Lung disease associated with systemic juvenile idiopathic arthritis (SJIA-LD) remains poorly understood. Evaluation of bronchoalveolar lavage fluid (BALF) may better reflect disease pathogenesis. The objectives of our study were to measure levels of cytokines and chemokines in BALF and their associations with clinical features and treatment in patients with SJIA-LD. Children with SJIA-LD undergoing clinically indicated diagnostic bronchoscopy were enrolled. Comparator BALF was collected from patients with other chronic inflammatory and non-inflammatory lung diseases. BALF was assayed for IL-6, 8 and 18, S100A8/9, S100A12, sCD25, CCL11, CCL17, CCL25, MMP7, and CXCL9. BALF was obtained from 21 patients with SJIA-LD and 54 comparator patients with other lung diseases. Compared to all controls, children with SJIA-LD had a significant elevation of IL-18 (median (IQR) 1406 (722.3–2812) vs 37.2 (25.3–70) pg/mL, p < 0.0001), S100A8/9 (4745.3 (3003–11506) vs. 1297.5 (260–7755) ng/mL, p = 0.02), sCD25 (31.6 (19–50.3) vs. 13.6 (8.6–37.3) pg/mL, p = 0.04), MMP-7 (18,466.7 (10,462.2–33,516.1) vs. 13.645 (8.6–37.3) pg/mL, p = 0.0384), and CCL17 (0 (0–63.1; p = 0.038) vs 0 (0–0) pg/mL. BALF IL-18 was significantly higher in children with SJIA-LD compared to all control subgroups (inflammatory and non-inflammatory airway disease, autoimmune pulmonary alveolar proteinosis, and poorly controlled asthma), in patients who were actively treated with anti-cytokine biologics (N = 9), and in patients who ultimately underwent hematopoietic stem cell transfer (N = 8). Patients receiving anti-cytokine biologics also had significant elevations in several other cytokines compared to patients without such treatments, while profiles in those treated with JAKi (N = 14) were largely similar. Linear regression analysis showed an association between BALF level of IL-18 and the number of immunosuppressive medications utilized (p = 0.0167), but not with O2 requirement, dose of anakinra or prednisone, plasma IL-18, ferritin, CRP or ESR. Patients with SJIA-LD showed a distinct BALF cytokine profile, including significant IL-18, S100A8/9 protein, sCD25, and CCL-17 elevation. The level of IL-18 was higher in patients who required more immunosuppressive medications and were actively treated with anti-cytokine biologics. The relationship between BALF cytokine profiles and anti-cytokine biologics and JAK inhibitors is unclear and should be evaluated further.

BACKGROUND AND OBJECTIVE:Pulmonary alveolar proteinosis (PAP) is a rare disease of inappropriate alveolar surfactant accumulation. The study objective was to compare Greece-Türkiye-Cyprus cohorts, followed-up for 20 years. METHODS:Data were retrieved retrospectively by chart review. RESULTS:One hundred and thirty patients, Greece 39, Türkiye 87, Cyprus 4, were included; 115 (89%) autoimmune (a)PAP, 13 (10%) secondary, 1 (1%) hereditary. Abnormal anti-GM-CSF antibody titre was available in 86/115 patients, further analyzed for aPAP. Forty (46%) were male, with median (IQR) age at diagnosis of 40 (31-50) years. At median (IQR) duration of clinical follow-up of 39 (18-78) months, three patients died. Non-survivors had higher rates of cardiovascular disease [67% vs. 5%, p < 0.001], LTOT (67% vs. 13%, p = 0.001), pulmonary fibrosis [67% vs. 5%] and worse functional status at follow-up [FVC% pred 49 (29) vs. 87 (74-97); p = 0.026, DLCO% pred 21 (46) vs. 72 (58-82); p = 0.016]. aPAP patients were stratified by therapy group (no WLL-no i-GM-CSF, WLL alone, i-GMCSF alone and both WLL and iGM-CSF). WLL was more frequently performed in Türkiye and i-GMCSF alone in Greece (p = 0.006). All therapies were effective. No difference was detected on outcome when sole iGM-CSF was compared to WLL alone or in combination with iGM-CSF [deceased/alive 0%/100% vs. 7%/93%, p = 0.491]. Sole iGM-CSF significantly ameliorated clinical and functional parameters of disease severity [DLCO% (p = 0.013), SatO2 (p = 0.002), 6MWT (p = 0.026)]. Across all therapy groups, pulmonary fibrosis eliminated beneficial response to treatment. CONCLUSION:This first real-life comparison of aPAP cohorts originating from three countries showed the non-inferiority of sole iGM-CSF treatment. Fibrosis negatively affects response to treatment and survival.

