Treatment and prognosis of pulmonary alveolar proteinosis in adults

INTRODUCTION — Pulmonary alveolar proteinosis (PAP), also known as pulmonary alveolar phospholipoproteinosis, is a diffuse lung disease characterized by the accumulation of amorphous, periodic acid-Schiff (PAS)-positive lipoproteinaceous material in the distal air spaces [1-4].

The most common symptoms are dyspnea and cough. Radiographic imaging typically reveals bilateral symmetric alveolar opacities located centrally in mid and lower lung zones, often in a "bat wing" distribution. Five forms of PAP are recognized (table 1):

●Disorders of surfactant production or metabolism due to genetic variants in surfactant and other proteins (also called congenital PAP)

●Disorders of granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling due to GM-CSF antibodies (also called primary PAP or autoimmune PAP in those with anti-GM-CSF antibodies)

●Recessive genetic variants of GM-CSF receptor subunits

●Underlying disorders that secondarily affect alveolar macrophage function, such as certain hematologic/immunologic/metabolic diseases, inhalational exposures, and infections (also called secondary PAP)

●Unclassified

The treatment and prognosis of PAP will be reviewed here. General approaches to adult and pediatric interstitial lung disease and the clinical manifestations and diagnosis of pulmonary alveolar proteinosis in adults are described separately. (See "Approach to the adult with interstitial lung disease: Clinical evaluation" and "Approach to the adult with interstitial lung disease: Diagnostic testing" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)" and "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults".)

ASSESSMENT OF DISEASE SEVERITY — In order to determine the appropriate treatment, severity of PAP is assessed using a combination of symptoms, serum level of lactic dehydrogenase (LDH), titer of serum antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in autoimmune PAP, pulmonary function tests, and extent of opacities on high resolution computed tomography (HRCT) imaging [5,6]. Pulmonary function tests, including lung volumes, diffusing capacity, and six-minute walk with oxygen saturation determination, are used to assess the degree of impairment and to provide a baseline for long-term monitoring. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Pulmonary function tests'.)

The interpretation of GM-CSF antibody titers in serum and BAL before and during treatment requires further investigation [7-9]. In one study of 13 patients, initial BAL fluid levels of GM-CSF antibodies correlated better with the severity of PAP than serum titers [10]. In a separate study that administered subcutaneous GM-CSF over 12 or more weeks, serial GM-CSF antibody titers declined in patients who demonstrated a clinical response, but did not decline in nonresponders [7]. In contrast, serum GM-CSF antibody titers increased in patients receiving nebulized GM-CSF (but not placebo), despite clinical improvement [9].

TREATMENT OF AUTOIMMUNE PAP

Overview — The choice of treatment options for autoimmune PAP depends upon the severity of disease. This approach is based on observations that show a high rate of spontaneous remission among those with mild disease. In the largest series to study the natural history of autoimmune PAP, asymptomatic patients were most likely to have a stable to improving course with only 8 percent worsening during follow up [5]. Among symptomatic patients, the proportions with stable, improved, and worsening disease were about 45, 30, and 25 percent, respectively. Patients with longer disease duration were more likely to have progressive disease.

In order to obtain the best risk benefit balance when choosing therapy, we divide patients into the following categories:

●Asymptomatic or mild symptoms (eg, dyspnea with moderate or greater exertion) with little or no physiologic impairment (eg, normal to mildly reduced diffusing capacity for carbon monoxide [DLCO], normal pulse oxygen saturation [SpO₂] at rest with or without a mild decrease on exertion)

●Moderate-to-severe symptoms (eg, dyspnea with minimal exertion or at rest) and physiologic abnormalities (eg, requiring supplemental oxygen at rest)

During the course of treatment or observation, symptoms (eg, dyspnea, exercise tolerance), spirometry, diffusing capacity, ambulatory oximetry, and chest computed tomography (CT) scan are monitored.

Supportive care — Since PAP causes dysfunction of lung macrophages, all patients with PAP should be counseled to obtain annual vaccinations against influenza, coronavirus disease 2019 (COVID-19), as well as age-appropriate vaccination against pneumococcal pneumonia and respiratory syncytial virus. (See "Seasonal influenza vaccination in adults" and "Pneumococcal vaccination in adults" and "COVID-19: Vaccines" and "Respiratory syncytial virus infection in adults", section on 'Vaccination'.)

