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Clinical Analysis of 15 Cases with Pulmonary Alveolar Proteinosis

目的:肺泡蛋白沉积症(pulmonary alveolar proteinosis,PAP)是一种少见的肺部疾病,由于临床医生认识不足,容易误诊,而PAP通过灌洗治疗常常可获得较好的预后。本文通过分析PAP病例,总结PAP患者的临床特点、影像学表现和治疗方法,以提高该病的诊疗水平。方法:回顾性分析2003年2月～2008年5月四川大学华西医院呼吸科经病理确诊的15例PAP患者临床资料,并观察了全肺灌洗治疗PAP的效果。结果:PAP患者常见临床症状为咳嗽和进行性呼吸困难,体征正常或无特异性。胸部CT可表现为“地图样”、“铺路石样”或间质纤维化改变。全肺灌洗治疗的14例患者临床症状明显缓解。结论:肺泡蛋白沉积症虽然少见,但只要提高认识,诊断并不困难。支气管肺泡灌洗和(或)肺活检是确诊PAP的重要方法,全肺灌洗是治疗PAP的主要方法。

Efficacy and Safety of Whole Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis

Objective To evaluate the efficacy and safety of whole lung lavage in the treatment of pulmonary alveolar proteinosis ( PAP) .Methods Twelve patients who were diagnosed as PAP from September 2008 to October 2011 in Hunan Occupational Disease Hospital were recruited in the study. The changes of dyspnea symptom, lung-function, arterial blood gas, and chest image were compared before and after whole lung lavage treatment. Meanwhile, the safety of lung lavage was evaluated. Results All patients were relieved from dyspnea. The lung function, hypoxia, hyperventilation, and chest image were all obviously improved. The vital signs in the process of lung lavage were stable without serious complications. Conclusion Whole lung lavage is an effective and safe treatment for PAP.

Three cases of pulmonary tuberculosis misdiagnosed as pulmonary alveolar proteinosis

ObjectiveThree cases of pulmonary tuberculosis misdiagnosed as pulmonary alveolar proteinosis were reported and analyzed in combination with literatures, so as to improve the ability of differential diagnosis of these two diseases. MethodsThe clinical data of 3 cases of pulmonary tuberculosis patients which were diagnosed by pathology whose imaging manifestations were similar to those of pulmonary alveolar proteinosis were collected and reviewed in combination with relevant literature. ResultsAll the 3 patients were male, with a chronic course , no typical clinical manifestations of pulmonary tuberculosis, CT imaging showed diffuse glass grinding shadow, thickened pulmonary lobular septa ,showed "Crazy-paving pattern". ALL the three patients were considered as " pulmonary alveolar proteinosis" initially, and finally confirmed by lung biopsy or acid-resistant bacilli found by bronchoalveolar lavage. Reviewing 8 literature reports with similar imaging findings, 1 case was misdiagnosed as pulmonary alveolar proteinosis, 3 cases were pulmonary alveolar proteinosis combined with pulmonary tuberculosis, and 4 cases were secondary pulmonary alveolar proteinosis. It was found that most patients had systemic or respiratory symptoms of pulmonary tuberculosis. CT images mainly showed diffuse ground glass shadows in bilateral lungs with thickening of lobular septa, and 3 patients also showed clustered small nodulars. Most patients improved after anti-tuberculosis treatment, with only one patient dying. ConclusionsThe imaging manifestations of atypical pulmonary tuberculosis are various, which are easy to be misdiagnosed when they are similar to " pulmonary alveolar proteinosis". Clinicians should raise their awareness of tuberculosis with this imaging characteristic.

Pneumocystis jirovecii colonization in patients with pulmonary alveolar proteinosis

Objective To investigate the colonization, risk factors and prognosis of Pneumocystis jirovecii (P.jirovecii) colonization in patients with Pulmonary alveolar proteinosis (PAP). Methods The patients with Pulmonary alveolar proteinosis who were admitted to the Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital from March 2019 to December 2022 were retrospectively analyzed. Polymerase chain reaction/next-generation metagenomic sequencing were used to detect the colonization of P. jirovecii in bronchoalveolar lavage fluid, and then to investigate the colonization rate, risk factors and outcome of P. jirovecii in PAP patients. Results A total of 25 patients were included in the study, of which 7 were colonized by P. jirovecii (28.0%). The rate of using antibiotics before admission in the colonizing group was significantly higher than that in the non-colonizing group (85.7% vs 33.3%, P=0.030). Total blood lymphocytes (1.4×109/L vs. 1.8×109/L, P=0.048), CD3+T cells (0.83×109/L vs. 1.34×109/L, P=0.010), CD4+T cells (0.48×109/L vs. 0.85×109/L, P=0.010) were significantly lower than those in the non-colonizing group, lactate dehydrogenase (469.9 U/L vs. 277.3 U/L, P=0.005) was significantly higher than those in the non-colonizing group. A higher proportion of colonizing group required combination therapy (57.1% vs. 11.1%, P=0.032); but there was no significant difference in the percentage of whole-lung ground-glass opacification, lung function, oxygen index and outcome. Lactate dehydrogenase was positively correlated with the percentage of whole-lung ground-glass opacification of PAP, but negatively correlated with oxygen index, percentage of predicted forced vital capacity and percentage of predicted diffusion capacity for carbon monoxide. Conclusions The colonization rate of P. jirovecii in PAP patients was high. Reduced lymphocyte count in peripheral blood of PAP patients and antibiotic use before diagnosing were risk factors for P. jirovecii colonization.

