Steffen Leth, Department of Respiratory Diseases and Allergology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. Email: email@example.com
Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by accumulation of a periodic acid Schiff (PAS)-positive eosinophilic material in the distal airways. For decades, the standard treatment of PAP has been whole lung lavage (WLL), where large quantities of saline are instilled into the lungs to remove the proteinaceous material. However, not all patients respond to this treatment. Thus, new treatment modalities, such as subcutaneous or inhaled granulocyte macrophage colony-stimulating factor (GM-CSF), and the CD20 antibody rituximab and plasmapheresis, have been investigated. Based on the current literature, a stepwise treatment plan is suggested starting with WLL, continuing to inhaled GM-CSF, and then to rituximab if the former treatment regimes are unsuccessful.
Pulmonary alveolar proteinosis (PAP) was first described by Rosen in 1958,1 and since then fewer than 1000 cases have been described.
PAP is a rare lung disease characterized by accumulation of eosinophilic periodic acid Schiff (PAS)-positive material in the distal airways. The accumulation of PAS-positive material causes restrictive pulmonary function and decreased diffusion capacity (DLCO), and can progress to respiratory failure and death. The lung architecture is preserved, and there are few or no signs of lung inflammation.
It is now recognized that PAP can be divided into two categories: (i) autoimmune PAP accounting for approximately 90% of all PAP cases, and (2) non-autoimmune PAP, which can be further subdivided into secondary PAP and congenital PAP.2–4
The secondary form is found in association with high level of dust, mineral and metal particles exposures (e.g. aluminium, titanium, indium, silica, titanium). It is further associated with haematological malignancies and has been seen after allogeneic bone marrow transplantation for myeloid malignancies. Secondary PAP often develops in adulthood and is likely related to a relative deficiency of granulocyte macrophage colony-stimulating factor (GM-CSF) and related macrophage dysfunction, thereby compromising surfactant clearance. The prognosis is often linked to the underlying disease, and haematological therapy alone and/or bone marrow transplantation has the potential to cure PAP in those patients.2,5–10
The causes of congenital PAP include mutations in surfactant, the GM-CSF receptor a or b subunit, or a defect in the transport of cationic amino acid at the membrane of epithelial cells in the intestine and kidney—known as lysinuric protein intolerance. It often presents in the neonatal period.11–17
Since autoimmune PAP represents the vast majority of PAP, the main focus of this review will be on autoimmune PAP and the development of treatment modalities.
A literature search using free term key words—pulmonary alveolar proteinosis, granulocyte macrophage colony stimulating factor, rituximab, plasmapheresis, bronchoalveolar lavage, whole lung lavage and lung transplantation—was performed in the PubMed database limited to articles in English, Danish, Norwegian and Swedish. References of primary studies, reviews, case reports and editorials were also reviewed.
PAP is rare before the age of 30 years. The predominant symptoms are progressive dyspnoea, cough, fatigue, weight loss and low-grade fever, but as many as one third of patients may be asymptomatic.3,18 The annual incidence and prevalence is, in larger studies, estimated to be 0.36–0.49 and 3.7–6.2 per million, respectively.2,3 The median age at diagnosis is 39 (30–46) years, and the male to female ratio is 2.1:1. One study reported that 56% of PAP patients had a history of smoking.
The cause of PAP is unknown. The breakthrough came in 1994 when initially Dranoff et al.,19 and shortly after, Stanley et al.20 showed that knockout mice lacking the ability to produce GM-CSF developed a condition similar to human PAP. In theory, GM-CSF in vivo should stimulate the survival, proliferation, differentiation and function of myeloid cells and their precursors, especially neutrophils, eosinophils and monocytes/macrophages. Stanley and colleagues found no major disturbance of haematopoiesis in the mice. Instead, the mice developed fungal and bacterial lung infections. Pathology of the mice lungs showed peribronchovascular infiltration with predominantly B lymphocytes, and also alveoli filled with a granular eosinophilic material and lamellar bodies (precursor of surfactant). This indicated surfactant accumulation, that is, a pathology resembling alveolar proteinosis in humans. This lead to the theory that absence of local GM-CSF-dependent activation of macrophages in the lungs was involved in either surfactant clearance or control of infections, and ultimately could lead to PAP.