Rationale: Molgramostim inhalation solution is an investigational recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). The efficacy and safety of molgramostim for the treatment of aPAP is being evaluated in a Phase 3 clinical trial (IMPALA-2). In the 48-week double-blind treatment period, greater mean improvements in health-related quality of life (HRQoL) as measured by Saint George's Respiratory Questionnaire (SGRQ) Total and Activity scores were observed in the molgramostim group compared with placebo. Here we report additional results on HRQoL and patient-reported outcomes (PROs) from IMPALA-2. Methods: IMPALA-2 is a global, randomized, double-blind, placebo-controlled Phase 3 trial conducted in adult aPAP patients who received nebulized molgramostim 300 µg or placebo once daily for 48 weeks. Exploratory measures evaluated included the SGRQ Impact and Symptom component scores, the EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L), Patient Global Impression of Severity (PGIS), and Patient Global Impression of Change (PGIC) at Weeks 24 and 48. Results: Mean improvements from baseline in the SGRQ Impact score were nominally significantly greater at Week 24 and numerically greater at Week 48 in the molgramostim group than the placebo group; mean improvements from baseline in the SGRQ Symptom score were numerically greater for molgramostim versus placebo at Weeks 24 and 48. The odds ratios of achieving a higher response rating on the EQ-5D-5L favored molgramostim compared with placebo on 4 of the 5 domains (Mobility, Self-Care, Usual Activities, and Pain/Discomfort) at one or both of Weeks 24 and 48, and were nominally significant for Mobility at Week 24 (P=0.0014) and Usual Activities at Week 48 (P=0.0304); there was no significant difference detected in the anxiety/depression domain. Nominally significant differences between molgramostim and placebo groups in severity of breathing problems, as assessed by distribution of PGIS categories (None, Mild, Moderate, Severe, and Very Severe), were reported at Weeks 24 (P=0.0305) and 48 (P=0.0049). For PGIC, better improvements in overall change in breathing problems and nominally significantly better improvements in overall change in daily physical activity level (Week 24, P=0.0470; Week 48, P=0.0193), as measured by more patients being assessed as Much better or A little better, were reported for molgramostim compared with placebo at Weeks 24 and 48. Conclusions: Molgramostim improved HRQoL as measured by SGRQ Impact and Symptom scores. More aPAP patients on molgramostim than on placebo reported improvements in mobility, self-care, usual activities, and pain/discomfort (EQ-5D-5L), as well as improvements in breathing problems and physical activity level (PGIS and PGIC).

