Methacholine-induced cough as an indicator of bronchodilator-responsive cough.

BACKGROUND: Cough variant asthma (CVA) is the most common cause of chronic cough and responds well to bronchodilator therapy. Previous studies on methacholine -induced cough have shown that heightened cough response due to bronchoconstriction is a feature of CVA. The aim of this study was to assess Mch-induced cough as an indicator of bronchodilator-responsive cough (BRC). METHODS: This was a single-center retrospective study of prolonged/chronic cough cases who underwent evaluation via spirometry, FeNO and bronchial challenge testing using Mch and capsaicin (C5). Resultant bronchoconstriction after Mch challenge was assessed by flow-volume curves measuring the expiratory flow of the partial flow-volume curve 40% above residual volume (PEF40) and FEV1. BRC was defined as a decrease in cough with bronchodilator therapy by 30% or more on a visual analog scoring scale. RESULTS: Of the 100 patients evaluated, 63 were diagnosed with BRC. Mch-induced cough at a decrease in PEF40 of 35% (PC35-PEF40) was predictive of BRC on AUROC analysis with an AUC of 0.82 (95% CI 0.73-0.90) and cut-off of 24. The AUC for C5, FeNO and PC20-FEV1 were 0.65, 0.47, and 0.58, respectively. CONCLUSION: Compared to C5, FeNO and PC20-FEV1, Mch-induced cough better supports a diagnosis of BRC.

Dynamic-Ventilatory Digital Radiography in Air Flow Limitation: A Change in Lung Area Reflects Air Trapping.

OBJECTIVE: The aim of this study was to determine the utility of dynamic-ventilatory digital radiography (DR) for pulmonary function assessment in patients with airflow limitation. METHODS: One hundred and eighteen patients with airflow limitation (72 patients with lung cancer before surgery, 35 patients with chronic obstructive pulmonary disease [COPD], 6 patients with asthma, and 5 patients with asthma-COPD overlap syndrome) were assessed with dynamic-ventilatory DR. The patients were instructed to inhale and exhale slowly and maximally. Sequential chest X-ray images were captured in 15 frames per second using a dynamic flat-panel imaging system. The relationship between the lung area and the rate of change in the lung area due to respiratory motion with respect to pulmonary function was analyzed. RESULTS: The rate of change in the lung area from maximum inspiration to maximum expiration (Rs ratio) was associated with the RV/TLC ratio (r = 0.48, p < 0.01) and the percentage of the predicted FEV1 (r = -0.33, p < 0.01) in patients with airflow limitations. The Rs ratio also decreased in an FEV1-dependent manner. CONCLUSION: The rate of change in the lung area due to respiratory motion evaluated with dynamic DR reflects air trapping. Dynamic DR is a potential tool for the comprehensive assessment of pulmonary function in patients with COPD.

Repeated bronchoconstriction attenuates the cough response to bronchoconstriction in naïve guinea pigs.

BACKGROUND: Cough variant asthma (CVA) is recognized as a precursor of bronchial asthma (BA). However, the cough response to bronchoconstriction differs between these similar diseases. Repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators may impact the cough response. METHODS: We investigated the influence of repeated bronchoconstriction on the cough response to bronchoconstriction using naïve guinea pigs. Bronchoconstriction was induced for 3 consecutive days and changes in the cough response and lipid mediators, such as PGE2, PGI2, and cysteinyl-LTs (Cys-LTs), in BAL fluid (BALF) were assessed. We investigated the effect of endogenous PGI2 on the cough response by employing a PGI2 receptor antagonist. In order to investigate the cough response over a longer period, we re-evaluated the cough response 2 weeks after repeated bronchoconstriction. RESULTS: The number of coughs induced by bronchoconstriction were significantly decreased by repeated bronchoconstriction. The levels of PGE2, PGI2, and Cys-LTs, and the ratio of PGI2/PGE2 were significantly increased, following repeated bronchoconstriction. This decrease in the cough response was suppressed by pretreatment with a PGI2 receptor antagonist. Two weeks after repeated bronchoconstriction, the cough response returned to the same level as before repeated bronchoconstriction along with a concomitant return of lipid mediators, such as PGE2, PGI2, and Cys-LTs and the ratio of PGI2/PGE2. CONCLUSIONS: Our results suggest that repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators contribute to the difference in cough responses to bronchoconstriction in CVA and BA.

Role of prostaglandin E2 in bronchoconstriction-triggered cough response in guinea pigs.