This theory was further substantiated by Reed et al., who showed different responses in GM-CSF knockout mice with a condition similar to human PAP treated daily or weekly with either recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection of GM-CSF for 4–5 weeks. The lungs of the mice treated with inhaled GM-CSF were largely normalized; in contrast to this, it appeared that systemically administered GM-CSF did not change the lungs of the mice.21
After the discovery of the role of neutralizing GM-CSF auto antibodies in serum and in bronchoalveolar lavage fluid (BALF),22–25 and the development of tests able to measure these antibodies,24,26 PAP is now considered to be an autoimmune disease. The recent assumption of PAP being an autoimmune disease is supported by studies demonstrating that passively injected human GM-CSF antibodies can lead to the development of PAP in non-human primates.27,28
Physiology of surfactant
Surfactant is a mixture of lipids and proteins synthesized and secreted onto the alveolar surface by type II epithelial cells to reduce surface tension, and thereby avoid alveolar collapse. The main proteins in surfactant are designated SP-A, SP-B, SP-C and SP-D, and they are important in various aspects of surfactant metabolism, structure and function. Together with alveolar macrophages, type II epithelial cells are involved in clearing of components of surfactant. Mutations or altered clearance of surfactant may result in either dysfunction of the proteins or alveolar cell injury.29
Abnormal surfactant turnover
GM-CSF plays a critical role in the surfactant system.19,20,30 In the lungs, it binds to receptors on monocytes, macrophages and type II epithelial cells to initiate the biological effect.
Alveolar macrophages from patients with autoimmune PAP have impaired chemotactic activity and decreased phagocytic capability, implying that macrophage dysfunction plays a role in the pathogenesis. The ETS family member PU.1 is a master transcriptional regulator of myeloid differentiation. It is markedly reduced in alveolar macrophages of GM-CSF knockout mice. Disruption of the PU.1 gene results in interrupted macrophage and B lymphocyte production, while production of neutrophils and T lymphocytes is delayed.31 By stimulating GM-CSF knockout mice with GM-CSF, PU.1 transcription factors are significantly upregulated, leading to a stimulation of the innate immune system, including surfactant turnover, cell adhesion, phagocytosis, bacterial killing, inflammatory cytokine response and expression of receptors for pathogen recognition.4,32,33 This indicates that addition of GM-CSF conditions the alveolar microenvironment in the lung, primarily through PU.1, and thereby restores alveolar macrophage function, including clearance of proteinaceous material which otherwise is accumulated within the alveoli; thus, it is a critical regulator of the innate immune system in the lungs.
The diagnosis of PAP is made on the basis of a combination of symptoms, high-resolution computed tomography (HRCT) and bronchoscopy with PAS stain of BALF;34 the latter sometimes includes a transbronchial lung biopsy and finally auto-antibodies against GM-CSF in BALF/serum.
Chest radiography is classically dominated by bilateral, symmetric, perihilar consolidations in a ‘bat-wing’ configuration. Typical computed tomography (CT) of the chest often visualizes patchy or geographic ground-glass opacity combined with interlobular septal thickening (crazy paving) or reticular interstitial opacity with a central or peripheral distribution (Fig. 1). Both chest CT and radiographs have been shown to correlate with functional impairment in patients with PAP.35,36
BALF from patients with PAP is milky.37 It has a unique pathological appearance with large acellular eosinophilic bodies on a background of eosinophilic granules, PAS staining of the proteinaceous material and few enlarged foamy alveolar macrophages.34 Upon histological examination of biopsies, the normal architecture of the alveoli is generally preserved, although the alveolar septae may be slightly thickened. The terminal bronchioles and alveoli are filled with lipoproteinaceous material, and there is little or no sign of inflammatory cell infiltration (Fig. 2).