Rationale: Pulmonary alveolar proteinosis (PAP) is a rare syndrome of surfactant accumulation that can result in respiratory failure. Autoimmune PAP (aPAP) accounts for ∼90% of all patients and is caused by granulocyte/macrophage-colony stimulating factor (GM-CSF) autoantibodies (GMAbs). Approximately 10% of cases are caused by other genetic and acquired conditions. Serum GMAb testing is 100% sensitive and specific for the diagnosis of aPAP. No FDA-approved therapy currently exists; patients are currently treated by whole lung lavage (WLL) and one of several off-label pharmacotherapies. Methods: The US National PAP Registry was initiated in 2015 to collect patient-reported questionnaire-based information regarding the presentation, diagnosis, and therapy of PAP-causing diseases. Information was also obtained by reviewing patients’ medical records. This report is focused on patients with aPAP. Data are mean ± SEM or percentages as appropriate. Results: Registry patients with aPAP (n=111) presented clinically at 38.6±1.5 years of age. The presenting symptoms included dyspnea (98%), fatigue (82%), cough (69%), sputum expectoration (61%), chest tightness (50%), and/or chest pain (45%). Less than half of the aPAP patients had a history of smoking. Diagnosis of aPAP occurred 1.0±0.2 years after the onset of symptoms and often followed a diagnosis of pneumonia (43%) or asthma (14%). Of those diagnosed with pneumonia, 93.5% received 2.8±0.7 courses of antibiotics before a diagnosis of aPAP was pursued. Medical records indicated 63 of 89 (71%) aPAP patients had a lung biopsy as part of their diagnostic evaluation; 30% had a surgical biopsy, 34% had a transbronchial biopsy, and 6.7% had both. None of the biopsies were diagnostic for aPAP and 9.5% failed to identify PAP. In all patients, the diagnosis of aPAP was made by serum GMAb testing, for which the median (and interquartile range) was 96.2 (57.6-182.5) mcg/ml. Most (86%) patients received therapy for PAP including WLL (79%), off-label GM-CSF (38%) (45% inhaled, 39% subcutaneous, 16% via both routes), corticosteroids (25%), or rituximab (8%). WLL was administered once in 25.5%, 2-5 times in 49%, and >5 times in 25.5% of patients; with 73% reporting a good response. Conclusions: Among US National PAP Registry participants, aPAP was the most common PAP-causing disease, dyspnea was the most common symptom, serum GMAb level was elevated and diagnostic in all aPAP patients while lung biopsies were unable to diagnose aPAP in any patient and failed to identify PAP in some. Studies evaluating the effectiveness of recombinant inhaled GM-CSF therapy are needed and ongoing.

BACKGROUND:Inhaled molgramostim, a form of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), is a promising investigational pharmacotherapy for autoimmune pulmonary alveolar proteinosis (aPAP); however, its pharmacology in healthy subjects has not been reported. METHODS:This randomised, double-blind, placebo-controlled, single-centre, phase 1 clinical trial assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled molgramostim in healthy adults in single ascending dose (SAD) and multiple ascending dose (MAD) studies: one 150, 300 or 600 µg administration or six consecutive daily 300 or 600 µg administrations with evaluations over 28 or 34 days, respectively. The primary endpoint was safety, which was evaluated based on the number and severity of treatment-emergent AEs following single and multiple inhaled doses of molgramostim. RESULTS:42 subjects were enrolled including 18 in the SAD study and 24 in the MAD study; all completed the study. Inhaled molgramostim in healthy people was well tolerated and no dose-limiting safety concerns or anti-drug antibody formation were observed in either study. GM-CSF was measurable in serum 30 min after administration of inhaled molgramostim, peaked at 2 hours for all three doses and had an elimination half-life of 1.7±0.0 to 5.9±0.9 hours in the SAD and MAD studies. Systemic GM-CSF exposure was non-linear in both the SAD and MAD studies. Inhaled molgramostim caused a rapid increase in white blood cells (WBC) counts and leucocyte subsets that normalised by 8 hours (SAD) or 15-21 days (MAD). Fractional exhaled nitric oxide remained within the normal range at all doses but was numerically, but not significantly, increased at the 600 μg dose. CONCLUSIONS:In healthy people, inhaled molgramostim was well-tolerated and resulted in systemic exposure at picogram levels, which had the expected PD effects on blood leucocyte levels that mostly remained within normal ranges. TRIAL REGISTRATION NUMBER:NCT02468908; EudraCT No. 2013-001687-32.

