Phase angle as an indicator of sarcopenia and malnutrition in patients with chronic obstructive pulmonary disease.

BACKGROUND: Phase angle (PhA), which is measured using bioelectrical impedance analysis, is an indicator of muscle quality and malnutrition. PhA has been shown to be correlated with sarcopenia and malnutrition; however, studies on patients with chronic obstructive pulmonary disease (COPD) are limited. In this study, we investigated the correlation between PhA and sarcopenia and malnutrition and determined the cutoff values of PhA for those in patients with COPD. METHODS: This study included 105 male patients with COPD (mean age 75.7 ± 7.7 years, mean forced expiratory volume in 1s % predicted [%FEV1] 57.0 ± 20.1%) and 12 male controls (mean age 74.1 ± 3.8 years) who were outpatients between December 2019 and March 2024. PhA was measured using the InBody S10, and its correlation with sarcopenia and malnutrition was assessed. The cutoff PhA values for sarcopenia and malnutrition were determined using receiver operating characteristic curves. RESULTS: The prevalence rates of sarcopenia and malnutrition were 31% and 22%, respectively, in patients with COPD. PhA significantly correlated with sarcopenia- and malnutrition-related indicators. Multivariate logistic regression analysis independently correlated PhA with sarcopenia and malnutrition. The cutoff values of the PhA for sarcopenia and malnutrition were 4.75° (AUC = 0.78, 95% CI = 0.68-0.88) and 4.25° (AUC = 0.75, 95% CI = 0.63-0.86), respectively. CONCLUSIONS: PhA was significantly correlated with sarcopenia and malnutrition in Japanese patients with COPD and may be a useful diagnostic indicator.

Current advances in pulmonary functional imaging.

Recent advances in imaging analysis have enabled evaluation of ventilation and perfusion in specific regions by chest computed tomography (CT) and magnetic resonance imaging (MRI), in addition to modalities including dynamic chest radiography, scintigraphy, positron emission tomography (PET), ultrasound, and electrical impedance tomography (EIT). In this review, an overview of current functional imaging techniques is provided for each modality. Advances in chest CT have allowed for the analysis of local volume changes and small airway disease in addition to emphysema, using the Jacobian determinant and parametric response mapping with inspiratory and expiratory images. Airway analysis can reveal characteristics of airway lesions in chronic obstructive pulmonary disease (COPD) and bronchial asthma, and the contribution of dysanapsis to obstructive diseases. Chest CT is also employed to measure pulmonary blood vessels, interstitial lung abnormalities, and mediastinal and chest wall components including skeletal muscle and bone. Dynamic CT can visualize lung deformation in respective portions. Pulmonary MRI has been developed for the estimation of lung ventilation and perfusion, mainly using hyperpolarized 129Xe. Oxygen-enhanced and proton-based MRI, without a polarizer, has potential clinical applications. Dynamic chest radiography is gaining traction in Japan for ventilation and perfusion analysis. Single photon emission CT can be used to assess ventilation-perfusion (V˙/Q˙) mismatch in pulmonary vascular diseases and COPD. PET/CT V˙/Q˙ imaging has also been demonstrated using "Galligas". Both ultrasound and EIT can detect pulmonary edema caused by acute respiratory distress syndrome. Familiarity with these functional imaging techniques will enable clinicians to utilize these systems in clinical practice.

A case report of Indium lung with progressive emphysema and fibrosis underwent lung unilateral transplantation 20 years after the end of the exposure.

BACKGROUND: Indium lung is characterized by interstitial pneumonia and/or emphysema which occurs in indium-tin oxide (ITO) workers. Indium lung is now known to progress after stopping exposure to ITO, but the long-term influences of ITO remain unclear. CASE PRESENTATION: Forty seven years old, a never-smoker, who had been engaged in an ITO manufacturing process for 8 years. Emphysema was indicated by the medical check-up for ex-ITO workers, and he was diagnosed with indium lung. He underwent partial lung resections for pneumothorax two times, and obstructive pulmonary dysfunction had progressed through the years. He underwent right single lung transplant 20 years after ITO exposure. Pathologically, his lung showed severe distal acinar emphysema and honeycomb change. Fibrosis and destruction of the lung tissue significantly progressed compared to the previous partial resections. Scanning electron microscopy combined with energy dispersive spectroscopy revealed that the deposited particles contained indium and tin. After the transplantation, his respiratory function was improved. CONCLUSIONS: In this case, ITO resided in the lung tissue for 20 years, and lung tissue destruction kept progressing. Careful medical follow-up is recommended for ITO-workers even if they are asymptomatic.