Patients should also be advised not to smoke cigarettes as one study showed that among patients who undergo whole lung lavage, those who smoke cigarettes require twice as many sessions of whole lung lavage as nonsmokers [11].

Supplemental oxygen is provided according to current guidelines. (See "Long-term supplemental oxygen therapy", section on 'Indications'.)

Asymptomatic or mild disease — Patients who are asymptomatic with little or no physiologic impairment and those who have mild symptoms, normoxia at rest, and normoxia or mild hypoxemia on exertion do not require immediate treatment and can be observed with periodic reassessment of symptoms, oxygen saturation, pulmonary function tests, and/or chest imaging to identify any further deterioration.

Occasional spontaneous remission has been reported [11,12]. In a series of 120 patients with autoimmune PAP, 40 were managed without therapeutic intervention for PAP. Of these, 39 remained stable or achieved remission, while one died of a pulmonary infection [12].

Moderate-to-severe respiratory impairment — Patients who have moderate to severe disease based on symptoms and physiologic testing may elect to proceed with whole lung lavage or a trial of experimental treatment (eg, subcutaneous or inhaled GM-CSF, or rituximab). A stepwise treatment approach has been suggested, beginning with whole lung lavage (WLL) for patients with moderate to severe symptoms [13]. If there is progression of disease or whole lung lavage is intolerable, inhaled GM-CSF can be given. Some patients may respond better to whole lung lavage followed by inhaled GM-CSF treatment, than to initial treatment with inhaled GM-CSF [14]. If there is inadequate response to whole lung lavage and GM-CSF or they are associated with unacceptable side effects, then rituximab may be tried. These options are described in the sections that follow.

Whole lung lavage — For patients who have moderate-to-severe symptoms and hypoxemia, WLL under general anesthesia via a double-lumen endotracheal tube is the most widely accepted and effective form of treatment [12,15-22].

●Patient selection – Specific indications for WLL have not been formally evaluated, but we use the combination of a definitive histologic diagnosis and one of the following:

•Resting PaO₂ <65 mmHg (8.67 kPa, at sea level)

•Alveolar-arterial oxygen (A-aO₂) difference ≥40 mmHg at rest

•Severe dyspnea and hypoxemia at rest or on exercise

Contraindications include uncorrectable clotting disorders, anesthetic risks, and cardiopulmonary instability.

●Technique – The technique of WLL is well described [15-17,20,23]. It is typically performed under general anesthesia [24]. A double-lumen endotracheal tube is inserted with the patient supine and the correct positioning of the tips in the trachea (lavage lung) and main bronchus (ventilated lung) confirmed by flexible bronchoscopy. The patient is placed in the lateral recumbent position with the lung to be lavaged nondependent. The dependent lung is ventilated and oxygenated using one lung ventilation. (See "One lung ventilation: General principles" and "Lung isolation techniques".).

A 15 to 20 L bag of normal saline is hung from an intravenous (IV) pole, and the fluid is warmed to 37ºC by passing through a blood warmer. The lavage is performed by instilling 0.8 to 1.5 L aliquots of the warmed normal saline [23]. During each instillation, the patient is slanted to elevate the head slightly (lateral reverse Trendelenburg). After instillation of the lavage fluid, chest percussion is performed for four to five minutes [25], followed by positioning the patient slanted with the head down (lateral Trendelenburg position) for gravity drainage of the fluid through the endotracheal tube into a collection canister. A modified technique, in which the lavaged lung is manually bag-ventilated with 300 mL of air five times after instillation of 500 mL of saline was shown to significantly increase the removal of the lipoproteinaceous material [26]. A flexible bronchoscope is used, as needed, to inspect the lung and suction residual fluid. It has been suggested that repetitive manual hyperinflation (MH) and intermittent chest percussions may further enhance WLL efficacy [27].

Careful count of the volumes instilled and recovered is needed to avoid overdistension of the lung with unrecovered fluid; not more than 200 to 300 mL should accumulate in the lungs unrecovered. While practice varies, the total volume of lavage fluid approximates 15 L, spread over 10 to 15 lavages (picture 1). The initial lavage effluent appears thick and milky, while the final lavage appears clear [20,28].

For the majority of patients, unilateral lung lavage is performed on the first day followed by lavage of the opposite lung one to two weeks later [23]. However, bilateral sequential WLL has been performed in a single treatment session. Because one lung is ventilated while the other undergoes lavage, it seems logical to first perform lavage on the side that is worse while ventilating the less affected lung to minimize desaturation during the procedure. For patients with severely compromised gas exchange, extracorporeal membrane oxygenation has been used to support the patient during WLL [29].