BACKGROUND:We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn's disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content. METHODS:Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested. RESULTS:Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = -0.39 [95% confidence interval {CI}: -0.61, -0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P < .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = -.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = -.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13). CONCLUSIONS:Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.

BACKGROUND:Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia caused by autoantibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), which alveolar macrophages require to clear surfactant. Molgramostim is a formulation of inhaled recombinant human GM-CSF, but its efficacy and safety in patients with aPAP have not been studied sufficiently. METHODS:In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with aPAP to receive molgramostim at a dose of 300 μg or placebo once daily for 48 weeks. The primary end point was the change from baseline to week 24 in the diffusing capacity of the lungs for carbon monoxide (DLCO), which was adjusted for hemoglobin concentration and expressed as a percentage of the predicted value. Secondary end points adjusted for multiplicity were the change from baseline in DLCO at 48 weeks and the change from baseline in the St. George's Respiratory Questionnaire total (SGRQ-T) and activity (SGRQ-A) scores (scores range from 0 to 100, with lower scores indicating better quality of life) and in exercise capacity at 24 and 48 weeks. RESULTS:A total of 164 patients underwent randomization: 81 were assigned to receive molgramostim and 83 to receive placebo. The least-squares mean change in DLCO from baseline to week 24 was 9.8 percentage points (95% confidence interval [CI], 7.3 to 12.3) with molgramostim and 3.8 percentage points (95% CI, 1.4 to 6.3) with placebo (estimated treatment difference, 6.0 percentage points; 95% CI, 2.5 to 9.4; P<0.001). The least-squares mean change in DLCO from baseline to week 48 was 11.6 percentage points (95% CI, 8.7 to 14.5) with molgramostim and 4.7 percentage points (95% CI, 1.8 to 7.6) with placebo (P<0.001), and the least-squares mean change in the SGRQ-T score at week 24 was -11.5 points (95% CI, -15.0 to -8.0) and -4.9 points (95% CI, -8.3 to -1.5), respectively (P = 0.007). No significant between-group difference in the change in SGRQ-A score was observed at 24 weeks, so no statistical inference was drawn with respect to subsequent secondary end points. The percentage of patients with at least one adverse event and the percentage with at least one serious adverse event were similar in the two groups. CONCLUSIONS:Once-daily inhaled molgramostim led to a greater increase in pulmonary gas transfer than placebo in patients with aPAP. (Funded by Savara; IMPALA-2 ClinicalTrials.gov number, NCT04544293; European Union Clinical Trials Information System number, 2024-511052-41-00.).

Abstract Background Sepsis is commonly associated with acute respiratory distress syndrome (ARDS). Although the exaggerated inflammation may damage intact lung tissues, a percentage of patients with ARDS are reportedly immunocompromised, with worse outcomes. Herein, using a murine sepsis model, time-course immune reprogramming after sepsis was evaluated to explore whether the host is immunocompromised. Leukocyte kinetics in the lung tissue were evaluated in a male C57/BL6 mouse model of mild peritoneal sepsis induced by cecal ligation and puncture, with the survival rate exceeds 90%. Lung immune reactivity was evaluated by intratracheal instillation of lipopolysaccharide (LPS; 30 µg). Furthermore, the effect of interferon (IFN)-β in vivo and ex vivo was evaluated. Results Four days after sepsis, the lung water content remained high, even among mice in clinical recovery. While monocytes and neutrophils gradually accumulated in the lung interstitium, the inflammatory cytokine/chemokine expression levels in the lungs continued to decline. Intratracheal LPS instillation induced more leukocyte trafficking and protein leakage into the alveoli in the septic lung, indicating more severe lung injury. However, LPS stimulation-associated mRNA expression of tnf, il6, ccl2, and cxcl1 was suppressed. Intra-alveolar expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and keratinocyte-derived cytokine (KC) was also suppressed. Monocytes isolated from the lung tissue showed an impaired response in il6, ccl2, and cxcl1 to LPS. Systemic IFN-β restored the above impaired regulator function of monocytes, as did coculturing these cells from lung tissue with IFN-β. Conclusions Histologically accelerated inflammation and paradoxically suppressed immunological regulator signaling were observed in the early recovery phase of sepsis. This observation may provide a model for the immunologically irresponsive state that occurs in some patients with sepsis. Systemic IFN-β partly restored the post-septic immunocompromised state, indicating its therapeutic potential for the immunosuppressive state seen in some patients with sepsis/ARDS.

