostasis. While the majority of PAP has an autoimmune etiology (triggered by autoantibodies targeting GM-CSF signaling), PAP can also occur due to genetic defects or secondary to other factors, including hematological disorders, infections, and environmental and occupational exposures. This review will focus on occupational and environmental inhalational exposures that have been implicated in PAP.

Classification of PAP

The primary pathophysiologic defect in adult PAP is defective surfactant clearance and altered surfactant homeostasis due to impaired alveolar macrophage function. Our knowledge of the pathogenesis of PAP was significantly enhanced by the landmark discovery of the relationship between GM-CSF signaling and alveolar macrophage function [1] . GM-CSF signaling is crucial for the development of alveolar macrophage metabolic and immune functions [2]. When autoantibodies to GM-CSF deplete bioavailable GM-CSF, it results in autoimmune PAP, formerly known as “primary” or “idiopathic” PAP. This autoimmune mechanism consti tutes the most common type of PAP (> 90%) [3]. Secondary PAP occurs when the underlying problem (hematologic disorder, malignancy, environmental/occupational exposure, drugs, etc.) imparts a defect in macrophage function, either qualitatively or quantitatively [4•] . Among the various causes of secondary PAP, hematologic diseases (myeloproliferative disorders, bone marrow transplantation) tend to be the most common [4•]. Other etiologies are listed in Table 1. Rarely, genetic mutations in genes encoding the GM-CSF receptor α and β chains (CSF2RA, CSF2RB) also lead to impaired macrophage maturation (hereditary PAP) [22].

Table 1 Classification of PAP based on etiology (adapted with permission from reference 2)
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Occupational Exposure and PAP

PAP has been reported in association with inhalational exposure to a wide variety of vapors, gases, dusts, and fumes [23•] (Table 2). Recently, the American Thoracic Society (ATS) and European Respiratory Society (ERS) jointly published their official statement on the occupational burden of PAP. Their analysis yielded 1539 cases of PAP with a pooled exposure prevalence of 29% (95% CI: 21–37%) [23]. This finding indicates that a substantial fraction of PAP cases are associated with occupational exposure, although not all of these associations are known to be causative.

Table 2 Examples of occupational exposures reported in association with pulmonary alveolar proteinosis
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Though the true contribution to PAP of inhalational exposure is unknown, there is strong evidence of causation for several exposures. One of the first recognized and most commonly implicated exposures associated with PAP is silica [24]. In contrast to chronic silicosis (characterized by silicotic nodules and, in advanced cases, progressive massive fibrosis), which evolves after exposure to relatively low concentrations of silica occurs over a longer period of time (> 10 years), silica-related PAP occurs over weeks to months of relatively high silica exposure [24, 25]. Silica-related PAP, or “acute silicoproteinosis,” has a dismal prognosis, typically of 2 years [24]. However, lower levels of silica exposure over a longer period of time have also been described in association with PAP [25] .

Features of PAP were described prior to 1930 in workers exposed to silica during abrasive soap manufacture in the USA and UK, although the term PAP was not yet used [26]. Subsequently, in the early 1930s, in what was arguably the largest industrial disaster in US history, hundreds of workers died from acute silicosis during the construction of a tunnel through a high-silica rock near Gauley Bridge, WV [26]. In 1969, a report of acute silicosis in four sandblasters noted the characteristic histological findings of PAP on autopsy, making the explicit connection to silica exposure and introducing the term “acute silicoproteinosis” [27] . Other case reports followed, including recent descriptions of PAP in denim sandblasters in Turkey and artificial stone fabricators in the USA and Australia [28,29,30]. The recent ATS/ERS statement found that among 786 PAP cases with information on silica exposure, the pooled prevalence of exposure was 5% (95% CI: 2–8%) [23•]. Demonstration of PAP in animals exposed to silica has confirmed a causal role for this exposure [31].

More recently, indium has been implicated in the development of PAP [21, 32]. Indium is used to make indium-tin oxide (ITO), which is applied as a thin film to create a transparent conductive coating for flat panel displays such as liquid crystal displays (LCDs), touch screens, and solar cells. A case series of ten indium oxide– and ITO-exposed workers who developed lung disease included three cases of PAP [32]. The authors observed that patients with relatively short latency period were diagnosed with PAP and those with longer latency were diagnosed with interstitial lung disease (pulmonary fibrosis). Patients initially diagnosed with pulmonary fibrosis, however, also had evidence of PAP on histopathology. There was histopathologic evidence of cystic changes and emphysema in several patients as well. It is possible to infer that PAP precedes inflammatory and fibrotic responses [33, 34]. As with silica, animal models confirm that indium compound exposure causes PAP [35, 36].