A feature of cough variant asthma is a heightened cough response to bronchoconstriction. The mediators of this response are unknown. This study was designed to elucidate the role of lipid mediators in bronchoconstriction-triggered cough response in an experimental animal model. We examined the influence of bronchoconstriction on cell components and mediators including prostaglandin E2 (PGE2) in bronchoalveolar lavage fluid (BALF). We studied the cough response to bronchoconstriction (CRB) by measuring the correlation between the increase in enhanced pause (Penh), an index of bronchoconstriction, and cough counts induced by methacholine (Mch) inhalation in conscious guinea pigs. We then examined the effects of intraperitoneal pretreatment with 16, 16-dimethyl-prostaglandin E2 (dm-PGE2) on CRB and cough counts. The total number of cells and cell components in the BALF were not influenced by bronchoconstriction. While levels of PGE2, prostaglandin I2, and cysteinyl leukotrienes were significantly increased, levels of prostaglandin D2, thromboxane B2, and substance P in the BALF were not. Dm-PGE2 significantly decreased the Mch-induced increase in Penh. Following bronchoconstriction by additional Mch inhalation, dm-PGE2 produced an increase in CRB and cough counts in a dose-dependent manner. Additionally, the heightened CRB following dm-PGE2 treatment was suppressed by pretreatment with PGE2 receptor (E-prostanoid EP) -1 and EP-3 antagonists in a dose-dependent manner, but not by EP-2 and EP-4 antagonists. The EP-1 antagonist also decreased cough counts. These results suggest that PGE2 acts as an exacerbating factor for bronchoconstriction-triggered cough. EP1 and EP3 may provide new therapeutic targets for cough variant asthma.

Role of prostaglandin I2 in the bronchoconstriction-triggered cough response in guinea pigs.

Purpose/Aim of the study: Methacholine chloride (MCh) inhalation causes bronchoconstriction and cough. Following MCh-induced bronchoconstriction, metabolic products of prostaglandin I2 (PGI2) increase in bronchoalveolar lavage fluid (BALF), suggesting that PGI2 plays a role in the cough response. Accordingly, we used an experimental guinea pig model to evaluate the role of PGI2 in the bronchoconstriction-triggered cough response. MATERIALS AND METHODS: Experiment 1: The concentration of PGF1α, a stable metabolite of PGI2, in BALF was assessed in animals exposed to nebulized MCh and animals exposed to nebulized saline. Experiment 2: Bronchoconstriction and cough were assessed in 3 groups of animals after MCh inhalation (a saline group, low-dose PGI2 group, and high-dose PGI2 group). Enhanced pause (Penh) was used as a measure of bronchoconstriction. Experiment 3: Bronchoconstriction and cough were assessed in 3 groups of animals (groups administered saline, a low dose of a specific antagonist of the PGI2 receptor (IP antagonist), and a high dose of a specific IP antagonist). RESULTS: The PGF1α concentration in BALF was significantly higher in the bronchoconstriction group than in the control group. In animals administered high-dose PGI2, the MCh-induced increase in Penh was significantly suppressed, and the number of coughs induced by bronchoconstriction was significantly decreased. In animals treated with a high dose of an IP antagonist, the MCh-induced increase in Penh was not affected, and the number of coughs increased. CONCLUSIONS: Our results suggest that PGI2 ameliorates a bronchoconstriction-triggered cough. The measurement and administration of PGI2 may assist in the diagnosis and treatment, respectively, of the cough response triggered by bronchoconstriction.

The measurement of cough response to bronchoconstriction induced by methacholine inhalation in healthy subjects: An examination using the Astograph method.

BACKGROUND: We demonstrated that heightened cough response to bronchoconstriction is a fundamental feature of cough variant asthma (CVA). To evaluate this physiological feature of CVA in daily clinical practice, it is necessary to clarify the cough response to bronchoconstriction in healthy subjects. We evaluated cough response to methacholine (MCh)-induced bronchoconstriction in healthy subjects. A forced oscillometry technique was used to measure airway resistance changes with Mch. METHODS: Healthy never-smokers (21 men, 20 women; mean 22.3 ± 3.7 years) participated. None had a >3-week cough history, clinically significant respiratory or cardiovascular disorders, or disorders that might put subjects at risk or influence the study results or the subjects' ability to participate. Twofold increasing concentrations of Mch chloride diluted in phosphate-buffered saline (0.039 to 160 mg/mL) were inhaled from nebulizers at 1-minute intervals during subjects' tidal breathing after the baseline respiratory resistance (Rrs) was recorded. Mch inhalation continued until Rrs reached twice the baseline value and forced expiratory volume in 1 second (FEV1) decreased to <90% of baseline value. Spirometry was measured before Mch inhalation and immediately after Rrs had increased twofold. Coughs were counted during and for 30 minutes after Mch inhalation. The cough reflex sensitivity to capsaicin was also examined. RESULTS: The number of coughs was 11.1 ± 14.3 (median, 7.0; range, 0 to 71; reference range, 0 to 39.7). There was no significant difference in the cough response between the sexes. The reproducibility of the cough response to bronchoconstriction was sufficient. No correlation existed between the bronchoconstriction-induced cough response and capsaicin cough-reflex sensitivity. CONCLUSIONS: Using the Astograph method, cough response to bronchoconstriction could be measured easily, safely and highly reproducibly in healthy subjects.

