Study population

This study was conducted in Shanghai Pulmonary Hospital and consisted of a retrospective cross-sectional analysis from January 2004 to December 2019. During this period, 168 patients were diagnosed with PAP in our institution. Of these, the data of 151 APAP patients were retrospective analyzed in this study after excluding 12 patients with second PAP and five patients whose data was incomplete. Among the enrolled patients, some had comorbidities, such as hypertension and a history of surgery at certain sites, but none of these comorbidities resulted in increased antibodies to GM-CSF. 27 patients were advised to delayed treatment and regular chest CT review, 19 patients refused whole lung lavage (WLL) or GM-CSF therapy, 105 patients received corresponding treatment (WLL: 35; subcutaneous GM-CSF: 49; inhaled GM-CSF: 6; WLL with subcutaneous GM-CSF: 9; WLL with inhaled GM-CSF: 6). Six months’ follow-up data of 88 patients were available. The normal control group was formed with 57 persons who were in the physical examination center. Written informed consent was obtained from all participants through letters. The study protocol was approved by the Ethics Committee of Shanghai Pulmonary Hospital (K19-142; Shanghai, China).

Diagnostic criteria

Eligibility criteria were selected as described by Ben-Dov et al. [12]. These criteria included histopathologic findings of specimens obtained by open lung biopsy or transbronchial lung biopsy (TBLB); a typical milk-like appearance of BALF, which with lamellar bodies visible in electron microscopy; ground-glass opacity and/or a crazy-paving pattern on HRCT; higher number of GM-CSF antibodies in serum; restrictive ventilation and diffusion dysfunction; clinical symptoms (i.e., dyspnea and cough). The patient would be diagnosed with APAP according to typical HRCT pattern, histopathologic findings or typical BALF, and a higher number of GM-CSF antibodies in serum after excluding other diseases which resulted in GM-CSF antibodies increasing. In this study, the diagnosis of APAP was established by BALF (n = 54), TBLB results (n = 55), or open lung biopsy results (n = 42).

Interview questionnaire and blood samples

A standardized protocol was used to obtain informed consent from each subject during a medical visit. The interview questionnaire that was used included questions on the following topics: general and anthropometric information (i.e., age and sex), smoking history (e.g., smoker, ex-smoker or never-smoked), and clinical manifestation (e.g., the onset of symptoms, the course of the disease and symptoms). The data about serum LDH, CEA and CYFRA21-1 of patients during the first hospitalization and follow-up in Shanghai Pulmonary Hospital, and normal control group were collected when physical examination. The standard scope of LDH, CEA and CYFRA21-1 were respectively (120–246) U/L, (0–10) ug/L and (0–3.3) ng/ml in our laboratory.

Severity and prognosis score of PAP (SPSP)

HRCT scans of the chest of 151 patients were analyzed and graded following the visual scoring methods based on two studies [7, 13]. We selected the HCRT grades in four representative regions, namely, the aortic arch, the tracheal carina, the convergence of the left and right inferior lung veins and above the diaphragm. The extent of lung opacity was estimated using a five-point scale: no opacity = 0; opacity involving ≤ 25% of a region of hemithorax = 1; 26–50% = 2; 51–75% = 3; > 75% =  4. The chest HRCT was examined and interpreted independently by two chest physicians. The mean values obtained from the two readers were used for analysis. The chest HRCT score was calculated by summing the lung opacity scores of the four representative regions of each hemithorax.

Pulmonary function was examined in each patient. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and DLCO data were presented as the percentages of predicted values (%predicted). Arterial blood measurements were performed on samples obtained while the patients were breathing room air at rest in the supine position.

The severity of patients was assessed based on the SPSP [6]. SPSP included smoking statues (never smoker, 0; smoker, 1); symptoms (No, 0; Yes, 1); PaO2 (≥ 80 mmHg, 0; ≥ 60 mmHg and < 80 mmHg, 1; < 60 mmHg, 2); HRCT score (≤ 8, 1; > 8 and ≤ 16, 2; > 16 and ≤ 24, 3; > 24, 4); and DLCO, %predicted (≥ 80%, 0; ≥ 60% and < 80%, 1; < 60%, 2). The SPSP was from 1 to 10. According to the SPSP, the patients were divided into five grades (grade I, SPSP 1–2; grade II, SPSP 3–4; grade III, SPSP 5–6; grade IV, SPSP 7–8; grade V, SPSP 9–10), and three severity grades: mild (grade I and II), moderate (grade III) and severe (grade IV and V).

Statistics

SPSS version 19.0 (SPSS, Chicago, Illinois) was used for statistical analysis. The data were tabulated as the means and standard deviations for quantitative variables or as absolute numbers and percentages for qualitative variables. The Kolmogorov–Smirnov test was used to analyze the data distribution for each variable. Serum biomarkers (LDH, CEA and CYFRA21-1) were comparatively analyzed between APAP patients and the normal control group. The relations between serum biomarkers and SPSP were analyzed. APAP patients were divided into higher and lower-level groups based on the comparison with the laboratory upper limit of serum biomarkers. The SPSP of patients in the corresponding two groups was comparatively analyzed. Serum biomarkers were pairwise comparatively analyzed among grade 1–5 groups. The 88 patients who had been followed up for six months were divided into three groups (aggravated group, relieved group and stable group) based on SPSP results after 6 months of follow-up as compared to the baseline. The variations in the serum biomarkers between the baseline and after 6 months in each group were subjected to comparative analysis. For the variables, we calculated sensitivity, specificity and critical point of biomarkers between APAP patients and normal control group, and between grades 1–2 and 3–5. We plotted the receiving operating characteristics (ROC) curve. In the bivariate analysis, the student’s t-test for independent variables was used to analyze variables that were normally distributed, and the Mann–Whitney U test was used to analyze variables that were non-normally distributed. Qualitative variables were compared using the chi-square test. P < 0.05 was considered indicative of a significant difference.

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