American Journal of Therapeutics 0, 1–9 (2015)
Efficacy of Whole-Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis Hai-tao Zhang, MM, Chun Wang, MM, Cai-ying Wang, MM, Shen-cun Fang, MD, Bin Xu, MD, and Ying-ming Zhang, MD*
The aim of the study was to investigate the therapeutic effect of whole-lung lavage (WLL) for pulmonary alveolar proteinosis (PAP). The cohort studies that investigated the therapeutic effect of WLL for PAP were selected strictly on the basis of the inclusion and exclusion criteria. The statistical analysis was performed using STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Twelve studies were included in this meta-analysis. Totally, 206 PAP patients who received WLL were recruited in the 12 studies. We compared the differences in blood gas analysis and lung function before and after the treatment in this meta-analysis. The results indicated that there were statistical differences in the levels of diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen after the treatment of WLL for patients with PAP, whereas there were no evident differences in the levels of arterial partial pressure of carbon dioxide and arterial oxygen saturation. In conclusion, WLL can evidently improve the diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen of patients with PAP, thus WLL may be an important treatment of PAP. Keywords: whole-lung lavage, pulmonary alveolar proteinosis, alveoli, arterial partial pressure of oxygen, carbon monoxide diffusion capacity, forced expiratory volume in 1 second, forced vital capacity, meta-analysis
INTRODUCTION Pulmonary alveolar proteinosis (PAP), known as a kind of uncommon lung disease with unknown etiology, is featured by filling of the alveola with protein, phospholipid, and some other floccular material, which stains with periodic acid–Schiff (PAS).1 The PAS-positive proteinaceous materials is made up primarily of lipoprotein together with surfactant-like material and damages gas exchange due to
Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China. The authors have no conflicts of interest to declare. *Address for correspondence: Ying-ming Zhang, MD, Nine Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China. E-mail: [email protected]
alveolar filling, alveolar membrane fibrosis, or alveolar thickening.2 It is estimated that the incidence of PAP all over the world is approximately 0.2/1,000,000 people every year, with a morbidity rate of 3.7/1,000,000.3 There was also a study indicating that incidence and morbidity were higher and amounted to 0.49 and 6.2 per 1,000,000 people, respectively, in the general population.4 The clinical characteristics of PAP are the PAS-positive lipoproteinaceous material accumulation, mainly surfactant apoproteins and phospholipid surfactants, in the distal air spaces, leading to the damage of gas transfer.2,5 According to the clinical observation, patients with PAP may usually suffer from aggravating cough and dyspnea, which might be along with exacerbated hypoxia.6 The course of PAP is variable, which range from a spontaneous improvement to a progressive deterioration that result in high death rate.7 The confirmed diagnosis of PAP is performed through the usage of findings in sputum, lung
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Zhang et al
2
washings, and lung biopsy specimens under the typical electron microscopic, without which the circumstance is often misdiagnosed as an interstitial lung disease, especially sarcoidosis.8 As for the etiology of PAP, environmental exposures, hematologic, or neoplastic disorders together with immunodeficiency states can result in limitation on the function of alveolar macrophages, leading to the development of PAP.9 There have been several different therapies applied over the years for the treatment of PAP, for instance, antibiotics, postural drainage, and the intermittent positive pressure breathing.8 Major improvements were accomplished by Tanaka et al and Kitamura et al, who designated the appearance of autoantibodies neutralizing granulocyte–macrophage colony-stimulating factor in serum and the lung tissue of idiopathic PAP patients in the late 90s, and since then several specific treatments were endeavored or introduced.10,11 However, despite this, whole-lung lavage (WLL) still remains the standard treatment of patients with PAP, which was adjusted subsequently after the original description by Ramirez et al in 1963 and was still the gold-standard therapy for PAP.12 As a matter of fact, this technique has been much improved over the past years, thus enhancing the effective removal of material from the alveoli.13 WLL for patients with PAP is considered as a procedure with security in an experienced setting and can supply the majority of patients long-lasting benefits at present (http://link. springer.com.proxy.its.virginia.edu/chapter/10.1007/ 978-1-4614-4292-9_71).14 However, in severe cases of PAP, WLL was also considered potentially harmful for the poor outcomes.15 Consequently, we aimed to explore whether WLL could be a good selection in the therapy for patients with PAP through meta-analysis.