Pathogenesis

It has been thought that the mechanism by which workplace inhalational exposures cause PAP involves impaired alveolar macrophage function independent of antibody production against GM-CSF (in contrast with autoimmune PAP). This inference is based on results of studies that have shown absence of antibodies to GM-CSF in patients with other forms of secondary PAP (such as hematological disorders) and animal models that have found macrophage dysfunction with exposure to silica and indium compounds [37,38,39,40,41]. More generally, inhalational injury might reduce the number of alveolar macrophages and/or inflict a qualitative injury to existing alveolar macrophages. There is also evidence that exposure to silica, in particular, stimulates increased surfactant production by type II cells, a protective mechanism that can become pathological over time [42]. The increased production combined with the inability of the functionally impaired alveolar macrophages to remove undegraded surfactant may lead to PAP.

Interestingly though, a subset of individuals with occupational PAP have been found to have anti-GM-CSF antibodies [32, 43, 44]. These findings blur the classification between autoimmune and occupational PAP (typically classified under secondary PAP). It also raises the possibility that occupational exposure, at least in some patients, could be a trigger for the development of autoimmune PAP, perhaps through exposure to or modification of endogenous proteins as a result of apoptosis, setting in motion an environment of self-reactivity [45]. Among patients classified as autoimmune PAP, 26% of patients in the Japanese cohort and 54% of patients in the German cohort reported occupational exposure, lending plausibility to this concept [3, 6]. Whether these patients had pre-existing autoantibodies to GM-CSF or whether autoimmunity was induced by occupational exposure remains unknown. A retrospective series also suggested poorer prognosis for those patients with occupational PAP and negative antibody to GM-CSF [14].

Clinical Features

For inhalation causing PAP, the development of PAP likely depends on the amount and duration of exposure. However, based on epidemiologic data, it most commonly presents in the 3rd to 6th decade [4•]. For all types of PAP, there is a higher than expected proportion of smokers (50–70%) and dust exposure (20–50%), although this does not establish causality [3, 4, 46]. Gender predilection is unclear. Several studies have reported higher dust exposure in males than females, which may reflect increased opportunities for exposure in men than women, rather than a difference in gender susceptibility [3, 6]. In patients with suspected occupational PAP, workup should include identifying the potential culprit agent, both to establish etiology for the patient and assess risk to co-workers. This may be a challenging process, and in situations where diagnosis is unclear, involvement of an occupational medicine specialist is important. Accurate characterization of the exposure may require obtaining safety data sheets (SDS) and other work exposure information from the patient’s worksite.

In regard to symptoms, patients with PAP may present with a spectrum of clinical manifestations. Acute silicoproteinosis is rapidly progressive and often fatal, while other low-grade exposures may have a longer latency period to manifest as PAP. Up to one-third of patients with PAP can be asymptomatic [(3], [47)]. Often, the diagnosis in these patients may be incidental based on an abnormal radiograph. Studies suggest that 50–90% of patients may develop progressive dyspnea [48]. Cough may be productive. Other symptoms are non-specific and include fatigue, chest discomfort, and joint aches. Fever maybe a manifestation of PAP but should prompt further investigation due to increased risk for opportunistic infections in PAP. Unfortunately, physical exam findings are non-specific, but may include presence of digital clubbing and lung crackles [4•].

Diagnosis

Pulmonary function tests may be normal or reveal restrictive impairment depending on the degree of pulmonary parenchymal involvement [32]. PAP may be associated with reduction of diffusing capacity for carbon monoxide (DLCO), reflecting impairment of gas exchange [3, 4, 6, 32]. There are no specific biomarkers for PAP. Previously, serum levels of lactate dehydrogenase (LDH) generated interest as a diagnostic test. LDH can be elevated in up to 80% of the patients with PAP; however, it also lacks specificity [4•]. Other biomarkers such as KL-6, CYFRA 21-1, CEA, and YKL-40 have been studied; however, most are not routinely used in the USA [49,50,51,52] . In Japan, KL-6 has been used as a component of medical surveillance of indium-exposed workers.

In autoimmune PAP, antibodies to GM-CSF can be identified both in the serum and bronchoalveolar lavage (BAL) fluid [3, 53, 54]. In contrast, serum autoantibodies to GM-CSF are not elevated in patients with other forms of PAP [55, 56]. However, as mentioned before, some cases of PAP secondary to exposure with elevated antibodies to GM-CSF blur our ability to categorize these entities into two different disorders [32]. Notwithstanding these discrepancies, the nearly 100% sensitivity and specificity of serum anti-GM-CSF antibody level make it a confirmatory diagnostic test for autoimmune-mediated PAP [57]. Thus, there is a case for checking for autoantibody to GM-CSF even for those with occupational PAP, as GM-CSF is also a therapeutic target. Elevated GM-CSF cytokine levels in the blood indicate impaired clearance and usually indicate hereditary PAP due to receptor mutations, a mechanism different from exposure-related PAP [22]. In occupation-related PAP, this test is of limited value.