局部肺叶灌洗治疗合并呼吸衰竭的重症肺泡蛋白沉积症三例并文献复习

目的探讨局部肺叶灌洗治疗合并呼吸衰竭的重症肺泡蛋白沉积症（pulmonary alveolar proteinosis，PAP）的可行性及安全性。方法回顾3例合并呼吸衰竭的PAP患者通过局部肺叶灌洗后逐渐自愈的诊治经过，并复习相关中外文献进行总结分析。结果3例患者均为男性，年龄50～55岁，有长期的粉尘、生物燃料或者消毒物质的密切接触史，以“咳嗽、呼吸困难”入院。入院时呼吸空气动脉血气分析均提示I型呼吸衰竭，胸部高分辨率CT（high-resolution computed tomography，HRCT）呈“铺路石征”；1例患者取支气管肺泡灌洗液、2例患者取支气管镜肺活检行过碘酸–雪夫染色结果均为阳性而确诊PAP。2例患者接受了1次局部肺叶灌洗，1例患者接受了2次局部肺叶灌洗，灌洗后1～5 d复查胸部HRCT与灌洗前相仿，但呼吸困难症状均较前明显改善，动脉血气分析提示呼吸衰竭纠正。出院后密切随诊1～6个月，患者均无呼吸困难复发，胸部HRCT提示双肺弥漫性斑片影几乎全部吸收。截止到2021年1月，在中国知网、维普、万方等数据库以“肺泡蛋白沉积症”和“支气管肺泡灌洗”为检索词，在PubMed数据库以“pulmonary alveolar proteinosis”和“lobar lavage”为关键词，共检索到相关中英文文献64篇，其中合并呼吸衰竭的重症PAP患者43例。大部分报道是利用反复、多次的局部肺叶灌洗，将双肺的所有肺叶逐一进行灌洗，最多者局部肺叶灌洗次数多达20次，时间跨度达4个月；一些研究是将局部肺叶、肺段灌洗作为“预洗”或者“桥梁”，改善临床症状后再进行全肺灌洗；一些研究对比了接受全肺灌洗或肺叶灌洗患者的治疗效果，认为两者疗效相仿，大部分患者仅需要1次灌洗，临床症状即有明显改善。结论肺叶局部灌洗治疗合并呼吸衰竭的重症PAP是安全有效的，同时在1～2次局部肺叶灌洗后，1～6个月随访PAP患者病情呈自愈倾向，短时间内反复、多次灌洗可能是不必要的。

粒细胞-巨噬细胞集落刺激因子吸入治疗肺泡蛋白沉积症两例

全肺灌洗治疗肺泡蛋白沉积症2例

【摘要】 目的 探讨全肺灌洗术在肺泡蛋白沉积症治疗的临床应用价值。方法 全麻下行双腔支气管导管全肺灌洗术。结果 两例肺泡蛋白沉积症患者各经5次全肺灌洗，疗后症状、血气、血乳酸脱氢酶及胸部CT均有好转。结论 全肺灌洗是治疗肺泡蛋白沉积症的有效方法。

The Value of Serum KL-6 Level as An Diagnostic Indicator in Patients with Interstitial Lung Diseases

ObjectiveTo determine the diagnostic value of serum KL-6 level in patients with interstitial lung diseases (ILD). MethodsAll the ILD patients enrolled were hospitalized from April 2013 to April 2014. Patients with other pulmonary diseases and healthy subjects were chosen as control groups simultaneously. Serum KL-6 concentrations were measured by chemiluminescent enzyme immunoassay. The association with serum KL-6 level and pulmonary function was analyzed. ResultsThere were 149 ILD patients, 155 patients with other pulmonary diseases, and 64 healthy subjects. The average serum levels of KL-6 were (1 801.86±2 831.36) U/mL, (267.00±124.41) U/mL, (201.28±81.18) U/mL in the patients with ILD, the patients with other pulmonary diseases and the healthy controls, respectively. The sensitivity and the specificity of the serum KL-6 for the diagnosis of ILD was 83.89% and 92.24% respectively when the cut-off level was set at 500 U/mL. The Kappa value was 0.767 (P < 0.001). The best cut-off value of KL-6 was 469.5 U/mL. Serum KL-6 levels in the patients with ILD were significantly higher compared with the patients with chronic obstructive pulmonary disease, pneumonia, tuberculosis, bronchiectasis and the healthy controls, respectively (all P < 0.001). The KL-6 levels in the pulmonary alveolar proteinosis patients were significantly higher compared with the patients with cryptogenic organizing pneumonia (COP), the patients with idiopathic pulmonary fibrosis (IPF) and the patients with connective tissue disease (CTD-ILD) (all P < 0.001). While the KL-6 concentration in IPF and CTD-ILD were significantly higher than that in COP (P=0.003 and P=0.008, respectively). Significant negative correlations were found between the levels of serum KL-6 and vital capacity as a percentage of the predicted value, forced vital capacity as a percentage of the predicted value, forced expiratory volume in one second as a percentage of the predicted value and carbon monoxide diffusing capacity as a percentage of the predicted value (all P < 0.001). Follow-up study showed the levels of serum KL-6 were consistent with clinical efficacy. ConclusionSerum KL-6 level is a reliable serum marker for ILD, and is related with the severity of disease and clinical efficacy.