Meticulous charting and monitoring of oxygenation, dynamic lung compliance, correct position of the double-lumen endotracheal tube, and recovery of the infused saline are necessary to avoid and to quickly diagnose complications.

After the procedure, an upright chest radiograph is obtained to exclude pneumothorax. As impairment of oxygenation can occur due to residual lavage fluid or incompletely treated PAP, continued intubation and mechanical ventilation in the intensive care unit may be required (typically <24 hours) prior to extubation and discharge [4,30].

Complications of WLL include malpositioning of the endotracheal tube, saline spillover into the opposite ventilated lung, intraprocedural hypoxemia, pneumothorax, and hydropneumothorax.

●Efficacy – After WLL, patients often feel dramatically better, with substantial improvement in exertional dyspnea and oxygenation despite only small changes in pulmonary function [31]. The subsequent clinical course is variable. Thirty to 50 percent of patients require only one lavage, while others require repeat lung lavages at intervals of 6 to 12 months [12,17,18]. Of note, cigarette smokers are more likely to require repeat WLL than nonsmokers [11,18].

•In a series of 80 patients with autoimmune PAP who received WLL, 56 (70 percent) achieved a sustained remission with one lavage, while 24 (30 percent) required one or more additional treatments [12]. Of those who required additional treatments, 19 remained stable or improved and 5 developed refractory disease. Patients with an initial DLCO of 42 percent predicted or less were more likely to require additional WLL.

•In a separate series of 60 patients who underwent WLL, 40 achieved remission after one or more lavages and another 10 required repeated WLL [18].

Recombinant GM-CSF — Experience with recombinant GM-CSF (molgramostim, sargramostim) by inhalation or subcutaneous injection is increasing, although it remains off-label for autoimmune PAP. Initial work suggests that the proportion of responders to GM-CSF is less than with WLL [32-35]. Given the investigational nature of GM-CSF therapy, we use WLL as primary therapy [32,33,36-39] and reserve recombinant GM-CSF for patients who cannot undergo or have failed WLL [14,40]. (See "Causes, clinical manifestations, and diagnosis of pulmonary alveolar proteinosis in adults", section on 'Role of GM-CSF'.)

Based on greater ease of administration and as good and possibly better response of nebulized compared with subcutaneous GM-CSF, the nebulized route can be tried first [33,35]. Sequential treatment with inhaled GM-CSF after initial WLL is a reasonable strategy that greatly reduced the need for repeat WLL over 30 months of follow-up (78 versus 11 percent) in one small placebo-controlled trial of patients with moderate to severe autoimmune PAP [41].

●Inhaled GM-CSF – Nebulized recombinant GM-CSF modestly improves lung function and may facilitate clearance of the GM-CSF-antibody complex from the lung [35,42-46]. For inhalational administration, recombinant GM-CSF is reconstituted in 2 mL of normal saline and administered via nebulizer. Accumulating data from randomized trials and observational studies suggest modest improvement in symptoms and respiratory physiology with inhaled GM-CSF therapy [47].

In the largest randomized trial, 138 adults with substantial respiratory impairment due to autoimmune PAP (baseline AaO₂ gradient approximately 40 mmHg, DLCO approximately 50 percent of predicted and an average of three to four prior whole lung lavages per patient) were assigned to one of three groups, recombinant GM-CSF (molgramostim) 300 mcg per day continuously, recombinant GM-CSF 300 mcg per day during alternate weeks (“intermittent”), or placebo, via mesh nebulizer [48]. After 24 weeks, the AaO₂ difference improved (decreased) from baseline to week 24 by -12.8 mmHg in the continuous group versus -6.6 mmHg in the placebo group (treatment difference -6.2 mmHg; p=0.03), with no significant difference in the change of the AaO₂ gradient between placebo and "intermittent" groups. The group that received continuous GM-CSF also had significantly greater improvement in DLCO compared with placebo (12.0 versus 4.2 percent). The St. George’s Respiratory Questionnaire (SGRQ) score, a measure of overall health status in patients with respiratory disease, improved by -7.4 points in the continuous molgramostim group compared with placebo (minimal clinically important difference -4 points). The six-minute walk distance and time to first WLL were similar between groups, although the rate of WLL decreased over time in the continuous therapy group. Adverse events were similar between groups. Chest pain was more frequent in the continuous treatment group.