MATERIALS AND METHODS Search strategy To collect all the relevant published studies, PubMed, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Wanfang database, China National Knowledge Infrastructure, and VIP database were searched (last updated search in October, 2014), utilizing selected common key words concerning PAP and WLL. As for the key words to be applied in the initial literature search, we selected (“pulmonary alveolar proteinosis” or “alveolar proteinosis, pulmonary” or “alveolar proteinoses, pulmonary” or “PAP”), (“bronchoalveolar lavage” or “lung lavage” or “bronchoalveolar lavage” or “bronchopulmonary lavage” or “bronchial lavage”) as a highly sensitive search strategy. No language American Journal of Therapeutics (2015) 0(0)
restriction was applied in including the relevant article. We also further scanned the bibliographies of relevant articles manually to identify additional potential relevant articles. Inclusion and exclusion criteria Studies were considered eligible for inclusion if they met the following criteria: (1) the cohort studies using WLL in the treatment of PAP, (2) included subjects were all patients with PAP, (3) included literature supplied complete data including number of cases, age, race, gender, pathological types, arterial partial pressure of oxygen (PaO2), carbon monoxide diffusion capacity (DLCO), the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and so on, (4) after careful reexamination, only the latest or complete study was included when the extracted studies were published by the same authors. Studies were excluded if (1) the articles were not related to the research topic, (2) there were no comparison between the curative effect of WLL before and after treatment, (3) the clinicopathologic data in articles were incomplete, unavailable, or inappropriate, (4) the articles were not in Chinese or English, (5) the articles were published repeatedly. Data extraction and quality evaluation Two investigators extracted information from the retrieved articles according to the selection criteria separately. Review reports of the 2 were then compared to identify any inconsistency, and differences were resolved by further discussion and reexaminations. The following relevant data were extracted from the eligible studies prospectively in the final analyses: surname of first author, country of origin, year of publication, language, ethnicity, study design, sample size, age, and pathological types. To decide whether the study in question is of high quality, 2 reviewers independently assessed the methodological quality of the included trials based on the Newcastle–Ottawa scale (NOS) criteria.16 The NOS criteria were displayed as follow: (1) selection of the cohort: representativeness of the exposed cohort (NOS1), selection of the nonexposed cohort (NOS2), ascertainment of exposure (NOS3), demonstration that outcome of interest was not present at the start of the study (NOS4), (2) comparability of the cohorts: whether the study was selected and analyzed according to the most important factor (NOS5), whether the study controlled other confounding factors (NOS6), and (3) assessment of outcome: was follow-up long enough for www.americantherapeutics.com
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Efficacy of WLL for PAP
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FIGURE 1. Flow chart shows study selection procedure. Twelve cohort studies were included in this meta-analysis.
outcomes to occur (NOS8); adequacy of follow-up of cohorts (NOS9). Statistical analysis Statistical analyses were performed with the STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Standardized mean difference (SMDs) and its 95% confidence interval (95% CI) were calculated to evaluate the differences between the therapeutic effects with WLL in patients with PAP. The www.americantherapeutics.com
statistical significance of pooled SMDs was estimated by the utilization of z test. We used Cochran’s Q statistic (P , 0.05 was considered significant) and I2 tests (0%, no heterogeneity; 100%, maximal heterogeneity) to quantify heterogeneity among studies.17 When there was great heterogeneity (Ph , 0.05 or I2 . 50%) among studies, a random effect model was used; otherwise, a fixed effect model was used.18,19 The 1-way sensitivity analysis was performed to evaluate whether the results could be affected significantly by deleting American Journal of Therapeutics (2015) 0(0)
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Zhang et al
4 Table 1. Baseline characteristics of eligible studies.
First author 28
Yang et al Zhou et al8 Fijolek et al4 Zhao and Zhu29 Ni et al25 Guan et al1 Lu et al24 Byun et al22 Fang23 Wang et al27 Sun26 Beccaria et al21
Year Country
Ethnicity
2014 China Asians 2014 China Asians 2014 Poland Caucasians 2013 China Asians 2013 China Asians 2012 China Asians 2010 China Asians 2010 Korea Asians 2009 China Asians 2008 China Asians 2008 China Asians 2004 Italy Caucasians
Language
Age, yr
Gender (M/F)
Number
Study design
NOS score
Chinese English English Chinese Chinese English Chinese English Chinese Chinese Chinese English
41.6 6 9.0 48.3 6 10.8 40.3 6 6.2 42.9 6 15.0 55.5 6 6.4 41.0 6 13.5 47.4 6 12.3 51.6 6 12.8 42.0 6 11.0 31.6 6 8.3 37.5 6 10.0 40.95
7/3 8/3 3/1 28/2 11/7 31/7 9/3 24/14 7/4 5/2 4/2 17/4
10 11 4 30 18 38 12 38 11 7 6 21
non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT RCT
6 7 7 6 6 7 6 7 6 6 6 7
F, female; M, male; RCT, randomized controlled trial.
a single study one by one to reflect the influence of the individual data on our meta-analysis. The funnel plot was performed to assess publication bias, which might affect the validity of the estimates. The symmetry of the funnel plot was further evaluated by Egger’s linear regression test.20 All tests were 2 sided, and a P value of ,0.05 was regarded as statistically significant.