The use of enzyme-linked immunosorbent assay or the latex agglutination tests using latex beads coupled with recombinant human GM-CSF are currently the most widely used tests for detection of GM-CSF in serum and BALF. The agglutination test has a high sensitivity and specificity (100% and 98%, respectively) for serological diagnosis. 0.3% of sera from healthy volunteers include GM-CSF autoantibodies,38 although sera concentration <10 µg/mL has a good negative predictive value.39 A recent study including 70 PAP patients, of which 64 had autoimmune PAP, reported that the mean concentration of GM-CSF in the autoimmune cohort was 64±25 µg/mL.40
Different treatment modalities have been applied since PAP was first described. By tradition, whole lung lavage (WLL) has been the first line of treatment. Other therapies have been investigated by targeting alveolar macrophages with GM-CSF substitution or reducing the levels of circulating auto-antibodies with rituximab and experimental plasmapheresis. (Table 1)
Table 1. Summary of prospective clinical trails
Effect in % (patients)
The dose was increased if the clinical response was suboptimal.
WLL,50–54 with the use of double-lumen-tubes for selective lavaging of each lung in order to physically remove the accumulated alveolar lipoproteinaceous material, has for many years been the only therapy since Ramirez introduced the treatment in 1965.50 Treatment has since been refined with the use of general anaesthesia, the use of extracorporeal membrane oxygenation for extreme situations,55,56 increasing saline volumes, same session bilateral sequential WLL,57 partial lung lavage performed with fiberoptic bronchoscope,58 addition of simultaneously manual chest percussion59 and positional changes during WLL.60 The technique of WLL has been modified to each centre performing WLL. So far, there is no consensus on performance of WLL, and there are no randomized controlled studies of WLL to determine the optimal strategy.
The outcome of WLL has been studied by Shah et al. who found that 60% of patients recovered after two lavages of each lung; 15% required a new WLL every 6 months, and less than 10% were unresponsive to the treatment.61 Beccaria et al. found a slightly higher success rate in a retrospective study of 21 patients with autoimmune PAP.62 All underwent WLL of both lungs once. Of the 21, 16 agreed to attend a follow-up study. Overall, 11 patients only required a single WLL over 3 years. Forced vital capacity, oxygenation and treadmill walking distance improved significantly 1 week after WLL. Improvements were sustained for more than 3 years, and for two patients for more than 7 years.
In conclusion, WLL is an effective treatment in about 2/3 patients and seldom causes complications. Complications include hypoxaemia, hydropneumothorax, ARDS, post-procedure infections (pneumonia, sepsis) and pneumothorax.
Preceded by a case report,41 Seymour et al. were the first to treat 14 patients with autoimmune PAP with subcutaneous GM-CSF.63 They gave GM-CSF 3 µg/kg/day for 5 days, and then increased the dose to 5 µg/kg/day for 12 weeks. All patients were evaluated by lung function tests, blood tests, CT of the lungs, 6-min walking test and arterial blood gases. One patient discontinued after 13 days due to neutropaenia, five patients discontinued therapy after six weeks due to lack of response, seven patients were treated for 10–12 weeks, and a single patient for 26 weeks.
No response was observed in seven patients after 6 weeks of treatment, although two of these improved after 3 months. Due to lack of response, the dose was increased in four patients to 7.5, 7.5, 10 and 20 µg/kg/day, respectively, but only one of these patients responded. The treatment was efficient in 6/14 patients (43%, 95% CI: 18–71%) with a median treatment time of 39 weeks. Five of six patients experienced subsequent deterioration of their disease after cessation, and four were retreated successfully, while one continued on a maintenance dose of 20 µg/kg/day three times a week. Among responders, there was a significant effect on partial pressure of oxygen in arterial blood (PaO2), alveolar–arterial oxygen gradient (P(A-a)O2), DLCO, CT scan and 6-min walking test.
Kavuru et al. treated four patients with autoimmune PAP with subcutaneous GM-CSF for 12 weeks.42 In the first four weeks, the patients received 250 µg daily. Dosage was increased to 5 µg/kg/day for the following 4 weeks, and finally to 7–9 µg/kg/day for the last 4 weeks if the clinical response was suboptimal. Three of four patients improved their lung function, oxygenation and exercise capacity.