Pulmonary macrophage transplantation (PMT) is a gene and cell transplantation approach in development as therapy for hereditary pulmonary alveolar proteinosis (hPAP), a surfactant accumulation disorder caused by mutations in CSF2RA/B (and murine homologs). We conducted a toxicology study of PMT of Csf2ra gene-corrected macrophages (mGM-Rα+Mϕs) or saline-control intervention in Csf2raKO or wild-type (WT) mice including single ascending dose and repeat ascending dose studies evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics. Lentiviral-mediated Csf2ra cDNA transfer restored GM-CSF signaling in mGM-Rα+Mϕs. Following PMT, mGM-Rα+Mϕs engrafted, remained within the lungs, and did not undergo uncontrolled proliferation or result in bronchospasm, pulmonary function abnormalities, pulmonary or systemic inflammation, anti-transgene product antibodies, or pulmonary fibrosis. Aggressive male fighting caused a similarly low rate of serious adverse events in saline- and PMT-treated mice. Transient, minor pulmonary neutrophilia and exacerbation of pre-existing hPAP-related lymphocytosis were observed 14 days after PMT of the safety margin dose but not the target dose (5,000,000 or 500,000 mGM-Rα+Mϕs, respectively) and only in Csf2raKO mice but not in WT mice. PMT reduced lung disease severity in Csf2raKO mice. Results indicate PMT of mGM-Rα+Mϕs was safe, well tolerated, and therapeutically efficacious in Csf2raKO mice, and established a no adverse effect level and 10-fold safety margin.

Infections that are unusually severe or caused by opportunistic pathogens are a hallmark of primary immunodeficiency (PID). Anti-cytokine autoantibodies (ACA) are an emerging cause of acquired immunodeficiency mimicking PID. Nocardia spp. are Gram-positive bacteria generally inducing disseminated infections in immunocompromised patients, but seldom also occurring in apparently immunocompetent hosts. Anti-GM-CSF autoantibodies are associated with autoimmune pulmonary alveolar proteinosis (PAP). In those patients, an increased incidence of disseminated nocardiosis and cryptococcosis has been observed. It is unclear whether the PAP or the autoantibodies predispose to the infection. We report an apparently immunocompetent woman presenting with disseminated nocardiosis without any evidence of PAP. Clinical data and radiological images were retrospectively collected. Lymphocyte populations were analyzed by flow cytometry. Anti-GM-CSF autoantibodies were measured by ELISA. A 55-year-old otherwise healthy woman presented with cerebral and pulmonary abscesses. Personal and familial history of infections or autoimmunity were negative. After extensive examinations, a final diagnosis of disseminated nocardiosis was made. Immunologic investigations including neutrophilic function and IFN-γ/IL-12 circuitry failed to identify a PID. Whole-exome sequencing did not find pathogenic variants associated with immunodeficiency. Serum anti-GM-CSF autoantibodies were positive. There were no clinical or instrumental signs of PAP. Trimethoprim-sulfamethoxazole and imipenem were administered, with progressive improvement and recovery of the infectious complication. We identified anti-GM-CSF autoantibodies as the cause of disseminated nocardiosis in a previously healthy and apparently immunocompetent adult. This case emphasizes the importance of including ACA in the differential diagnosis of PID, especially in previously healthy adults. Importantly, anti-GM-CSF autoantibodies can present with disseminated nocardiosis without PAP.