of the included studies were shown in Table 1 and Figure 2, respectively. Therapeutic effect of WLL on PAP The heterogeneity test indicated that there was heterogeneity among included studies (DLCO: P , 0.001, I2 5 91.3%; FEV1: P , 0.001, I2 5 93.4%; FVC: P , 0.001,
RESULTS Baseline characteristics of included studies Initially, a total of 767 articles were selected from the 9 databases through screening the title and key words. Followed by excluding the duplicates (n 5 209), letters, reviews or meta-analysis (n 5 2), nonhuman studies (n 5 10), and the studies not related to research topics (n 5 511), the left studies (n 5 35) were reviewed, and additional 21 studies were excluded in that they were not case–control or cohort study (n 5 5), not relevant to WLL (n 5 7), or not relevant to PAP (n 5 9). After the remaining 14 trials being further reviewed, 2 studies were removed for not supplying enough information and final 12 eligible articles1,4,8,21–29 that published between 2004 and 2014 were enrolled in this meta-analysis. Two hundred six PAP patients who received WLL were included in those 12 studies, and we compared the differences in blood gas analysis and lung function before and after the treatment in this metaanalysis. In addition, as for the step of screening, a flow chart of the study selection process was shown in Figure 1. All baseline characteristics and NOS score American Journal of Therapeutics (2015) 0(0)
FIGURE 2. Quality assessment of all included studies by NOS. www.americantherapeutics.com
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Efficacy of WLL for PAP
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FIGURE 3. Forest plots of blood gas analysis and lung function differences in patients with PAP before and after WLL.
I2 5 75.2%; PaO2: P , 0.001, I2 5 78.5%; arterial partial pressure of carbon dioxide (PaCO2): P , 0.001, I2 5 90.8%; arterial oxygen saturation (SaO2): P 5 0.001, I2 5 91.5%); thus, a random effect model was applied to analysis. The results of this meta-analysis suggested there were statistical differences in the levels of DLCO, FEV1, FVC and PaO2 after the treatment of WWL for patients with PAP when compared with www.americantherapeutics.com
prior treatment (DLCO: SMD 5 1.71, 95%CI 5 0.87 ; 2.55; P , 0.001; FEV1: SMD 5 1.33, 95%CI 5 0.31 ; 2.35; P 5 0.010; FVC: SMD 5 0.71, 95%CI 5 0.21 ; 1.21; P 5 0.005; PaO2: SMD 5 1.77, 95%CI 5 1.18 ; 2.36; P , 0.001) (Figure 3A-D), while there was no evident differences in the levels of PaCO2 and SaO2 before and after the treatment of WLL (PaCO2: SMD 5 0.52, American Journal of Therapeutics (2015) 0(0)
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FIGURE 4. Sensitiveness analysis of blood gas analysis and lung function differences in patients with PAP before and after WLL. American Journal of Therapeutics (2015) 0(0)
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Efficacy of WLL for PAP
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FIGURE 5. Publication bias of blood gas analysis and lung function differences in patients with PAP before and after WLL.
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95%CI 5 21.20 ~ 2.24; P 5 0.553; SaO2: SMD 5 2.29, 95%CI 5 20.72 ~ 5.30; P 5 0.136) (Figure 3E-F). Sensitivity analysis and publication bias A leave-one-out sensitivity analysis was carried out to evaluate whether the present meta-analysis is stable. Each study enrolled in our meta-analysis was evaluated one by one to reflect the effect the significance of pooled SMDs. The overall statistical significance does not change when any single study was omitted (Figure 4A-F). The shapes of the funnel plots of the levels of FEV1 and PaCO2 indicate symmetry. Thus, Egger’s test was used to provide statistical evidence of funnel plot symmetry and also did not show any evidence of publication bias in the levels of FEV1 and PaCO2 (P . 0.05) (Figure 5B, E), while Egger’s test on levels of DLCO, FVC and PaO2 suggested publication bias (P , 0.05) (Figure 5A, C, D). Because there were only two included studies explored the levels of SaO2, the specific P value was not available and thereby the publication bias in level of SaO2 couldn’t be obtained (as shown in Figure 5F).
DISCUSSION PAP, as a rare disorder of unknown etiology, has variable natural courses, which might range from respiratory failure to spontaneous resolution with high mortality rate.30 To our knowledge, it was first described by Rosen in 1958, and until today, no more than 500 cases have been revealed in the literature. PAP is featured by the accumulation of lipid and proteinaceous material within alveolus, which is PAS positive when observed with light microscopy.31 Clinically, PAP is correlated with an increased work of breathing and disturbance of gas exchange.30 Moreover, congenital, acquired, and secondary PAPs are the 3 distinct types of PAP described, and each with different etiology, course, therapy, and outcomes.32 WLL has been considered as a well-established method in the treatment of PAP that was described by RamirezRivera.33 But there has been controversy on therapeutic effect of WLL in patients with PAP; therefore, we explored whether WLL could be an effective treatment of PAP on the basis of previous relevant studies. We investigated the therapeutic effect of WLL on PAP patients with regard to levels of DLCO, FEV1, FVC, PaO2, PaCO2, and SaO2. According to the results of this meta-analysis, we found that there were significant improvements in DLCO, FEV1, FVC, and PaO2 of PAP patients, suggesting that WLL could be considered as an important therapy for PAP. WLL, as American Journal of Therapeutics (2015) 0(0)
a treatment of PAP, is a procedure that each lung is lavaged sequentially with abundant amount of sediment to remove from the alveoli in which proteinaceous material may contribute to the disease.11,34 Therefore, WLL is a distinctive human model of very controlled changes of air content in lung, where the status of lung in different stages of PAP, conceptually, closely appears multiple pathological conditions: first, deaeration of nonventilated lung composes the model of undergoing reabsorption atelectasis; second, alveolar flooding with saline exhibits the model of consolidation; last but not least, a model of pulmonary edema and the progressive resolution is set up in the recovery phase when the treated lung begin to reventilate, following the treatment with positive end-expiratory pressure and diuretics accelerate the removal of saline.35 Efficacy of WLL utilizing a double-lumen tube has been attributed not only in removing the lipoproteinaceous materials from alveolar spaces but also in the removal of alveolar macrophages, anti granulocyte–macrophage colonystimulating factor antibodies, and type II epithelial cells.36,37 In view of these advantages of WLL, it has been a well-established gold treatment for patients with PAP, which is consistent with the result revealed by this meta-analysis.12 Of note, there were also some limitations in this meta-analysis. First, the sample size of included studies was relatively small, which could influence the overall results related to the therapy of WLL. Second, data of relevant parameters in included studies might have been lost, and it might also affect the final result. Third, most of the included studies investigated the therapy of WLL in China; there might be some deviation in the results of the present analysis due to the geographical restrictions. In summary, we considered that WLL might be a good selection in the therapy of patients with PAP on account of the significant improvement in DLCO, FEV1, FVC, and PaO2.