In a prospective study, Bonfield et al. included 14 patients with PAP, of which 11 completed the study.43 All had undergone WLL prior to treatment with GM-CSF, all had biopsy verified autoimmune PAP, and secondary PAP was excluded. Prior to the treatment, blood samples, chest X-ray, BALF and serum samples for anti-GM-CSF were registered, and were repeated after treatment. The patients started subcutaneous GM-CSF 250 µg daily, and dosage was increased every second week to a maximum dose of 18 µg/kg/day after 8 weeks. The total length of therapy was 12–48 weeks. Clinical improvement was defined as ≥ 10 mm Hg improvement from baseline PaO2. Six of 11 patients experienced a significant improvement in their baseline PaO2, from 69.1 ± 3.4 mm Hg to 84.0 ± 2.0 mm Hg. The patients experiencing improvement had lower serum and BALF anti-GM-CSF antibodies at baseline compared with patients not responding to treatment. Responders experienced a significant decrease in anti-GM-CSF titres as opposed to non-responders that lasted 26 weeks after treatment. There were dramatic improvements in HRCT.
Also, a few case series found that subcutaneously administered GM-CSF 3–5 µg/kg/day resulted in complete remission.64
Venkateshiah et al. did a prospective open-label clinical trial with subcutaneously administered GM-CSF, including 25 adults with PAP.44 Of the 25 enrolled, 21 patients completed the treatment. Twelve of the twenty-one patients (57%) improved. Of the 12 responders, eight (67%) did not require WLL or home oxygen after treatment.
In conclusion, subcutaneously administered GM-CSF was effective in about ½–2/3 who completed the trial with varying doses and treatment durations. Complications are considered minor, and include injection-site oedema, erythema, malaise and shortness of breath. Neutropenia has been reported.
Tazawa et al. were the first to use inhaled GM-CSF.45 They treated three patients with PAP with inhaled GM-CSF 125 µg twice daily, every second week for 24 weeks. All three patients improved by a reduced P(A-a)O2 (17–27 mm Hg). The number of alveolar macrophages in BALF was significantly increased, while the amount of extracellular proteinaceous material was reduced after treatment.
Tazawa et al. included in another study with inhaled GM-CSF 50 patients with autoimmune PAP.46 GM-SCF 125 µg was administered twice daily on day 1–8 and paused on day 9–14, and repeated in six 2-week cycles (12 weeks in total). In the next phase, GM-SCF 125 µg was administered once daily on day 1–4 and paused on day 5–14 for six 2-week cycles (12 weeks in total). The last phase was a follow-up period of 52 weeks. Of the 35 patients with PAP that completed the trial, 24 improved with a reduction of the alveolar–arterial oxygen gradient ≥ 10 mm Hg giving an overall response rate of 62%. A total of 29 of the 35 remained stable without further therapy during the follow-up period.
Robinson et al. described the effects of inhaled GM-CSF on HRCT in two patients.65 After treatment, ground-glass opacities and lung weight were reduced, and airspace was increased.
Wylam et al. conducted a retrospective study including 12 patients with PAP.66 All were treated with aerosolized GM-CSF 25 µg b.i.d every second week with dose escalation to a max of 500 µg b.i.d if unresponsive to treatment after 12 weeks of therapy. Two patients had undergone WLL before GM-CSF treatment.
Eleven patients had significant improvement in symptoms, especially cough, and also significant improvement in lung function. Ten of twelve patients had improved gas exchange. The largest improvements were recorded in P(A-a)O2 gradient, resting PaO2 and DLCO. Three patients achieved complete radiological remission, and eight achieved partial remission.
In conclusion, inhaled GM-CSF was effective in 4/5 patients with varying doses and treatment durations, and with few complications, such as fever, otitis media, upper respiratory infection and diarrhoea.
Rituximab is a monoclonal antibody directed against the CD20 antigen on B lymphocytes. In B-lymphoproliferative disorders, the mechanism of action is mediated by eradication of the malignant CD20 positive B cells. In autoimmune diseases, the depletion of B cells will deplete antigen-presenting B cells, thereby affecting T-cell activation, decreasing cytokine production and the amount of plasma cells producing the (GM-CSF) auto-antibodies. Thus, rituximab is an interesting treatment option in autoimmune PAP.
Borie et al. described in a case report the effect of rituximab in a patient with autoimmune PAP who received 1000 mg of rituximab intravenously on day 1 and day 15, after he refused WLL.47 The treatment resulted in a decrease in B lymphocytes and a decrease in anti-GM-CSF concentration. Six months after treatment, the alveolar–arterial gradient improved. DLCO and CT were unchanged. Nine months after the treatment, dyspnoea improved from NYHA III to NYHA I; similarly, the DLCO, CT scan and P(A-a)O2 at rest improved. The improvement was sustained at 12-month follow up.