Radiology

Chest radiographs are non-specific in PAP. With extensive pulmonary involvement, a “bat wing” appearance with central hilar prominence may be seen. High-resolution chest CT (HRCT) scans are significantly superior in characterizing pulmonary parenchymal involvement. Diffuse ground glass opacification is almost universal [58, 59]. Interlobular septal thickening is present in up to 85% of patients [59] (Fig. 1). The pattern of septal thickening frequently identified with PAP is termed “crazy paving,” which refers to the polygonal appearance of the secondary pulmonary lobules with interspersed ground glass attenuation [60]. Crazy paving occurs in more than 80% of patients with PAP [58, 61]. Despite the nearly ubiquitous nature of this radiology finding, it is important to recognize that “crazy paving” is not specific for PAP, as it can be seen in other conditions, including pulmonary edema, organizing pneumonia, alveolar hemorrhage, and pneumocystis pneumonia.

Fig. 1
figure 1

High-resolution CT (HRCT) scan images of patient with PAP showing diffuse ground glass opacification and “crazy paving” pattern (Figure adapted with permission from reference number 2.)

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HRCT scans can also differentiate some forms of secondary PAP from autoimmune PAP, as the distribution of ground glass opacities was found to be typically diffuse in PAP secondary to hematologic disorders rather than geographic as seen in autoimmune PAP [58]. One study that examined autoimmunity and occupational exposures found that all 13 patients with autoimmune PAP and an occupational exposure history had geographic distribution and 11 (85%) had crazy paving [14]. However, of 4 patients without autoantibodies to GM-CSF and an occupational exposure history, just 1 had geographic distribution and 1 had crazy paving, suggesting these findings are associated with autoimmune PAP, regardless of occupational history. About 20% of patients with PAP of any kind may develop pulmonary fibrosis, which indicates poor prognosis [62].

Confirmation of Diagnosis

The confirmation of PAP ideally requires tissue diagnosis. Particularly in occupation-related PAP without antibody to GM-CSF, tissue diagnosis could be critical. BAL may demonstrate characteristic opaque or milky-appearing fluid (Fig. 2). Under light microscopy, characteristic acellular oval bodies that are basophilic on May-Grünwald-Giemsa staining may be observed. Transbronchial biopsy increases the diagnostic yield and is a valuable tool in scenarios where diagnosis is in question [3, 6]. Less than 10–20% of patients require surgical biopsy for confirmation [3, 6, 19]. Histopathology demonstrates diffuse dense acellular eosinophilic material in the airways with minimal interstitial inflammation (Fig. 3a, b). The accumulated material is characteristically periodic acid-Schiff (PAS) positive and Oil Red O positive [4, 63]. The use of brightfield and polarized light microscopy to assess the presence, abundance, and types of dust particles can be valuable as well [64]. In lung disease related to indium, other histopathologic changes include cholesterol clefts, brown particles composed of indium, emphysema, and fibrosis [32]. Figure 4 shows a proposed algorithm for the diagnosis of suspected PAP.

Fig. 2
figure 2

Characteristic milky or opalescent appearance of fluid return from whole lung lavage in a patient with PAP (Figure adapted with permission from reference number 2.)

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Fig. 3
figure 3

Histopathology showing spectrum of histopathologic features of indium lung disease (hematoxylin and eosin stains). a intraalveolar exudate characteristic of alveolar proteinosis, with occasional cholesterol clefts (magnification 3200). b innumerable cholesterol clefts (magnification 3200). c intraalveolar exudate characteristic of alveolar proteinosis, cholesterol clefts, and fibrosis (magnification 3100). d cholesterol clefts, associated multinucleated giant cells, interstitial fibrosis, and brown particles composed predominantly of indium (magnification 3200) (Figure adapted from Cummings KJ, Nakano M, Omae K, Takeuchi K, Chonan T, Xiao YL, et al. Indium lung disease. Chest. 2012 Jun;141(6):1512-21.)

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Fig. 4
figure 4

Suggested diagnostic algorithm for PAP (Note that in some patients with occupational PAP, antibody to GM-CSF may be elevated-prevalence is not known) (Figure adapted with permission from reference number 2.)