ACKNOWLEDGMENTS The authors acknowledge the helpful comments on this paper received from our reviewers.
DISCLOSURE Key Medical Project of Nanjing City Board of Health: The research of whole-lung lavage in clinical application, Item No.ZKY12036. www.americantherapeutics.com
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Efficacy of WLL for PAP
REFERENCES 1. Guan Y, Zeng Q, Yang H, et al. Pulmonary alveolar proteinosis: quantitative CT and pulmonary functional correlations. Eur J Radiol. 2012;81:2430–2435. 2. Sadeghi HA. Segmental lung lavage with fiberoptic bronchoscopy in a patient with special presentation of pulmonary alveolar proteinosis. Tanaffos. 2013;12: 48–52. 3. Wang T, Lazar CA, Fishbein MC, et al. Pulmonary alveolar proteinosis. Semin Respir Crit Care Med. 2012;33: 498–508. 4. Fijolek J, Wiatr E, Radzikowska E, et al. Pulmonary alveolar proteinosis during a 30-year observation. Diagnosis and treatment. Pneumonol Alergol Pol. 2014;82:206–217. 5. Gu P, Fang X, Luo B, et al. A noninvasive examination for the diagnosis of pulmonary alveolar proteinosis: induced sputum in conjunction with transmission electron microscopy. Int J Clin Exp Pathol. 2014;7:1200–1205. 6. Patel SM, Sekiguchi H, Reynolds JP, et al. Pulmonary alveolar proteinosis. Can Respir J. 2012;19:243–245. 7. Shende RP, Sampat BK, Prabhudesai P, et al. Granulocyte macrophage colony stimulating factor therapy for pulmonary alveolar proteinosis. J Assoc Physicians India. 2013;61:209–211. 8. Zhou X, Lu G, Yu Z, et al. Long-term follow-up of whole lung lavage in patients with pulmonary alveolar proteinosis. Exp Ther Med. 2014;8:763–768. 9. Hasan N, Bagga S, Monteagudo J, et al. Extracorporeal membrane oxygenation to support whole-lung lavage in pulmonary alveolar proteinosis: salvage of the drowned lungs. J Bronchology Interv Pulmonol. 2013;20:41–44. 10. Nakamura A, Ebina-Shibuya R, Itoh-Nakadai A, et al. Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function. J Exp Med. 2013;210:2191–2204. 11. Ben-Dov I, Segel MJ. Autoimmune pulmonary alveolar proteinosis: clinical course and diagnostic criteria. Autoimmun Rev. 2014;13:513–517. 12. Gao F, Lu GC, Zhou XY, et al. Repeated whole-lung lavage for unremitting pulmonary alveolar proteinosis: a eight-year follow-up of a case. Genet Mol Res. 2014;13: 6135–6141. 13. Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol. 2014;32:635–657. 14. Morgan RK, Ernst A. Interventional chest procedures in pregnancy. Clin Chest Med. 2011;32:61–74, viii. 15. Leth S, Bendstrup E, Vestergaard H, et al. Autoimmune pulmonary alveolar proteinosis: treatment options in year 2013. Respirology. 2013;18:82–91. 16. da Costa AG, Gago MF, Garrett C. Cerebrospinal fluid biomarkers for the early diagnosis of Parkinson’s disease [in Portuguese]. Acta Med Port. 2011;24(suppl 4): 761–768. 17. Zintzaras E, Ioannidis JP. HEGESMA: genome search meta-analysis and heterogeneity testing. Bioinformatics. 2005;21:3672–3673. www.americantherapeutics.com
9 18. Zintzaras E, Ioannidis JP. Heterogeneity testing in metaanalysis of genome searches. Genet Epidemiol. 2005;28: 123–137. 19. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558. 20. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634. 21. Beccaria M, Luisetti M, Rodi G, et al. Long-term durable benefit after whole lung lavage in pulmonary alveolar proteinosis. Eur Respir J. 2004;23:526–531. 22. Byun MK, Kim DS, Kim YW, et al. Clinical features and outcomes of idiopathic pulmonary alveolar proteinosis in Korean population. J Korean Med Sci. 2010;25:393–398. 23. Fang X-Q. Eleven cases analysis of pulmonary alveolar proteinosis. J Clin Intern Med. 2009;26:623–625. 24. Lu G-F, Zhang Y-F, Weng H-W, et al. Strategies of monitoring patients with pulmonary alveolar proteinosis treated by whole lung lavage. Mod Clin Nurs. 2010;09: 58–59. 25. Ni X-H, Jiao Y, Zhu P, et al. The clinical analysis of the whole lung lavage surgical treatment of 18 cases of pulmonary alveolar proteinosis under general anesthesia state. J Med Theor Prac. 2013;26:150–151. 26. Sun Y-X. Large capacity whole lung lavage in patients with pulmonary alveolar proteinosis care. Chin J Pract Nurs. 2008;24:24–25. 27. Wang X-J, Lin C-X, Liu J-C, et al. Large capacity whole lung lavage treatment of pulmonary alveolar proteinosis anesthetic management. Guangxi Med J. 2008;30:362–363. 28. Yang J, Jiang D, Lu J-C, et al. Efficacy of the treatment of 10 cases of pulmonary alveolar proteinosis large capacity whole lung lavage. Zhejiang Clin Med J. 2014;16:397–398. 29. Zhao H-c, Zhu Q-s. Effect of whole lung lavage therapy at the same period on pulmonary alveolar proteinosis disease. Pract J Clin Med. 2013;10:88–90. 30. Jayaraman S, Gayathri AR, Senthil Kumar P, et al. Whole lung lavage for pulmonary alveolar proteinosis. Lung India. 2010;27:33–36. 