A Novel Development of Sarcoidosis Following COVID-19 Vaccination and a Literature Review.

BNT162b2 (Pfizer/BioNTech) is a coronavirus disease 2019 (COVID-19) vaccine containing nucleoside-modified messenger RNA encoding the severe acute respiratory syndrome coronavirus 2 spike glycoprotein. Recently, ocular complications of mRNA vaccines have been reported increasingly frequently. However, immunological adverse events due to mRNA vaccines in real-world settings are not fully known. We herein report the novel development of sarcoidosis manifested as uveitis, bilateral hilar lymphadenopathy, angiotensin-converting enzyme elevation, and epithelioid and giant cell granuloma formation in the lung soon after the first BNT162b2 injection and review the current literature, including three reported cases of sarcoid-like reaction following COVID-19 vaccination.

Metabolic and Epigenetic Regulation of SMAD7 by STC1 Ameliorates Lung Fibrosis.

As shown in our previous studies, the intratracheal-administration of STC1 (stanniocalcin-1) ameliorates pulmonary fibrosis by reducing oxidative and endoplasmic reticulum stress through the uncoupling of respiration in a bleomycin-treated mouse model. However, the overall effect of STC1 on metabolism was not examined. Therefore, we first conducted a comprehensive metabolomics analysis to screen the overall metabolic changes induced by STC1 in an alveolar epithelial cell line using capillary electrophoresis time-of-flight mass spectrometry. The results were subsequently validated in multiple alveolar epithelial and fibroblast cell lines by performing precise analyses of each substance. STC1 stimulated glycolysis, acetyl-CoA synthesis, and the methionine and cysteine-glutathione pathways, which are closely related to the uncoupling of respiration, modulation of epigenetics, and reduction in oxidative stress. These results are consistent with our previous study. Subsequently, we focused on the inhibitory factor SMAD7, which exerts an antifibrotic effect and is susceptible to epigenetic regulation. STC1 upregulates SMAD7 in an uncoupling protein 2-dependent manner, induces demethylation of the SMAD7 promoter region and acetylation of the SMAD7 protein in human alveolar epithelial and fibroblast cell lines and a bleomycin-treated mouse model, and subsequently attenuates fibrosis. The antifibrotic effects of STC1 may partially depend on the regulation of SMAD7. In the evaluation using lung tissue from patients with idiopathic pulmonary fibrosis, SMAD7 expression and acetylation were high in the alveolar structure-preserving region and low in the fibrotic region. The intratracheal administration of STC1 may prevent the development of pulmonary fibrosis by regulating the metabolism-mediated epigenetic modification of SMAD7 in patients.

Association between Fathers' Use of Heated Tobacco Products and Urinary Cotinine Concentrations in Their Spouses and Children.

Heated tobacco products (HTPs) have become increasingly popular among smokers, especially among young adults in Japan in recent years. Assessments of secondhand tobacco smoke (SHS) exposure due to HTPs are scarce. The present study aimed to assess the urinary levels of total nicotine metabolites (TNMs) of non-smoking spouses and their children following SHS exposure due to their fathers' use of HTPs. A total of 41 families including 129 participants were recruited between 2018 and 2021. The number of non-smoking spouses and children of the fathers who smoke combustion cigarettes, the fathers who use HTPs, and the fathers who are non-users or have never smoked was 27, 66, and 36, respectively. The urinary levels of TNMs, including cotinine (Cot) and 3'-hydroxycotinine (3-OHCot), were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The spouses and children of fathers who use HTPs had significantly higher levels of TNMs in their urine compared to those with fathers who were non-smokers or non-users. The current study is the first to assess SHS exposure due to HTP use, and to suggest the importance of strategies to prevent exposure to SHS from HTP use in public places and educational strategies to protect non-smokers from secondhand HTP aerosol exposure in households and other private places.

Clinical significance and applications of oscillometry.