In a prior randomized trial of patients with autoimmune PAP and mild-to-moderate respiratory impairment, patients (n = 64) received GM-CSF 125 mcg or placebo by nebulization twice daily on days 1 through 7 and none on days 8 through 14 with the two-week cycles repeated 12 times (24 week period) [9]. After 25 weeks, the A-aO₂ difference improved from baseline in the GM-CSF treatment group relative to the placebo group (difference -5.70 [95% CI -10.50 to -1.40]). Borderline improvements were noted in the modified Medical Research Council dyspnea scale, DLCO, and lung density on chest CT. There was no difference in the six-minute walk distance between the GM-CSF and placebo groups. While there was individual variability, serum GM-CSF antibodies increased in the GM-CSF group and decreased in the placebo group. The patients in this study had milder respiratory impairment compared with prior studies, which may explain the lack of clinical benefit.

In a separate placebo-controlled trial, inhaled recombinant human GM-CSF was associated with decreased (improved) mean (±SD) alveolar-arterial oxygen gradient in the GM-CSF group (33 patients) than in the placebo group (30 patients; mean change from baseline, −4.50±9.03 versus 0.17±10.50 mm Hg; 95% CI of the difference -1.4 to -10.5 mm Hg) [9]. There was no significant difference in adverse events between the GM-CSF and placebo-treated patients (six and three events, respectively), and the serious events were felt likely unrelated to treatment.

Small open-label studies support a beneficial effect with no reported adverse effects during 12- to 24-week trials [35,49-51]. In another study, GM-CSF inhalation was associated with a decrease in GM-CSF autoantibodies in the bronchoalveolar lavage fluid from improved patients, but not in the serum, suggesting that GM-CSF inhalation did not affect autoantibody production [52].

●Subcutaneous GM-CSF – The response rate to subcutaneous recombinant GM-CSF is slightly less than 50 percent. In an open label trial of 25 patients, recombinant human GM-CSF was given subcutaneously, starting at 250 mcg/day for one month, increasing to 5 mcg/kg/day for the second month, and 9 mcg/kg/day for the third month [33]. Responders were continued on this dose for 12 months; those with a suboptimal clinical response were given further dose escalations up to 18 mcg/kg/day. Overall, 48 percent experienced symptomatic and radiographic improvement. (See "Introduction to recombinant hematopoietic growth factors" and 'Clinical trials' below.)

Declining serum GM-CSF antibody levels appear to correlate with a positive response to GM-CSF therapy [7,33,39]. Adverse effects are mild and include fever, fatigue, headache, and injection site complications [33].

Many patients with autoimmune PAP do not manifest a normal hematologic response to parenteral GM-CSF; very high doses of the growth factor may be required to achieve a modest elevation in the white blood cell count [34,49].

Refractory disease — The optimal therapy for patients with progressive respiratory impairment despite WLL and therapy with GM-CSF is not known. Choosing among investigational therapy (eg, rituximab, therapeutic plasma exchange), participation in a clinical trial, or lung transplantation will need to be made on a case-by-case basis.

Rituximab — A few studies have investigated the role of the anti-CD20 monoclonal antibody, rituximab [53-56]. In an open-label, phase II study of 10 patients with autoimmune PAP, rituximab (1 g) was infused intravenously for two doses about two weeks apart [55]. Compared with pretreatment values, both the arterial oxygen tension (PaO₂) and A-aO₂ difference significantly improved at three and six months after treatment. The mean HRCT score also improved following rituximab treatment. Interestingly, both the total anti-GM-CSF IgG level and the capacity to neutralize GM-CSF activity decreased in the bronchoalveolar lavage fluid six months after treatment but no difference in either was seen in the pre- and post-treatment sera. In contrast, a retrospective study of 13 patients failed to support rituximab as a second line therapy for patients with refractory autoimmune PAP. Rituximab was well tolerated, however, objective improvement was seen in only 4 of the 13 patients treated (30 percent) after 12 months of follow-up [57].

Therapeutic plasma exchange — A small number of reports describe therapeutic plasma exchange (TPE, plasmapheresis) in patients who have failed to improve with WLL [7,8,58,59]. One patient did not improve with TPE, another responded to low intensity TPE over two months, and a third responded to five consecutive days of TPE followed by rituximab. It is possible that a more intensive TPE regimen is needed to clear anti-GM-CSF antibodies [58].