Bronchoconstriction-triggered cough in atopic cough: A retrospective study.

BACKGROUND: Atopic cough (AC) and cough variant asthma (CVA) were identified as major causes of chronic non-productive cough in a Japanese study. A characteristic feature of CVA is the presence of a heightened cough response to bronchoconstriction. On the other hand, the cough response to bronchoconstriction in AC remains unclear. METHODS: Methacholine (Mch)-induced cough in AC was measured and compared with that in CVA. Diagnoses of AC and CVA were made based on patient history, physical examination, response to bronchodilator therapy, cough reflex sensitivity to capsaicin, spirometry, and airway responsiveness to methacholine. RESULTS: Thirteen AC patients and 12 CVA patients in whom the criteria were met were recruited to the study. After inhalation of Mch at PC35-PEF40 that means milder bronchoconstriction than PC20-FEV1, cough was triggered a few times in AC. [cough number: 1/ 32 min (0-40)]. Conversely, significantly greater number of coughs was provoked in CVA, compared with AC [cough number: 35.5/ 32 min (25-125), p < 0.05]. CONCLUSIONS: The cough response to bronchoconstriction is reduced in AC compared to CVA. This feature may be useful in the diagnosis of chronic cough.

Prognostic value of coexisting conditions and complications in pleuroparenchymal fibroelastosis: a single-center retrospective study.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is a rare idiopathic interstitial lung disease (ILD) characterized by subpleural parenchymal fibrosis and elastosis mainly in the upper lobes. PPFE occurs in a secondary form that overlaps with underlying medical conditions or complications. This study evaluated the clinical impact of coexisting factors on the survival of patients with PPFE. METHODS: Fifty-five PPFE patients were retrospectively evaluated. The patients' diagnoses were categorized as "idiopathic PPFE" with no known cause or "secondary PPFE" with underlying medical conditions or complications. The clinical characteristics and survival rates of these groups were compared. RESULTS: Twenty-eight patients (50.9%) were diagnosed with idiopathic PPFE and 27 (49.1%) with secondary PPFE, including cases of occupational dust exposure, connective tissue disease (CTD), post-hematopoietic stem cell transplantation (HSCT), and a family history of ILD. The idiopathic and secondary PPFE groups had similar clinical features, laboratory tests, and pulmonary function profiles, including a low body mass index, normal Krebs von den Lungen-6, high surfactant protein-D, and high residual volume/total lung capacity. In the secondary PPFE group, post-HSCT was associated with a worse prognosis, and CTD was associated with better prognosis. A multivariate analysis demonstrated that post-HSCT and a reduced forced vital capacity were significantly associated with a worsened survival in patients with PPFE. CONCLUSIONS: The prognosis of PPFE is highly influenced by underlying medical conditions or complications. Patients with post-HSCT PPFE should be monitored particularly closely, as they are at higher risk of a poor prognosis than others.

Patients with idiopathic pulmonary fibrosis and refractory cough have traction bronchiectasis and distorted airway architecture: a retrospective case review study.

Cough is a common and important sign/symptom in patients with idiopathic pulmonary fibrosis (IPF). However, there have been few reports focusing on cough, and the exact mechanisms for cough in patients with IPF have remained unclear. The objective of this study was to investigate the clinical features of IPF patients with refractory cough and to clarify mechanisms for cough in these patients. We retrospectively reviewed the files of patients with the diagnosis of IPF at Kanazawa University Hospital and compared the clinical features of IPF patients with refractory cough with the clinical features of IPF patients without refractory cough. Among a total of 23 patients with IPF, 10 patients (43.5%) had chronic cough. Of the ten patients, seven patients had concomitant conditions that could lead to cough. Of these seven patients, the cough of four patients was resolved after treatment of their concomitant condition. Finally, among the 23 patients there were 6 (26.1%) with refractory cough associated with IPF. Significant differences were seen between the following clinical features of IPF patients with or without refractory cough, respectively, as follows: lower body mass index (BMI; 18.8±2.5 vs. 22.8±2.5 kg/m2, P<0.01), lower forced vital capacity (FVC; 77.5%±30.4% predicted vs. 99.9%±0.53% predicted, P=0.046), and presence of traction bronchiectasis and distorted airway architecture on high-resolution computed tomography (HRCT; 83.3% vs. 11.8%, P<0.01). The difference between the proportions of patients with or without refractory cough with capsaicin cough sensitivity was not significant. Mechanical stress on the airways due to traction bronchiectasis and distorted airway architecture is a possible mechanism for cough in IPF patients.

