Serum vascular endothelial growth factor-D as a diagnostic and therapeutic biomarker for lymphangioleiomyomatosis.

BACKGROUND: In lymphangioleiomyomatosis (LAM), tuberous sclerosis gene mutations activate the mechanistic target of the rapamycin pathway, resulting in vascular endothelial growth factor-D (VEGF-D) overproduction. While the utility of serum VEGF-D testing for the diagnosis of LAM is outlined in ATS/JRS LAM Guidelines, the assay has not been fully validated for Asian populations. Our aims were to validate serum VEGF-D testing in Japan, by directly comparing measurements in Japan and the U.S., determining the diagnostic cut-off for serum VEGF-D levels among the Japanese women with typical thin walled cystic change on CT, and determining the performance of VEGF-D as a prognostic biomarker. SUBJECTS AND METHODS: We determined serum VEGF-D levels from 108 LAM patients, 14 disease controls, and 51 healthy volunteers from the Japanese population. Measurements of 61 LAM patients were compared to those from the principal VEGF-D laboratory in the U.S at Cincinnati Children's Hospital Medical Center. We correlated baseline serum VEGF-D levels with baseline and longitudinal clinical data to determine how pregnancy, sirolimus or gonadotrophin-releasing hormone (GnRH) agonists influence serum VEGF-D levels. RESULTS: Serum VEGF-D measurements in Japan and the U.S. were very similar. Baseline serum VEGF-D levels effectively distinguished LAM from other diseases and healthy volunteers at a cut-off level of 645 pg/ml and were diagnostically specific at 800 pg/ml, consistent with the recommendations of the ATS/JRS LAM Guidelines. Baseline serum VEGF-D correlated negatively with the DLco baseline % predicted and with the annual decrease in DLco % predicted. There was no significant association between baseline serum VEGF-D level and the outcomes of death or transplant. Serum VEGF-D levels markedly decreased during treatment with sirolimus, but not with GnRH analogues. Serum VEGF-D levels of most LAM patients did not increase over time, and neither pregnancy nor menopause significantly modulated serum VEGF-D levels. CONCLUSIONS: Serum VEGF-D is a useful diagnostic and therapeutic biomarker for LAM. Satisfactory precision and international inter-laboratory agreement of the clinical assay support VEGF-D recommendations in the ATS/JRS LAM Guidelines for the Japanese population.

A Semiquantitative Computed Tomographic Grading System for Evaluating Therapeutic Response in Pulmonary Alveolar Proteinosis.

RATIONALE: A useful semiquantitative method of using computed tomographic (CT) images to evaluate therapeutic response in pulmonary alveolar proteinosis (PAP) has not been established, although the extent score or grading score of ground-glass opacities has been used. OBJECTIVES: The purpose of this study was to establish a semiquantitative method for evaluating therapeutic response in PAP. METHODS: CT scans were obtained within 1 month before and after therapy from 32 patients with PAP who participated in a multicenter phase II trial of granulocyte-macrophage colony-stimulating factor inhalation therapy. The scans were evaluated by two chest radiologists independently. Increased parenchymal opacity was evaluated on the basis of its intensity and extent (CT grade), and the severity scores were compared with CT scores based on the extent alone (CT extent), as well as on the basis of physiological and serological results. RESULTS: CT grade score and CT extent score had significant correlation with diffusing capacity of the lung for carbon monoxide percent predicted (%DlCO), PaO2, VC percent predicted (%VC), Krebs von den Lungen (KL)-6, and surfactant protein D. The change in CT grade score between pre- and post-treatment examinations (ΔCT grade) correlated better with difference of PaO2 between pre- and post-treatment examinations (ΔPaO2) than ΔCT extent (difference of CT extent score between pre- and post-treatment examinations). In univariate analysis, ΔCT grade, ΔCT extent, ΔKL-6, Δ%DlCO, Δ%VC, and change in surfactant protein D correlated significantly with ΔPaO2. In multivariate analysis, ΔCT grade and ΔKL-6 correlated more closely with ΔPaO2. CONCLUSIONS: Although a number of CT variables were collected, the currently proposed grading system that correlates well with PaO2 should be viewed as a retrospective scoring system that needs future validation with another PAP cohort.

Temporary remission of autoimmune pulmonary alveolar proteinosis after infectious episodes.

Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown aetiology. Although resolution occurs in about 30% of autoimmune PAP (APAP) cases, its pathogenesis is not yet sufficiently understood. Two APAP cases at our institute showed remission following infectious episodes. Case 1: a 40-year-old female APAP patient suffered from herpes encephalitis and was treated with an antiviral drug. Her symptoms and radiological results resolved within two months of her recovery from the encephalitis. Case 2: A 53-year-old male current-smoker APAP patient was admitted for pneumonia. After treatment with antibiotics, his radiological results and symptoms improved. He experienced a similar resolution of APAP after another infectious episode two years later. Remission of APAP may occur following viral or bacterial infection. We hypothesise that remission of APAP is triggered by the induction of granulocyte-macrophage colony-stimulating factor (GM-CSF) following viral or bacterial infection. Further studies of APAP remission, and especially of the effects of GM-CSF induction, are needed. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 85-90).

CYFRA 21-1 as a disease severity marker for autoimmune pulmonary alveolar proteinosis.

BACKGROUND AND OBJECTIVE: Serum markers, including Krebs von den Lungen (KL-6), surfactant protein (SP)-D, SP-A and carcinoembryonic antigen (CEA), are reported to reflect autoimmune pulmonary alveolar proteinosis (APAP) disease severity. We evaluated serum CYFRA21-1 levels as a marker of APAP. METHODS: In addition to KL-6, SP-D and CEA, we prospectively measured serum CYFRA 21-1 levels in 48 patients with APAP, consecutively diagnosed between 2002 and 2010. Diagnostic usefulness of CYFRA 21-1 was determined from 68 patients with interstitial lung diseases by receiver operator characteristic curve analysis. We evaluated the association between these serum markers and other disease severity markers, including pulmonary function parameters, alveolar-arterial oxygen gradient, British Medical Research Council score reflecting shortness of breath, and disease severity score. CYFRA 21-1 localization in the lung was examined by immunohistochemistry. RESULTS: Receiver operator characteristic curve demonstrated that CYFRA 21-1 effectively identified APAP. Serum CYFRA 21-1 levels at diagnosis were significantly associated with the measured disease severity parameters. Following whole lung lavage (n = 10) and granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation (n = 20), serum CYFRA 21-1 levels were significantly decreased. Responders (n = 11) to GM-CSF inhalation revealed significantly higher serum CYFRA 21-1 levels than non-responders (n = 9). Serum CYFRA 21-1 appeared to be a significant predictor of effectiveness of GM-CSF based on regression analysis. Immunohistochemistry showed that CYFRA 21-1 was localized on hyperplastic alveolar type II cells and lipoproteinaceous substances in alveoli. CONCLUSIONS: Serum CYFRA 21-1 is a sensitive and useful serum marker for diagnosis and evaluation of disease severity of APAP, and may predict the response to GM-CSF inhalation.

[Multidisciplinary assessment of effects, safety and procedure of whole lung lavage for 8 patients with autoimmune pulmonary alveolar proteinosis].

We treated 8 cases of autoimmune pulmonary alveolar proteinosis (APAP) with whole lung lavage (WLL) in our hospital and evaluated the disease severity of APAP before and after WLL, adverse events (AEs) and recurrence-free survival in those cases who improved. In all cases, unilateral WLL was performed in both lungs. The median of total lavage volume in unilateral WLL was 17.9 L, and the median procedure time of unilateral WLL was 105 min. Fever was the most frequently observed AE (87.5% of all procedures). Pulmonary function tests (percentage of predicted value of VC, FEV1 and diffusing capacity of carbon monoxide), serum markers (KL-6, surfactant apoprotein (SP)-D, SP-A and carcinoembryonic antigens), arterial blood gas analyses (PaO2, AaDO2) and disease severity score all significantly improved after WLL. The serum levels of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody temporarily decreased after unilateral WLL, but returned to previous levels (before WLL) in 7 cases. The radiological findings improved in 6 cases. In the 7 improved cases in whom AaDO2 decreased more than 10 Torr, the median recurrence-free survival of APAP after WLL was 17.5 months. We concluded that WLL is an effective and safe method for the treatment of APAP, and all parameters except for anti GM-CSF antibody are useful to evaluate the effect of WLL.