Recently, "Technical standards for respiratory oscillometry" was published, which reviewed the physiological basis of oscillometric measures and detailed the technical factors related to equipment and test performance, quality assurance and reporting of results. Here we present a review of the clinical significance and applications of oscillometry. We briefly review the physiological principles of oscillometry and the basics of oscillometry interpretation, and then describe what is currently known about oscillometry in its role as a sensitive measure of airway resistance, bronchodilator responsiveness and bronchial challenge testing, and response to medical therapy, particularly in asthma and COPD. The technique may have unique advantages in situations where spirometry and other lung function tests are not suitable, such as in infants, neuromuscular disease, sleep apnoea and critical care. Other potential applications include detection of bronchiolitis obliterans, vocal cord dysfunction and the effects of environmental exposures. However, despite great promise as a useful clinical tool, we identify a number of areas in which more evidence of clinical utility is needed before oscillometry becomes routinely used for diagnosing or monitoring respiratory disease.

Risk prediction for new-onset atrial fibrillation using the Minnesota code electrocardiography classification system.

BACKGROUND: Few risk models are available to predict future onset of atrial fibrillation (AF) in workers. We aimed to develop risk prediction models for new-onset AF, using annual health checkup (HC) data with electrocardiogram findings. METHODS AND RESULTS: We retrospectively included 56,288 factory or office workers (mean age = 51.5 years, 33.0% women) who underwent a HC at a medical center and fulfilled the following criteria; age ≥ 40 years, no history of AF, and greater than 1 annual follow-up HC in 2013-2016. Using Cox models with the Akaike information criterion, we developed and compared prediction models for new-onset AF with and without the Minnesota code information. We externally validated the discrimination accuracy of the models in a general Japanese population cohort, the Hisayama cohort. During the median 3.0-year follow-up, 209 (0.37%) workers developed AF. Age, sex, waist circumference, blood pressure, LDL cholesterol, and γ-GTP were associated with new-onset of AF. Using the Minnesota code information, the AUC significantly improved from 0.82 to 0.84 in the derivation cohort and numerically improved from 0.78 to 0.79 in the validation cohort, and from 0.77 to 0.79 in the Hisayama cohort. The NRI and IDI significantly improved in all and male subjects in both the derivation and validation cohorts, and in female subjects in both the validation and the Hisayama cohorts. CONCLUSIONS: We developed useful risk model with Minnesota code information for predicting new-onset AF from large worker population validated in the original and external cohorts, although study interpretation is limited by small improvement of AUC.

Questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation in Japan.

OBJECTIVE: Current interventions of dysphagia are not generalizable, and treatments are commonly used in combination. We conducted a questionnaire survey on nurses and speech therapists regarding dysphagia rehabilitation to understand the current situation in Japan. METHODS: The questionnaire was sent to 616 certified nurses in dysphasia nursing and 254 certified speech-language-hearing therapists for dysphagia. Based on "Summaries of training methods in 2014" by JSDR, 24 local indirect exercises, 11 general indirect exercises, and 13 direct exercises were selected. The Likert scale "How do you feel about each method" was used as follows: A; Frequency, B; Ease, C; Adherence, D; Effectiveness (1-5))?". RESULTS: Two hundred fifty (40%) nurses and 145 (57%) speech-language-hearing therapists (ST) responded to the questionnaire. The direct exercise was associated with a significantly high score in every question. In indirect exercises, "Cervical range of motion exercise," "Orofacial myofunctional exercise," "Lip closure exercise." "Ice massage of pharynx" and "Huffing" were used relatively frequently. "Balloon dilatation therapy" and "Tube exercise" was associated with a relatively high discrepancy for two questions. Frequency" and the sum of "Ease," "Adherence," and "Effectiveness." was significantly correlated for local indirect exercises (r2 = 0.928, P < 0.01), general indirect exercises (r2 = 0.987, P < 0.01), and direct exercises (r2 = 0.996, P < 0.01) (Fig. 5). CONCLUSION: This study examined the current situation of dysphagia rehabilitation in Japan. Our results aid to increase understanding and selection of rehabilitative treatments for dysphagia patients in Japan.

Prevalence and Risk Factor for Antibiotic-resistant Escherichia coli Colonization at Birth in Premature Infants: A Prospective Cohort Study.