Clinical trials — Patients with PAP may wish to participate in a clinical trial (eg, rituximab, GM-CSF). Additional information is available at https://clinicaltrials.gov.

Lung transplantation — Lung transplantation has been performed in a small number of patients with autoimmune PAP, some of whom developed recurrent disease in the lung allograft [60-63]. Selection of potential lung transplant recipients is discussed separately. (See "Lung transplantation: An overview" and "Lung transplantation: General guidelines for recipient selection".)

Future directions

●Gene-corrected pluripotent stem cells – Derivation of macrophages from gene-corrected pluripotent stem cells is a promising investigational method of reconstituting the defective macrophage population in patients with hereditary PAP [64,65].

●Statins – Because alveolar macrophages from patients with autoimmune PAP have a markedly increased ratio of cholesterol to phospholipids, studies have explored the possibility that targeting cholesterol homeostasis might be a useful therapeutic approach for PAP [66]. Statin-induced lowering of intracellular cholesterol accumulation leads to improvements in surfactant uptake and clearance by alveolar macrophages. Several reports describe patients with autoimmune PAP in whom treatment with statins led to improvements in lung function, oxygenation and radiologic findings [66,67].

Ineffective therapies — There is no role for glucocorticoids or other immunosuppressive agents as primary therapy for autoimmune PAP; glucocorticoids may actually increase mortality [68,69].

TREATMENT OF OTHER TYPES OF PAP — The optimal treatment of secondary, hereditary, and congenital PAP has not been determined. As in autoimmune PAP, whole lung lavage (WLL) is often used for patients with moderate to severe symptoms and hypoxemia [11]. All patients are advised to obtain annual vaccinations against influenza and COVID-19, as well as age-appropriate vaccination against pneumococcal pneumonia and respiratory syncytial virus. Cigarette smokers should be advised to stop smoking.

Treatments that are more specific to the cause of PAP include the following:

●Secondary PAP due to hematologic dyscrasias – For patients with hematologic malignancy or myelodysplasia, treatment of the underlying process may lead to improvement in PAP [70,71]. For patients with myelodysplastic syndrome in general, WLL has had mixed success [70,72].

Nonmyeloablative hematopoietic stem cell transplantation (HSCT) has been used to treat immunodeficiency due to familial myelodysplastic syndrome (genetic variants in GATA2), sometimes in combination with WLL [70]. (See 'Whole lung lavage' above and "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial MDS/AML with mutated GATA2'.)

●Secondary PAP due to inhalational exposures – For patients with PAP following inhalational exposure, the most important intervention is to completely discontinue further exposures. Results with WLL have been mixed: one patient with dust exposure following an earthquake did respond [73]; one of two patients with PAP following indium tin oxide exposure experienced improvement with WLL [74]; and one patient with PAP following aluminium exposure did not respond [75]. Case reports have described successful WLL in some but not all patients with acute silicoproteinosis, as described separately. (See "Silicosis", section on 'Treatment'.)

●PAP due to GM-CSF receptor variants – HSCT may be a potential treatment for patients with abnormal GM-CSF signalling due to GM-CSF receptor variants. HSCT has reversed PAP in GM-CSF receptor-deficient mice and has been suggested (but not yet undertaken) in humans [76]. One patient with a CSF2RB (gene that encodes for beta-subunit of the receptor for GM-CSF) nonsense mutation who underwent bilateral lung transplantation developed recurrent PAP after nine months [77]. It was noted that the alveolar macrophage population in the lung allograft had been almost completely replaced by macrophages of recipient origin, suggesting that HSCT may be necessary to prevent the return of alveolar macrophages with aberrant GM-CSF receptors.

●Congenital PAP – The management of congenital disorders of surfactant production, such as variants in the genes for surfactant proteins (SP)-B or C, proteins involved in the metabolism of surfactant (ATP-binding cassette, subfamily A (ABCA3), or NK2 homeobox-1 (NKX2.1) thyroid transcription factor-1 (TTF1), is discussed separately. (See "Genetic disorders of surfactant dysfunction", section on 'Treatment'.)

Based on a few cases, patients with lysinuric protein intolerance and certain methionyl-tRNA synthetase (MARS) variants, which lead to impaired surfactant production, are managed with dietary modification, occasionally WLL, and rarely inhaled GM-CSF in refractory cases [40]. (See "Genetic disorders of surfactant dysfunction", section on 'Related disorders' and "Pulmonary alveolar proteinosis in children", section on 'Congenital PAP'.)