31. Choi YR, Chang YJ, Kim SW, et al. Crazy paving radiography finding in asymptomatic pulmonary alveolar proteinosis. Asian Cardiovasc Thorac Ann. 2014. 32. Hammami S, Harrathi K, Lajmi K, et al. Congenital pulmonary alveolar proteinosis. Case Rep Pediatr. 2013;2013: 764216. 33. Chan AK, Takano A, Hsu AL, et al. Pulmonary alveolar proteinosis. J Thorac Dis. 2014;6:E77–E80. 34. Cai C, Ye M, Xu H, et al. Pulmonary alveolar proteinosis treatment by whole-lung lavage. Postgrad Med J. 2012;88: 492–493. 35. Via G, Lichtenstein D, Mojoli F, et al. Whole lung lavage: a unique model for ultrasound assessment of lung aeration changes. Intensive Care Med. 2010;36:999–1007. 36. Michaud G, Reddy C, Ernst A. Whole-lung lavage for pulmonary alveolar proteinosis. Chest. 2009;136:1678–1681. 37. Silva A, Moreto A, Pinho C, et al. Bilateral whole lung lavage in pulmonary alveolar proteinosis—a retrospective study. Rev Port Pneumol. 2014;20:254–259. American Journal of Therapeutics (2015) 0(0)
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Efficacy of Whole-Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis Hai-tao Zhang, MM, Chun Wang, MM, Cai-ying Wang, MM, Shen-cun Fang, MD, Bin Xu, MD, and Ying-ming Zhang, MD*
The aim of the study was to investigate the therapeutic effect of whole-lung lavage (WLL) for pulmonary alveolar proteinosis (PAP). The cohort studies that investigated the therapeutic effect of WLL for PAP were selected strictly on the basis of the inclusion and exclusion criteria. The statistical analysis was performed using STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Twelve studies were included in this meta-analysis. Totally, 206 PAP patients who received WLL were recruited in the 12 studies. We compared the differences in blood gas analysis and lung function before and after the treatment in this meta-analysis. The results indicated that there were statistical differences in the levels of diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen after the treatment of WLL for patients with PAP, whereas there were no evident differences in the levels of arterial partial pressure of carbon dioxide and arterial oxygen saturation. In conclusion, WLL can evidently improve the diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen of patients with PAP, thus WLL may be an important treatment of PAP. Keywords: whole-lung lavage, pulmonary alveolar proteinosis, alveoli, arterial partial pressure of oxygen, carbon monoxide diffusion capacity, forced expiratory volume in 1 second, forced vital capacity, meta-analysis
INTRODUCTION Pulmonary alveolar proteinosis (PAP), known as a kind of uncommon lung disease with unknown etiology, is featured by filling of the alveola with protein, phospholipid, and some other floccular material, which stains with periodic acid–Schiff (PAS).1 The PAS-positive proteinaceous materials is made up primarily of lipoprotein together with surfactant-like material and damages gas exchange due to
Nine Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing, China. The authors have no conflicts of interest to declare. *Address for correspondence: Ying-ming Zhang, MD, Nine Department of Respiratory Medicine, Nanjing Chest Hospital, 215 Guangzhou Road, Nanjing, 210029, China. E-mail: [email protected]
alveolar filling, alveolar membrane fibrosis, or alveolar thickening.2 It is estimated that the incidence of PAP all over the world is approximately 0.2/1,000,000 people every year, with a morbidity rate of 3.7/1,000,000.3 There was also a study indicating that incidence and morbidity were higher and amounted to 0.49 and 6.2 per 1,000,000 people, respectively, in the general population.4 The clinical characteristics of PAP are the PAS-positive lipoproteinaceous material accumulation, mainly surfactant apoproteins and phospholipid surfactants, in the distal air spaces, leading to the damage of gas transfer.2,5 According to the clinical observation, patients with PAP may usually suffer from aggravating cough and dyspnea, which might be along with exacerbated hypoxia.6 The course of PAP is variable, which range from a spontaneous improvement to a progressive deterioration that result in high death rate.7 The confirmed diagnosis of PAP is performed through the usage of findings in sputum, lung
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www.americantherapeutics.com
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Zhang et al
2