Amital et al. described a woman who, despite WLL and subcutaneously GM-CSF, deteriorated.48 Rituximab 375 mg/m2 administered weekly over 4 weeks improved DLCO, 6-min walking test, chest CT and X-ray.
Recently, Kavuru and colleagues conducted an open-label proof-of-concept Phase II clinical trial in 10 PAP patients. The treatment consisted of two intravenous infusions of rituximab (1000 mg) on day 0 and day 15. BALF and peripheral blood was collected. The P(A-a)O2 gradient and PaO2 improved in seven of nine patients who completed the trial. Also, HRCT scans and lung function test improved. A decrease in B lymphocytes and BALF anti-GM-CSF IgG levels was noted. Fifteen days post therapy, anti-GM-CSF IgG levels remained unchanged in sera.49
In conclusion, rituximab shows promising results in most of the treated patients, and adverse reactions to rituximab in PAP patients are generally few and minor (e.g. fatigue, headache, dizziness, nausea, anorexia, nasal congestion, upper respiratory infection and chest pain). However, serious side effects have been described.
Bonfield et al. proved a correlation between anti-GM-CSF titres and the likelihood to respond to GM-CSF.43 One patient unresponsive to GM-CSF treatment was listed for lung transplantation. On the waiting list, plasmapheresis was tried in order to lower the level of systemic anti-GM-CSF. Over 2 months, 10 sessions were conducted with replacement of 1.5 L plasma volume at each session. Anti-GM-CSF titres were reduced from baseline 1:6400 to 1:400. Chest radiograph improved, and PaO2 increased from 50 to 70 mm Hg.
Luisetti et al. also reported a patient who received 10 plasmapheresis sessions with replacement of 1.5 L plasma volume at each session.67 Anti-GM-CSF decreased already after three sessions, from 250 µg/mL to 130 µg/mL. The patient's symptoms, chest CT and pulmonary function were unchanged, but after plasmapheresis, the duration between WLL could be extended. Anti-GM-CSF levels continued to decline 24 months after plasmapheresis to 56 µg/mL.
Based on the rationale that antibodies play a pathogenic role in PAP,27 the use of plasmapheresis yields a plausible approach in order to reduce circulating antibodies, and thus restore the surfactant catabolism. Gram-negative sepsis has been described as a complication.
Lung transplantation is an option in non-responsive patients, but the literature is scarce on outcome. Parker and Novotny described in a case report the recurrence of PAP after double lung transplantation in a 41-year-old woman, with end-stage lung disease due to PAP.68 Further, a few case reports have described autoimmune PAP as a complication following lung transplantation.69,70 Huddleston et al. identified 207 lung transplantations performed in 190 children between 1990 and 2002. Twelve (6.3%) of these had PAP. Overall survival was similar to other lung diseases.71
No studies have systematically addressed the effect of combination therapy. In a case report, both inhaled GM-CSF and WLL were tried.72 One of two identical twin girls developed autoimmune PAP at the age of 13, diagnosed on HRCT, bronchoscopy, and detection of anti-GM-CSF in serum and BALF. The girl responded only briefly after three WLL, and 3 months after the last WLL, inhaled GM-CSF 250 µg b.i.d. was initiated. Already 1 month later, she experienced clinical improvement, and after 4 months of therapy, GM-CSF was tapered to 250 µg × 1. After 1 year of treatment, the therapy was successfully stopped.
Yamamoto et al. described a 9-year-old girl with autoimmune PAP.73 The diagnosis was based on BALF, an elevated serum anti-GM-CSF and characteristic PAP changes on CT of the chest. The girl started inhaling GM-CSF 125 µg b.i.d. in cycles of 8 days of treatment and 6 days pause. After the second cycle, CT of the chest showed progression of ground-glass opacity, and the PaO2 decreased. WLL was performed twice of the right lung and one time of the left over a 2-month period. The girl continued inhalation of GM-CSF between and after each WLL. One month after the last WLL, PaO2 increased and ground-glass opacity on CT scan began to fade during continued inhaled therapy.
In conclusion, these innovative combination therapies present interesting results in difficult PAP cases refractory to monotherapy.