INFECTIOUS COMPLICATIONS — Patients with PAP have an increased risk of superinfection with opportunistic organisms such as Nocardia, actinomyces, mycobacteria, and various endemic or opportunistic fungi, due to impaired macrophage and neutrophil function [5,78-85].

PROGNOSIS — The long-term prognosis of PAP has not been extensively described [12,17,18,86]. Up to 30 percent may achieve remission or remain stable without specific therapy, while 70 to 90 percent achieve remission or stability with one or more whole lung lavages(WLLs) [11,12,18]. The development of high-resolution computed tomography (HRCT) findings consistent with parenchymal fibrosis portends a poorer outcome [87].

The fact that some patients with autoimmune PAP have a self-limited course has led to the hypothesis that some cases of PAP result from an acquired clonal disorder of hematopoietic cells [49]. Remission may result from subsequent displacement of this abnormal clone from the hematopoietic pool.

SUMMARY AND RECOMMENDATIONS

●General measures – The choice of treatment options for patients with pulmonary alveolar proteinosis (PAP) depends on the etiology of PAP and the severity of symptoms and gas exchange abnormalities.

•Patients who smoke should be advised to stop smoking.

•All patients with PAP should be counseled to obtain annual vaccinations against influenza, COVID-19, and respiratory syncytial virus (if no contraindications) as well as age-appropriate vaccination against pneumococcal pneumonia. (See 'Treatment of autoimmune PAP' above.)

●Minimal or mild disease – For patients with minimal or no symptoms or physiologic impairment (eg, normal blood oxygen levels at rest, mild reduction in diffusing capacity for carbon monoxide [DLCO], or exercise-related hypoxemia), we prefer supportive care with supplemental oxygen, as needed, over more invasive therapy. These patients need periodic reassessment of symptoms, rest and walking oxygen saturation, pulmonary function tests, and chest imaging to identify deterioration that would require specific therapy, but many have a spontaneous remission. (See 'Treatment of autoimmune PAP' above.)

●Moderate or severe autoimmune PAP

•For patients with moderate-to-severe dyspnea and hypoxemia due to autoimmune PAP, we recommend whole lung lavage (WLL) (Grade 1B). The procedure is performed under general anesthesia via a double-lumen endotracheal tube. Generally, one lung is lavaged in the first procedure, followed by lavage of the opposite lung one to two weeks later. (See 'Whole lung lavage' above.)

•Recombinant granulocyte macrophage-colony stimulating factor (GM-CSF, sargramostim) administered by inhalation or subcutaneous injection is not approved for use in autoimmune PAP, but it may be an option for those who cannot undergo or have not responded to WLL. It may also be effective in reducing need for or frequency of recurrent WLL. (See 'Recombinant GM-CSF' above.)

•Glucocorticoids are not indicated for autoimmune PAP. (See 'Ineffective therapies' above.)

●Additional options for autoimmune PAP in those with refractory disease or who do not tolerate therapy

•Therapies such as rituximab and therapeutic plasma exchange have been employed in individual patients who did not respond to or were intolerant of WLL and/or GM-CSF; further data are needed before routinely recommending these options. (See 'Refractory disease' above.)

•For patients who wish to participate in a clinical trial, additional information is available at https://clinicaltrials.gov. (See 'Clinical trials' above.)

•Lung transplantation is reserved for selected patients with severe, refractory PAP, although PAP sometimes recurs in the allograft. (See 'Lung transplantation' above.)

●Treatment of secondary and hereditary PAP – Treatment options for patients with secondary and hereditary PAP are less clear and depend in part on the specific cause. (See 'Treatment of other types of PAP' above.)

•For most of these processes, WLL is performed in patients with moderate-to-severe symptoms and hypoxemia, based on the success in autoimmune PAP, although experience is limited.

•Additionally, certain types of secondary PAP may respond to specific therapy, such as treatment of an underlying hematologic malignancy, hematopoietic stem cell transplantation (HSCT) for familial myelodysplastic syndrome, and avoidance of occupational dust exposures.

•The management of congenital disorders of surfactant production, which usually present in childhood, is discussed separately. (See "Genetic disorders of surfactant dysfunction", section on 'Treatment'.)

●Infectious complications of PAP – Patients with PAP have an increased risk of superinfection with opportunistic organisms such as Nocardia, mycobacteria, and various endemic or opportunistic fungi. (See 'Infectious complications' above.)