BACKGROUND: Escherichia coli causes neonatal early-onset sepsis (EOS) that is associated with high mortality and increasing antibiotic resistance. Thus, we estimated the prevalence, antibiotic susceptibility and risk factors for colonization of E. coli in premature infants at birth and characterized the pathogenicity of the isolates. METHODS: A prospective surveillance study was conducted at three Japanese perinatal centers between August 2014 and February 2017. Infants weighing <2 kg and/or at gestational age <35 weeks at birth were enrolled. We screened the mothers and neonates for E. coli colonization. Pulsed-field gel electrophoresis was used to analyze the relatedness between the maternal and neonatal isolates. Virulence factors for the isolates were determined using polymerase chain reaction. RESULTS: We enrolled 421 premature infants born to 382 mothers. The rate of colonization in mothers was 47.6%, comprising 5.9% extended-spectrum beta-lactamase-producing E. coli (ESBL-E) and 20.0% ampicillin-resistant strains. Ten (2.4%) infants exhibited colonization; ESBL-E and ampicillin-resistant strains colonized three and four infants, respectively. Three antibiotic-resistant, strain-positive infants developed EOS. Pulsed-field gel electrophoresis revealed vertical transmission of bacteria in four infants. Multivariate logistic regression analysis revealed that ESBL-E-positive mothers [odds ratio (OR), 19.2; 95% confidence interval (CI), 2.5-145.7)] and vaginal delivery (OR, 9.4; 95% CI, 1.7-50.7) were risk factors for neonatal colonization. The infant isolates possessed numerous virulence factors. CONCLUSIONS: Although the prevalence of E. coli-colonized premature infants at birth was low, the rate of antibiotic resistance and the attack rate for EOS were high. Infants with ESBL-E positive mothers should be closely monitored for EOS.

Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed. She eventually underwent right single LDLLT from her mother when she was 14 years old. A pathological examination of the excised lung confirmed the finding of diffuse bronchiolitis obliterans and unexpectedly revealed widespread alveolar proteinosis. Interestingly, the GGO of her native left lung on chest X-ray was improved after LDLLT. We present the very unique clinical course of this patient and discuss the mechanisms underlying the development of PAP after BMT and its improvement after LDLLT from the same donor.

Technical standards for respiratory oscillometry.

Oscillometry (also known as the forced oscillation technique) measures the mechanical properties of the respiratory system (upper and intrathoracic airways, lung tissue and chest wall) during quiet tidal breathing, by the application of an oscillating pressure signal (input or forcing signal), most commonly at the mouth. With increased clinical and research use, it is critical that all technical details of the hardware design, signal processing and analyses, and testing protocols are transparent and clearly reported to allow standardisation, comparison and replication of clinical and research studies. Because of this need, an update of the 2003 European Respiratory Society (ERS) technical standards document was produced by an ERS task force of experts who are active in clinical oscillometry research.The aim of the task force was to provide technical recommendations regarding oscillometry measurement including hardware, software, testing protocols and quality control.The main changes in this update, compared with the 2003 ERS task force document are 1) new quality control procedures which reflect use of "within-breath" analysis, and methods of handling artefacts; 2) recommendation to disclose signal processing, quality control, artefact handling and breathing protocols (e.g. number and duration of acquisitions) in reports and publications to allow comparability and replication between devices and laboratories; 3) a summary review of new data to support threshold values for bronchodilator and bronchial challenge tests; and 4) updated list of predicted impedance values in adults and children.

Association between Family History of Cancer and Lung Cancer Risk among Japanese Men and Women.

Although cigarette smoking is a major risk factor for lung cancer, genetic susceptibility may also affect lung cancer risk. To explore the role of genetic risk, this case-control study investigated the association between family history of cancer at several sites and lung cancer risk. A total of 1,733 lung cancer cases and 6,643 controls were selected from patients aged 30 years and over admitted to a single hospital in Japan between 1997 and 2009. Information on family history of cancer was collected using a self-administered questionnaire and odds ratios (ORs) were estimated by unconditional logistic regression. Family history of lung cancer in first-degree relatives was associated with an increased risk of lung cancer among both sexes. According to histology and type of relatives, a parental history of lung cancer was significantly associated with an increased risk of female adenocarcinoma (OR = 1.72). Stratification by smoking status revealed that this significant positive association in women was limited to ever-smokers (OR = 4.13). In men, a history of lung cancer in siblings was significantly associated with an increased risk of small cell carcinoma (OR = 2.28) and adenocarcinoma (OR = 2.25). Otherwise, positive associations between history of breast (OR = 1.99) and total (OR = 1.71) cancers in siblings and the risk of male adenocarcinoma were observed. These results suggest that inherited genetic susceptibility may contribute to the development of lung cancer. In men, shared exposure to environmental factors among siblings may also be responsible for the increase in lung cancer risk.