washings, and lung biopsy specimens under the typical electron microscopic, without which the circumstance is often misdiagnosed as an interstitial lung disease, especially sarcoidosis.8 As for the etiology of PAP, environmental exposures, hematologic, or neoplastic disorders together with immunodeficiency states can result in limitation on the function of alveolar macrophages, leading to the development of PAP.9 There have been several different therapies applied over the years for the treatment of PAP, for instance, antibiotics, postural drainage, and the intermittent positive pressure breathing.8 Major improvements were accomplished by Tanaka et al and Kitamura et al, who designated the appearance of autoantibodies neutralizing granulocyte–macrophage colony-stimulating factor in serum and the lung tissue of idiopathic PAP patients in the late 90s, and since then several specific treatments were endeavored or introduced.10,11 However, despite this, whole-lung lavage (WLL) still remains the standard treatment of patients with PAP, which was adjusted subsequently after the original description by Ramirez et al in 1963 and was still the gold-standard therapy for PAP.12 As a matter of fact, this technique has been much improved over the past years, thus enhancing the effective removal of material from the alveoli.13 WLL for patients with PAP is considered as a procedure with security in an experienced setting and can supply the majority of patients long-lasting benefits at present (http://link. springer.com.proxy.its.virginia.edu/chapter/10.1007/ 978-1-4614-4292-9_71).14 However, in severe cases of PAP, WLL was also considered potentially harmful for the poor outcomes.15 Consequently, we aimed to explore whether WLL could be a good selection in the therapy for patients with PAP through meta-analysis.
MATERIALS AND METHODS Search strategy To collect all the relevant published studies, PubMed, EBSCO, Ovid, SpringerLink, Wiley, Web of Science, Wanfang database, China National Knowledge Infrastructure, and VIP database were searched (last updated search in October, 2014), utilizing selected common key words concerning PAP and WLL. As for the key words to be applied in the initial literature search, we selected (“pulmonary alveolar proteinosis” or “alveolar proteinosis, pulmonary” or “alveolar proteinoses, pulmonary” or “PAP”), (“bronchoalveolar lavage” or “lung lavage” or “bronchoalveolar lavage” or “bronchopulmonary lavage” or “bronchial lavage”) as a highly sensitive search strategy. No language American Journal of Therapeutics (2015) 0(0)
restriction was applied in including the relevant article. We also further scanned the bibliographies of relevant articles manually to identify additional potential relevant articles. Inclusion and exclusion criteria Studies were considered eligible for inclusion if they met the following criteria: (1) the cohort studies using WLL in the treatment of PAP, (2) included subjects were all patients with PAP, (3) included literature supplied complete data including number of cases, age, race, gender, pathological types, arterial partial pressure of oxygen (PaO2), carbon monoxide diffusion capacity (DLCO), the forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and so on, (4) after careful reexamination, only the latest or complete study was included when the extracted studies were published by the same authors. Studies were excluded if (1) the articles were not related to the research topic, (2) there were no comparison between the curative effect of WLL before and after treatment, (3) the clinicopathologic data in articles were incomplete, unavailable, or inappropriate, (4) the articles were not in Chinese or English, (5) the articles were published repeatedly. Data extraction and quality evaluation Two investigators extracted information from the retrieved articles according to the selection criteria separately. Review reports of the 2 were then compared to identify any inconsistency, and differences were resolved by further discussion and reexaminations. The following relevant data were extracted from the eligible studies prospectively in the final analyses: surname of first author, country of origin, year of publication, language, ethnicity, study design, sample size, age, and pathological types. To decide whether the study in question is of high quality, 2 reviewers independently assessed the methodological quality of the included trials based on the Newcastle–Ottawa scale (NOS) criteria.16 The NOS criteria were displayed as follow: (1) selection of the cohort: representativeness of the exposed cohort (NOS1), selection of the nonexposed cohort (NOS2), ascertainment of exposure (NOS3), demonstration that outcome of interest was not present at the start of the study (NOS4), (2) comparability of the cohorts: whether the study was selected and analyzed according to the most important factor (NOS5), whether the study controlled other confounding factors (NOS6), and (3) assessment of outcome: was follow-up long enough for www.americantherapeutics.com
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Efficacy of WLL for PAP
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FIGURE 1. Flow chart shows study selection procedure. Twelve cohort studies were included in this meta-analysis.