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Treatment

Currently, there are no standardized guidelines for the treatment of PAP. Therapeutic decisions are based on disease severity (symptoms, physiologic impairment) and type of PAP (autoimmune vs non-autoimmune). Patients with a milder degree of severity can be safely monitored for disease progression (worsening of symptoms, serial pulmonary function testing, oxygenation, and chest radiography). Patients with moderate-to-severe disease require closer monitoring and interventions.

The experience with managing work restrictions for occupational PAP is necessarily limited, but lessons from more common occupational lung diseases, such as work-related asthma, may be informative, with some caveats. Removal from exposure is associated with the best outcomes in work-related asthma and would be expected to be more favorable for occupational PAP as well, although because of the rarity of the disease, data are lacking [65]. It is also important to note that for insoluble dusts like silica and ITO, exposure cessation does not address the material that is already in the lung and interfering with surfactant homeostasis, so it may not have much impact on disease progression.

Nonetheless, for patients still well enough to work, exposure cessation is ideally accomplished through substitution of the hazard or relocating the patient to an area without exposure. If substitution or job reassignment is not possible, removal from work ensures exposure avoidance. However, physicians must consider the adverse economic impact of job change or loss, as well as patient preferences to continue in the same occupation. Transfer to lower levels of exposure and use of respiratory protection with close monitoring for disease progression would also be an option for early disease. Notably, the poor prognosis for silica-associated PAP even with complete exposure removal argues against any continued work with silica regardless of disease stage [24]. Furthermore, the diagnosis of PAP related to silica or another exposure for which occupational exposure limits exist should prompt physician reporting to the Occupational Safety and Health Administration (OSHA) and, in many states, the health department. A workplace inspection can determine compliance with regulations on exposure limits and ensure the patient’s co-workers are receiving mandated medical surveillance. For PAP related to a novel exposure or other occupational exposures for which regulations do not exist, the National Institute for Occupational Safety and Health, a research agency within the Centers for Disease Control and Prevention, can provide guidance to physicians and potentially carry out a health hazard evaluation to better understand disease risk [66].

Among treatment options, whole lung lavage (WLL) has been the most commonly used modality for the past several decades. This review will not address the technical details of performing WLL. Despite differences in the technique of performing WLL, the contemporary version of WLL involves performing single or sequential bilateral lavage by isolating each lung using a double-lumen endotracheal tube. In the cases of severe hypoxia, extracorporeal membrane oxygenation (ECMO) to facilitate completion of WLL should be considered [67]. WLL is generally well tolerated though. Most commonly reported complications include fever (18%) and hypoxemia (14%) [68]. In terms of efficacy, there is no robust data. However, cumulative results indicate an improvement in oxygenation parameters [4•]. The median duration before recurrence requiring another WLL procedure is about 15 months. It is estimated that up to 50% of patients may experience a relapse [69].

The use of recombinant GM-CSF is based on the premise that repletion of bioavailable GM-CSF can restore alveolar macrophage function and homeostasis. Recombinant GM-CSF may be delivered through inhalation or subcutaneous injections. However, GM-CSF–based therapies are of use only in patients with elevated autoantibody to GM-CSF, i.e., autoimmune PAP. It likely has limited role in PAP strictly due to exposure with no evidence of autoimmunity. Studies that have assessed the impact of recombinant GM-CSF (subcutaneous or nebulized) have not yielded decisive answers though. Cumulative results suggest salutary benefits with 40–60% patients demonstrating a clinical response with improvement in alveolar-arterial oxygen gradient [1, 70,71,72]. Further studies are required to determine the dosing regimens and selection of appropriate candidates. Corticosteroids are not recommended due to likely harm, while data regarding the use of rituximab or modalities like plasmapheresis for exposure-related PAP is limited [73,74,75]. For patients with advanced progressive PAP, lung transplantation may be considered. The caveat to lung transplantation for PAP is the potential for recurrence of PAP in the allograft.

Summary

While most of PAP is considered to be autoimmune in nature, due to production of antibodies against GM-CSF, exposure to various inhalational agents has also been implicated in causing PAP. Occupational PAP has been described most commonly secondary to exposure to silica, but a wide variety of vapors, gases, dusts, and fumes have been implicated. In some patients with occupational exposure, it is possible that the offending agent may trigger autoimmunity against GM-CSF that can induce PAP. Patients with occupational PAP may have concomitant emphysema and/or pulmonary fibrosis. Depending on the degree of manifestations, treatment approach ranges from watchful monitoring to invasive procedures like WLL. Physician reporting to regulatory and public health authorities can ensure that existing exposure limits and medical surveillance requirements, such as are in place for silica, are enforced.