Respiratory resistance among adults in a population-based cohort study in Northern Japan.

BACKGROUND: Forced oscillation technique (FOT) is a noninvasive method used to measure respiratory system resistance (Rrs) and reactance (Xrs) during quiet breathing, which has been extensively studied in clinical settings. The distribution of measured FOT values was previously assessed in a community-based cohort study. In this study, we aimed to confirm the distribution of measured FOT values in a different cohort in order to investigate the relationship between these values and patient clinical and biological data. METHODS: We reviewed FOT data and relevant patient clinical and biological information collected from the Community-Based Cohort Study (CommCohort Study), carried out between 2013 to 2016 as a part of the Tohoku Medical Megabank project (TMM). In total, 16,231 adults were enrolled in the study (Male/Female: 4886/11,345). RESULTS: Significant gender differences were observed in distributions of Rrs and Xrs values at 5 Hz (termed R5 and X5, respectively). R5 values in males were lower than those in females, while X5 values in males were slightly less negative. High R5 values were strongly associated with high BMI, short height, smoking status in males, high serum IgE level, and high peripheral blood eosinophil count. CONCLUSION: The present distribution values and their relation to clinical and biological data should provide useful insights for clinical settings and serve as a helpful guide in implementing FOT. Forced oscillation technique, respiratory system resistance, respiratory system reactance, gender difference, obesity.

Correlation between the native lung volume change and postoperative pulmonary function after single lung transplantation for lymphangioleiomyomatosis: Evaluation of lung volume by three-dimensional computed tomography volumetry.

PURPOSE: Whereas native lung overinflation has been thought to happen in recipients of single lung transplantation for lymphangioleiomyomatosis because of its increased compliance, there is no study that has reported the details on the change of the native lung volume after single lung transplantation by three-dimensional computed tomography volumetry. The purpose of the present study was to evaluate the lung volume after single lung transplantation for lymphangioleiomyomatosis by three-dimensional computed tomography volumetry and investigate the correlation between the native lung volume change and postoperative pulmonary function. METHODS: We retrospectively reviewed the data of 17 patients who underwent single lung transplantation for lymphangioleiomyomatosis. We defined the ratio of the native lung volume to total lung volume (N/T ratio) as an indicator of overinflation of the native lung. In order to assess changes in the N/T ratio over time, we calculated the rate of change in the N/T ratio which is standardized by the N/T ratio at 1 year after single lung transplantation: rate of change in N/T ratio (%) = {(N/T ratio at a certain year)/(N/T ratio at 1 year)- 1}× 100. RESULTS: We investigated the correlations between the N/T ratio and the pulmonary function test parameters at 1 year and 5 years; however, there was no significant correlation between them. On the other hand, there was a significant negative correlation between the rate of change in the N/T ratio and that in forced expiratory volume in 1 second %predicted (%FEV1) at 5 years after single lung transplantation. CONCLUSION: The single lung transplantation recipients for lymphangioleiomyomatosis showed increased rate of change in the N/T ratio in the long-time course after lung transplantation with the decrease of %FEV1. We expect that these cases will probably cause the overinflation of the native lung in the future.

Update of occupational lung disease.

OBJECTIVE: Occupational Lung Disease is an oldest but still a biggest problem in occupational health. METHODS: Steering Committee members of the Japan Society for Occupational Health (JSOH) Occupational Lung Disease Study Group selected and summarized current topics on occupational lung diseases based on expert opinion, as informed by governmental regulation, public health concerns, and frequently discussed in related academic conferences. RESULTS: The topics included in this review are professional education in medical screening skills, 2014 update of Helsinki Criteria, respiratory diseases found in the earthquake and tsunami affected regions, newly recognized occupational lung diseases, and potential respiratory health hazards. DISCUSSIONS: Although occupational lung diseases seem to stay as one of the major concerns in occupational health, screening tools and control measures are standardized for the better prevention of the diseases. As this health problem usually occurs in where the most actively economically developing area is, the patients tend to increase in emerging economic powers with huge population.