outcomes to occur (NOS8); adequacy of follow-up of cohorts (NOS9). Statistical analysis Statistical analyses were performed with the STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Standardized mean difference (SMDs) and its 95% confidence interval (95% CI) were calculated to evaluate the differences between the therapeutic effects with WLL in patients with PAP. The www.americantherapeutics.com
statistical significance of pooled SMDs was estimated by the utilization of z test. We used Cochran’s Q statistic (P , 0.05 was considered significant) and I2 tests (0%, no heterogeneity; 100%, maximal heterogeneity) to quantify heterogeneity among studies.17 When there was great heterogeneity (Ph , 0.05 or I2 . 50%) among studies, a random effect model was used; otherwise, a fixed effect model was used.18,19 The 1-way sensitivity analysis was performed to evaluate whether the results could be affected significantly by deleting American Journal of Therapeutics (2015) 0(0)
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4 Table 1. Baseline characteristics of eligible studies.
First author 28
Yang et al Zhou et al8 Fijolek et al4 Zhao and Zhu29 Ni et al25 Guan et al1 Lu et al24 Byun et al22 Fang23 Wang et al27 Sun26 Beccaria et al21
Year Country
Ethnicity
2014 China Asians 2014 China Asians 2014 Poland Caucasians 2013 China Asians 2013 China Asians 2012 China Asians 2010 China Asians 2010 Korea Asians 2009 China Asians 2008 China Asians 2008 China Asians 2004 Italy Caucasians
Language
Age, yr
Gender (M/F)
Number
Study design
NOS score
Chinese English English Chinese Chinese English Chinese English Chinese Chinese Chinese English
41.6 6 9.0 48.3 6 10.8 40.3 6 6.2 42.9 6 15.0 55.5 6 6.4 41.0 6 13.5 47.4 6 12.3 51.6 6 12.8 42.0 6 11.0 31.6 6 8.3 37.5 6 10.0 40.95
7/3 8/3 3/1 28/2 11/7 31/7 9/3 24/14 7/4 5/2 4/2 17/4
10 11 4 30 18 38 12 38 11 7 6 21
non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT non-RCT RCT
6 7 7 6 6 7 6 7 6 6 6 7
F, female; M, male; RCT, randomized controlled trial.
a single study one by one to reflect the influence of the individual data on our meta-analysis. The funnel plot was performed to assess publication bias, which might affect the validity of the estimates. The symmetry of the funnel plot was further evaluated by Egger’s linear regression test.20 All tests were 2 sided, and a P value of ,0.05 was regarded as statistically significant.
of the included studies were shown in Table 1 and Figure 2, respectively. Therapeutic effect of WLL on PAP The heterogeneity test indicated that there was heterogeneity among included studies (DLCO: P , 0.001, I2 5 91.3%; FEV1: P , 0.001, I2 5 93.4%; FVC: P , 0.001,
RESULTS Baseline characteristics of included studies Initially, a total of 767 articles were selected from the 9 databases through screening the title and key words. Followed by excluding the duplicates (n 5 209), letters, reviews or meta-analysis (n 5 2), nonhuman studies (n 5 10), and the studies not related to research topics (n 5 511), the left studies (n 5 35) were reviewed, and additional 21 studies were excluded in that they were not case–control or cohort study (n 5 5), not relevant to WLL (n 5 7), or not relevant to PAP (n 5 9). After the remaining 14 trials being further reviewed, 2 studies were removed for not supplying enough information and final 12 eligible articles1,4,8,21–29 that published between 2004 and 2014 were enrolled in this meta-analysis. Two hundred six PAP patients who received WLL were included in those 12 studies, and we compared the differences in blood gas analysis and lung function before and after the treatment in this metaanalysis. In addition, as for the step of screening, a flow chart of the study selection process was shown in Figure 1. All baseline characteristics and NOS score American Journal of Therapeutics (2015) 0(0)
FIGURE 2. Quality assessment of all included studies by NOS. www.americantherapeutics.com
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Efficacy of WLL for PAP
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FIGURE 3. Forest plots of blood gas analysis and lung function differences in patients with PAP before and after WLL.