吸入粒/ 巨噬细胞刺激因子治疗肺泡蛋白沉积症（ Inhaled granulocyte /macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis

吸入粒/ 巨噬细胞刺激因子治疗肺泡蛋白沉积症（ Inhaled granulocyte /macrophage-colony stimulating factor as therapy for pulmonary alveolar proteinosis 【摘要翻译】 研究理由: 吸入粒/ 巨噬细胞刺激因子( GM-CSF) 治疗肺泡蛋白沉积症( PAP) 虽具有一定前途, 但目前研究较少。目的: 评估吸入GM-CSF 治疗无缓解或进展的PAP患者的有效性和安全性。方法: 我们在全日本9 个呼吸病中心进行了多中心、自身对照的Ⅱ期临床研究。对有肺活检或细胞学依据诊断为PAP, 且血清GM-CSF 抗体升高、PaO2 小于75 mm Hg患者进行为期12 周的观察。排除在观察期中有改善的患者( 即肺泡-动脉血氧分压差下降大于10 mm Hg) 。其余患者随后给予治疗并随访52 周, 治疗包括先给予高剂量( 第1 ～8 d每天250 μg, 第9 ～14 d不给药; 如此6 个周期共12 周) , 然后给予低剂量维持( 第1 ～5 d 每天125 μg, 第5 ～14 d不给药; 如此6 个周期共12 周) 。检测和主要结果: 研究共纳入55 例PAP 患者。观察期内共排除11例, 其中9 例患者改善, 2 例退出。余下的35 例患者完成了高剂量和低剂量治疗,24 例改善, 总的有效率达到62% ( 24 /35, 意向治疗分析) , 肺泡-动脉血氧分压差降低12. 3 mm Hg( 95% CI 8. 4 ～16. 2, n =35, P lt;0. 001) 。未发现明显不良反应, 血清GM-CSF 抗体水平无明显变化。肺弥散功能检测发现肺泡-动脉血氧分压差改善与治疗相关。高分辨率CT 也证实该治疗可改善肺的磨砂玻璃样改变。35 例患者中的29例在1 年内未进行进一步治疗但病情维持稳定。结论: 吸入GM-CSF 是一种治疗自身免疫性PAP 持续有效的安全方法。 【述评】 PAP是一种少见疾病, 自身免疫性PAP 主要是体内GM-CSF 自身抗体水平升高, 中和了GM-CSF 的, 影响巨噬细胞清除肺泡表面物质, 导致其在肺泡的堆积。临床常通过纤维支气管镜进行全肺灌洗以清除堆积的肺泡表面物质, 但需要反复进行这种有创操作, 并且不适合于重症患者。另外, 灌洗后肺内残留大量液体, 需几天才能完全吸收,部分患者难以耐受。此研究报道的吸入GM-CSF 治疗自身免疫性PAP疗效较好, 患者呼吸困难症状、需要吸氧的比例均较治疗前明显改善, 且无明显的不良反应, 可免除患者进行纤维支气管镜治疗之苦, 值得推广。患者平均动脉氧分压在60 mm Hg左右, 对动脉氧分压更低的患者效果如何值得研究。与治疗有效的患者相比, PaCO2 增高的患者疗效较差, 估计和患者肺功能较差有关。由于本病发病率低, 故该研究纳入样本较小, 需进一步扩大样本量, 并在更长时间观察其疗效和安全性。

Secondary Pulmonary Alveolar Proteinosis Associated with Hematological Malignancy: Three Cases Report and Literature Review

ObjectiveTo highlight the characteristics of secondary pulmonary alveolar proteinosis (PAP) associated with malignant hematological diseases. MethodsThe clinical data of three patients with secondary PAP were analyzed and the related literature was reviewed. ResultsThree patients were diagnosed with secondary PAP by exclusion of primary or autoimmune PAP and denied the history of inhalation of occupational dusts. Two patients with secondary PAP were associated with chronic myelocytic leukemia, and the third one was associated with myelodysplastic syndrome. The performance on HRCT of the PAP associated with hematological malignancy was different from the primary PAP. Three patients were pathologically diagonised by brochoalveolar lavage fluid. One patient was successfully treated with inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF). ConclusionsSecondary PAP associated with hematological malignancy is very rare. The untypical HRCT is the main cause of misdiagnosis. Some patients may benefit from GM-CSF theatment.