Novel Respiratory Impedance-Based Phenotypes Reflect Different Pathophysiologies in Chronic Obstructive Pulmonary Disease Patients.

Purpose: The forced oscillation technique (FOT) is a non-invasive method to measure respiratory impedance, the respiratory resistance (Rrs) and reactance (Xrs). The disease probability measure (DPM) is a useful computed tomography (CT) imaging variable for the assessment of gas trapping and emphysema in patients with chronic obstructive pulmonary disease (COPD) using pairs of inspiratory and expiratory CT images. We aimed to develop FOT-based phenotypes and determine whether the phenotypes and their imaging characteristics could facilitate the understanding of COPD pathophysiology. Patients and methods: FOT and spirometry were examined in 164 COPD patients and 22 non-COPD smokers. COPD patients were divided into four FOT-based phenotypes (NL, normal group; RD, resistance-dominant group; XD, reactance-dominant group; and MIX, mixed group) based on the 3rd quartile values of R5 (Rrs at 5Hz) and X5 (Xrs at 5Hz) in the non-COPD group. The emphysematous lesions and the airway lesions were quantitatively assessed in CT images by low attenuation volume and the square root of the wall area of a hypothetical airway with an internal perimeter of 10 mm (√Aaw at Pi10), respectively. DPM imaging analysis was also performed in 131 COPD patients. We investigated the differences in COPD parameters between the FOT-based phenotypes. Results: √Aaw at Pi10 were significantly higher in the RD, XD, and MIX groups than in the NL group. The XD group showed lower pulmonary function and higher dyspnea scores than the RD group. No significant changes in DPM values were observed between the RD and the NL groups. The gas-trapping area was significantly higher in the XD group than in the NL group. The MIX group showed the highest dyspnea score, most emphysematous lesions, and the lowest forced expiratory volume in 1 s % predicted value. Conclusion: The FOT-based phenotyping may be useful to assess pathophysiological changes of COPD with CT assessments.

Peripheral alveolar nitric oxide concentration reflects alveolar inflammation in autoimmune pulmonary alveolar proteinosis.

Nitric oxide and alveolar macrophage inflammation http://ow.ly/czCx30i12n8.

Fractional Exhaled Nitric Oxide (FeNO) and Spirometry as Indicators of Inhalation Exposure to Chemical Agents in Pathology Workers.

OBJECTIVE: The objective of this study was to examine whether fractional exhaled nitric oxide (FeNO) and spirometry can be used as indices to evaluate adverse health effects of low-concentrated chemical inhalation exposure, mainly to formaldehyde. METHODS: Thirty-three subjects (pathology technicians) and 30 controls (workers without handling any chemicals in the same hospitals) participated in this study. All participants underwent FeNO measurement and spirometry before and after 5 days of work. RESULTS: FeNO significantly increased in the subjects with a history of asthma (P < 0.05), whereas forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1) decreased in the subjects (P < 0.05). Furthermore, work duration and pre-work levels of FEV1 in the subjects had a significant association. CONCLUSION: The results suggest that FeNO, FVC, and FEV1 represent effective health-effect indices of low-concentrated chemical inhalation exposure.

Sequential Granulocyte-Macrophage Colony-Stimulating Factor Inhalation after Whole-Lung Lavage for Pulmonary Alveolar Proteinosis. A Report of Five Intractable Cases.

Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by the excessive accumulation of surfactant proteins within the alveolar spaces and by higher titers of autoantibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF) in the serum and bronchoalveolar lavage fluid. The antibodies inhibit the maturation and phagocytosis of alveolar macrophages. Although the standard therapy for aPAP has been whole-lung lavage (WLL), this procedure is invasive and needs to be repeated for several years. GM-CSF inhalation therapy is a new procedure for treating aPAP and can induce remission with less invasiveness, although it is generally less effective in severe cases. We evaluated five cases with remarkable improvement by using sequential GM-CSF inhalation therapy after WLL; however, the treatment failed when this therapy preceded WLL. Therefore, sequential GM-CSF inhalation after WLL may reinforce the efficiency of WLL in patients with severe aPAP.