I2 5 75.2%; PaO2: P , 0.001, I2 5 78.5%; arterial partial pressure of carbon dioxide (PaCO2): P , 0.001, I2 5 90.8%; arterial oxygen saturation (SaO2): P 5 0.001, I2 5 91.5%); thus, a random effect model was applied to analysis. The results of this meta-analysis suggested there were statistical differences in the levels of DLCO, FEV1, FVC and PaO2 after the treatment of WWL for patients with PAP when compared with www.americantherapeutics.com
prior treatment (DLCO: SMD 5 1.71, 95%CI 5 0.87 ; 2.55; P , 0.001; FEV1: SMD 5 1.33, 95%CI 5 0.31 ; 2.35; P 5 0.010; FVC: SMD 5 0.71, 95%CI 5 0.21 ; 1.21; P 5 0.005; PaO2: SMD 5 1.77, 95%CI 5 1.18 ; 2.36; P , 0.001) (Figure 3A-D), while there was no evident differences in the levels of PaCO2 and SaO2 before and after the treatment of WLL (PaCO2: SMD 5 0.52, American Journal of Therapeutics (2015) 0(0)
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FIGURE 4. Sensitiveness analysis of blood gas analysis and lung function differences in patients with PAP before and after WLL. American Journal of Therapeutics (2015) 0(0)
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FIGURE 5. Publication bias of blood gas analysis and lung function differences in patients with PAP before and after WLL.
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95%CI 5 21.20 ~ 2.24; P 5 0.553; SaO2: SMD 5 2.29, 95%CI 5 20.72 ~ 5.30; P 5 0.136) (Figure 3E-F). Sensitivity analysis and publication bias A leave-one-out sensitivity analysis was carried out to evaluate whether the present meta-analysis is stable. Each study enrolled in our meta-analysis was evaluated one by one to reflect the effect the significance of pooled SMDs. The overall statistical significance does not change when any single study was omitted (Figure 4A-F). The shapes of the funnel plots of the levels of FEV1 and PaCO2 indicate symmetry. Thus, Egger’s test was used to provide statistical evidence of funnel plot symmetry and also did not show any evidence of publication bias in the levels of FEV1 and PaCO2 (P . 0.05) (Figure 5B, E), while Egger’s test on levels of DLCO, FVC and PaO2 suggested publication bias (P , 0.05) (Figure 5A, C, D). Because there were only two included studies explored the levels of SaO2, the specific P value was not available and thereby the publication bias in level of SaO2 couldn’t be obtained (as shown in Figure 5F).
DISCUSSION PAP, as a rare disorder of unknown etiology, has variable natural courses, which might range from respiratory failure to spontaneous resolution with high mortality rate.30 To our knowledge, it was first described by Rosen in 1958, and until today, no more than 500 cases have been revealed in the literature. PAP is featured by the accumulation of lipid and proteinaceous material within alveolus, which is PAS positive when observed with light microscopy.31 Clinically, PAP is correlated with an increased work of breathing and disturbance of gas exchange.30 Moreover, congenital, acquired, and secondary PAPs are the 3 distinct types of PAP described, and each with different etiology, course, therapy, and outcomes.32 WLL has been considered as a well-established method in the treatment of PAP that was described by RamirezRivera.33 But there has been controversy on therapeutic effect of WLL in patients with PAP; therefore, we explored whether WLL could be an effective treatment of PAP on the basis of previous relevant studies. We investigated the therapeutic effect of WLL on PAP patients with regard to levels of DLCO, FEV1, FVC, PaO2, PaCO2, and SaO2. According to the results of this meta-analysis, we found that there were significant improvements in DLCO, FEV1, FVC, and PaO2 of PAP patients, suggesting that WLL could be considered as an important therapy for PAP. WLL, as American Journal of Therapeutics (2015) 0(0)
a treatment of PAP, is a procedure that each lung is lavaged sequentially with abundant amount of sediment to remove from the alveoli in which proteinaceous material may contribute to the disease.11,34 Therefore, WLL is a distinctive human model of very controlled changes of air content in lung, where the status of lung in different stages of PAP, conceptually, closely appears multiple pathological conditions: first, deaeration of nonventilated lung composes the model of undergoing reabsorption atelectasis; second, alveolar flooding with saline exhibits the model of consolidation; last but not least, a model of pulmonary edema and the progressive resolution is set up in the recovery phase when the treated lung begin to reventilate, following the treatment with positive end-expiratory pressure and diuretics accelerate the removal of saline.35 Efficacy of WLL utilizing a double-lumen tube has been attributed not only in removing the lipoproteinaceous materials from alveolar spaces but also in the removal of alveolar macrophages, anti granulocyte–macrophage colonystimulating factor antibodies, and type II epithelial cells.36,37 In view of these advantages of WLL, it has been a well-established gold treatment for patients with PAP, which is consistent with the result revealed by this meta-analysis.12 Of note, there were also some limitations in this meta-analysis. First, the sample size of included studies was relatively small, which could influence the overall results related to the therapy of WLL. Second, data of relevant parameters in included studies might have been lost, and it might also affect the final result. Third, most of the included studies investigated the therapy of WLL in China; there might be some deviation in the results of the present analysis due to the geographical restrictions. In summary, we considered that WLL might be a good selection in the therapy of patients with PAP on account of the significant improvement in DLCO, FEV1, FVC, and PaO2.
ACKNOWLEDGMENTS The authors acknowledge the helpful comments on this paper received from our reviewers.
DISCLOSURE Key Medical Project of Nanjing City Board of Health: The research of whole-lung lavage in clinical application, Item No.ZKY12036. www.americantherapeutics.com
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Efficacy of WLL for PAP
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