Long-term prognosis of PAP is not well known, but in observational studies, there is a tendency to spontaneous remission underscoring the need for controlled randomized studies.74 Asymptomatic patients often seem to have a stable or improved course of disease, whereas symptomatic patients have a more varied course, in which 45% are stable, 30% improve and 25% experience deterioration.3 Seymour and Presneill found in a retrospective review of all published studies prior to 2001 that the current survival rate at 2, 5 and 10 years, respectively, was 78.9% ± 8.2%, 74.7% ± 8.1% and 68.3% ± 8.6%.
The overall 5-year survival after diagnosis was higher for patients undergoing therapeutic WLL (n = 146) compared with patients not treated with WLL (n = 85) (94% ± 2% vs 85% ± 5%). They further grouped the patients in 10-year cohorts by initial publication. They found, using disease-specific survival and restricting analysis to patient diagnosed ante mortem, that the 5-year actuarial survival rates for patients reported in the years 1958–1967, 1968–1977, 1978–1987 and 1988–1997 were 77% ± 6%, 91% ± 4%, 96% ± 3% and 100%, respectively.2
WLL has been used to treat autoimmune PAP for decades, and anecdotally, many patients have been reported just to need a single WLL to be cured. However, experience and studies have shown that a substantial portion of patients needs more than one and even repeated WLL.40,61,65,66,72
Substitution with GM-CSF has recently been introduced with a favourable outcome, but as the complicated immunological mechanisms have been further sorted out, more refined and more specific treatments have been introduced, with rituximab and plasmapheresis as the most recent.
GM-CSF both systemically and targeted directly to the lungs improves the condition of about two thirds of patients, still leaving a substantial amount of patients in whom there is only a limited number of treatment options. Rituximab and maybe plasmapheresis may help these patients. Obviously, combination therapy should be pursued as a future goal in investigations, but until such studies are performed, it is up to each individual centre to decide on a treatment strategy.
We are all aware that single case reports have little weight when suggesting a treatment algorithm, but with the rarity of PAP and the lack of controlled combination therapy studies, one could argue to include results of case reports, although with great caution until further controlled clinical trials have been performed.
An algorithm based on the current knowledge would help standardize and ease the treatment decisions in relation to this rare disease. It would further contribute to evaluate and develop the treatment, as more immunological mechanisms are disclosed and more data are presented.
SUGGESTION TO ALGORITHM OF TREATMENT
Based on the literature review and our clinical experience, we propose that autoimmune PAP patients should be divided into three stages based on disease severity score (DSS), which is based on the presence of symptoms and degree of reduction in PaO2, as suggested by Inoue et al.:3 DSS 1 = no symptoms and PaO2 ≥ 70 mm Hg; DSS 2 = symptomatic and PaO2 ≥ 70 mm Hg; DSS 3 = PaO2 ≥ 60 mm Hg but <70 mm Hg; DSS 4 = PaO2 ≥ 50 mm Hg but <60 mm Hg; DSS 5 = PaO2 < 50 mm Hg. In the following, we combine DSS 3 + 4 + 5 in Stage 3 (Fig. 3).
1Patients who are asymptomatic or only mildly affected: minimal desaturation during physical activity, or a slight reduction in diffusion capacity (DSS 1).3 These patients should be observed with a reassessment of symptoms, arterial blood gas analyses, lung function test and chest X-ray every 3–6 months.
2Patients who are mildly to moderately affected (DSS 2), that is, patients who desaturate during minimal physical activity.3 These patients should be monitored more closely to detect any further deterioration. We recommend shortening the observation period from 3 months to 4 weeks in Stage 2, in order to closely follow this patient group for signs of disease progression and initiation of treatment (as per Stage 3). If patients in the intensified observation period remit and are stable for 3–6 months, one can again expand the observation frequency to 3 months. In case of many symptoms, the patient can be considered for treatment.Reassessment should include the same parameters as Stage 1.
3Although there are no clear guidelines for timing of initiating treatment, we suggest that patients with moderate to severe symptoms, that is, patients who require oxygen or who are hypoxaemic at rest (DSS 3 + 4 + 5, P(A-a)O2 > 40 mm Hg or shunt fraction >10–12%3,74,75), and with progression of ground-glass opacity on HRCT, should be treated.