BACKGROUND:Despite advances in medical therapy, many children and adults with ileal Crohn's disease (CD) progress to fibrostenosis requiring surgery. We aimed to identify MRI and circulating biomarkers associated with the need for surgical management. METHODS:This prospective, multicenter study included pediatric and adult CD cases undergoing ileal resection and CD controls receiving medical therapy. Noncontrast research MRI examinations measured bowel wall 3-dimensional magnetization transfer ratio normalized to skeletal muscle (normalized 3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, intravoxel incoherent motion (IVIM) diffusion-weighted imaging metrics, and the simplified magnetic resonance index of activity (sMaRIA). Circulating biomarkers were measured on the same day as the research MRI and included CD64, extracellular matrix protein 1 (ECM1), and granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies (Ab). Associations between MRI and circulating biomarkers and need for ileal resection were tested using univariate and multivariable LASSO regression. RESULTS:Our study sample included 50 patients with CD undergoing ileal resection and 83 patients with CD receiving medical therapy; mean participant age was 23.9 ± 13.1 years. Disease duration and treatment exposures did not vary between the groups. Univariate biomarker associations with ileal resection included log GM-CSF Ab (odds ratio [OR], 2.87; P = .0009), normalized 3D MTR (OR, 1.05; P = .002), log MOLLI T1 (OR, 0.01; P = .02), log IVIM perfusion fraction (f; OR, 0.38; P = .04), and IVIM apparent diffusion coefficient (ADC; OR, 0.3; P = .001). The multivariable model for surgery based upon corrected Akaike information criterion included age (OR, 1.03; P = .29), BMI (OR, 0.91; P = .09), log GM-CSF Ab (OR, 3.37; P = .01), normalized 3D MTR (OR, 1.07; P = .007), sMaRIA (OR, 1.14; P = .61), luminal narrowing (OR, 10.19; P = .003), log C-reactive protein (normalized; OR, 2.75; P = .10), and hematocrit (OR, 0.90; P = .13). CONCLUSION:After accounting for clinical and MRI measures of severity, normalized 3D MTR and GM-CSF Ab are associated with the need for surgery in ileal CD.

BACKGROUND:Pulmonary alveolar proteinosis (PAP) is a rare syndrome caused by several distinct diseases leading to progressive dyspnoea, hypoxaemia, risk of respiratory failure and early death due to accumulation of proteinaceous material in the lungs. Diagnostic strategies may include computed tomography (CT) of the lungs, bronchoalveolar lavage (BAL), evaluation of antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), genetic testing and, eventually, lung biopsy. The management options are focused on removing the proteinaceous material by whole lung lavage (WLL), augmentation therapy with GM-CSF, rituximab, plasmapheresis and lung transplantation. The presented diagnostic and management guidelines aim to provide guidance to physicians managing patients with PAP. METHODS:A European Respiratory Society Task Force composed of clinicians, methodologists and patients with experience in PAP developed recommendations in accordance with the ERS Handbook for Clinical Practice Guidelines and the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach. This included a systematic review of the literature and application of the GRADE approach to assess the certainty of evidence and strength of recommendations. The Task Force formulated five PICO (Patients, Intervention, Comparison, Outcomes) questions and two narrative questions to develop specific evidence-based recommendations. RESULTS:The Task Force developed recommendations for the five PICO questions. These included management of PAP with WLL, GM-CSF augmentation therapy, rituximab, plasmapheresis and lung transplantation. Also, the Task Force made recommendations regarding the use of GM-CSF antibody testing, diagnostic BAL and biopsy based on the narrative questions. In addition to the recommendations, the Task Force provided information on the hierarchy of diagnostic interventions and therapy. CONCLUSIONS:The diagnosis of PAP is based on CT and BAL cytology or lung histology, whereas the diagnosis of specific PAP-causing diseases requires GM-CSF antibody testing or genetic analysis. There are several therapies including WLL and augmentation therapy with GM-CSF available to treat PAP, but supporting evidence is still limited.