Patients with PAP Stage 3 should initially have WLL performed once, maybe twice on each affected lung, depending on the response. WLL serves primarily to cure the patient, and secondly to remove as much of the PAS-positive material as possible. Theoretically, this could be speculated to allow the following treatment with inhaled GM-CSF to be able to exert its effect in more peripheral lung areas. The method for WLL depends on the individual centre's anaesthetic experience in bilateral or single sequential WLL and the patient's clinical condition. It is important to rinse until there is a clear liquid and to use percussion techniques, and finally to repeat the procedure with the patient lying in prone position.
In severe cases of PAP where WLL is considered potentially harmful, or in patients with less advanced disease whose proteinaceous material can be removed with a small volume of lavage fluid, partial lung lavage performed with fiberoptic bronchoscope can be performed as described by Cheng et al.58
There seems to be a tendency for non-responding patients to be younger. Otherwise, there is no difference in response when adjusting for gender, smoking status, P(A–a)O2 or time from diagnosis to lavage.2 Within the first week of WLL, a significant response, compared with baseline values, is expected in PaO2, P(A-a)O2 gradient and forced vital capacity, whereas DLCO and 6-min walking test significantly improves over time, reaching a plateau at 6–12 months, as indicated by Beccaria et al.62 To reduce test variability, we recommend the use of standardized measurement of DLCO according to the American Thoracic Society/European Respiratory Society Task Force recommendations.76
If WLL fails, inhaled GM-CSF 250 µg b.i.d. every second week for 12 weeks should be attempted. If the clinical response is unsatisfying, dosage should be increased to 500 µg b.i.d. every second week for another period of 12 weeks.66 We recommend inhaled GM-CSF as the best route of administration to ensure a high dose in the target organ and to avoid systemic adverse reactions.21 Clinical response has, in one study, been defined as an improvement in one of the following parameters: >10 mm Hg increase in (PaO2), >12 mm Hg reduction in (P(A–a)O2), >12% increase in DLCO or >7% increase in forced vital capacity.66
Rituximab should be administered as 1000 mg intravenously on day 0 and day 15 if WLL and inhaled GM-CSF therapy fail or are associated with unacceptable side effects.47,49 Plasmapheresis might help patients unresponsive to WLL, but should, in our opinion, only be applied after all other treatments, including combination therapy, have been attempted.
Treatment should result in a significant and steady increase in pulmonary function or stabilization of pulmonary function close to normal. In case of only minor responses, one should proceed to the next treatment step.
Although some studies have been unable to demonstrate a significant correlation between anti-GM-CSF IgG and the disease, including DSS, spirometry, DLCO, PaO2 or P(A–a)O2, more recent studies have demonstrated a correlation on outcome. Until further studies on the area have been done, we suggest the use of anti-GM-CSF titres at baseline, before and after treatment, and at progression.
Follow up of autoimmune PAP patients should include pulmonary function tests, arterial blood gas analyses, 6-min walking test, chest X-ray and yearly HRCT.
The follow-up intervals depend on the severity of the disease and the treatment response, but in most patients, evaluation every 3 months will be appropriate. Shortened follow-up intervals are needed in case of exacerbations, and a new evaluation is crucial before stepping up the treatment. Long-term follow up should continue for at least 1 year without evidence of exacerbations or need for new treatments. Due to the rare reoccurrence of the disease, a 1-year follow up might be sufficient.
Ultimately, lung transplantation has been used in a few cases, but relapse in the transplanted lung has been reported.68 With the new treatment modalities, lung transplantation can hopefully be avoided in the future.
Although the mechanism leading to the development of autoimmune antibodies towards GM-CSF are poorly understood, the discovery of the background of autoimmune alveolar proteinosis in the past two decades has contributed to the development of more refined treatment modalities of PAP. As more clinical data regarding the disease and the detailed immunological mechanisms are disclosed, more specific treatment options and combinations are expected. Until then, we propose a treatment algorithm based on the current literature on this rare disease.
We would like to thank Associate clinical Professor Henrik Hager from the Department of Pathology, Aarhus University Hospital, Aarhus, Denmark, for the assistance and preparation of the histology, and Associate Professor Finn Rasmussen from the Department of Radiology, Aarhus University Hospital, Aarhus, Denmark, for the assistance and preparation of the CT scanning.