Comparing region of interest selection and whole-field analysis for measurement of ciliary beat frequency in high-speed video analysis.

BACKGROUND: Ciliary beat frequency (CBF) is crucial in mucociliary clearance. High-speed video analysis (HSVA) is commonly used to measure CBF but lacks standardization. We compared visual observation and computer-assisted calculation using fast Fourier transformation (FFT) in freshly collected bronchial ciliary epithelial cells and cultured cells. METHODS: Bronchial epithelial cells were obtained from 12 patients who required bronchoscopic examination. Eighty-five videos of ciliary movement of freshly collected and cultured cells were recorded and used to calculate CBF using manual observation, region of interest (ROI) selection, and whole-field analysis. RESULTS: CBF measured by the ROI selection method strongly correlated with that measured using manual observation, especially in freshly collected cells. However, 27.8% of the manual observation method values were doubled in the ROI selection method, probably because a round trip of cilia was calculated as two cycles and needed to be corrected to 1/2 value. Upon increasing the number of ROIs, the results of the ROI selection method came closer to that of WFA. CONCLUSIONS: Computer-assisted calculation using FFT can aid in measuring CBF; however, current methods require visual confirmation. Further automated evaluation techniques are needed to establish more standardized and generalized CBF measurement methods using HSVA.

Practical guide for the diagnosis and management of primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a relatively rare genetic disorder that affects approximately 1 in 20,000 people. Approximately 50 genes are currently known to cause PCD. In light of differences in causative genes and the medical system in Japan compared with other countries, a practical guide was needed for the diagnosis and management of Japanese PCD patients. METHODS: An ad hoc academic committee was organized under the Japanese Rhinologic Society to produce a practical guide, with participation by committee members from several academic societies in Japan. The practical guide including diagnostic criteria for PCD was approved by the Japanese Rhinologic Society, Japanese Society of Otolaryngology-Head and Neck Surgery, Japanese Respiratory Society, and Japanese Society of Pediatric Pulmonology. RESULTS: The diagnostic criteria for PCD consist of six clinical features, six laboratory findings, differential diagnosis, and genetic testing. The diagnosis of PCD is categorized as definite, probable, or possible PCD based on a combination of the four items above. Diagnosis of definite PCD requires exclusion of cystic fibrosis and primary immunodeficiency, at least one of the six clinical features, and a positive result for at least one of the following: (1) Class 1 defect on electron microscopy of cilia, (2) pathogenic or likely pathogenic variants in a PCD-related gene, or (3) impairment of ciliary motility that can be repaired by correcting the causative gene variants in iPS cells established from the patient's peripheral blood cells. CONCLUSION: This practical guide provides clinicians with useful information for the diagnosis and management of PCD in Japan.

Prevalence and causes of chronic cough in Japan.

BACKGROUND: Chronic cough is one of the most common symptoms of respiratory diseases and can adversely affect patients' quality of life and interfere with social activities, resulting in a significant social burden. A survey is required to elucidate the frequency and treatment effect of chronic cough. However, clinical studies that cover all of Japan have not yet been conducted. METHODS: Patients who presented with a cough that lasted longer than 8 weeks and visited the respiratory clinics or hospitals affiliated with the Japan Cough Society during the 2-year study period were registered. RESULTS: A total of 379 patients were enrolled, and those who did not meet the definition of chronic cough were excluded. A total of 334 patients were analyzed: 201 patients had a single cause, and 113 patients had two or more causes. The main causative diseases were cough variant asthma in 92 patients, sinobronchial syndrome (SBS) in 36 patients, atopic cough in 31 patients, and gastroesophageal reflux (GER)-associated cough in 10 patients. The time required to treat undiagnosed patients and those with SBS was significantly longer and the treatment success rate for GER-associated cough was considerably poor. CONCLUSIONS: We confirmed that the main causes of chronic cough were cough variant asthma, SBS, atopic cough, and their complications. We also showed that complicated GER-associated cough was more likely to become refractory. This is the first nationwide study in Japan of the causes and treatment effects of chronic cough.

Bronchial Thermoplasty Attenuates Cough Reflex Sensitivity in Severe Asthma : A Single-Center Retrospective Study with 2-year Follow-up.

Despite the relatively short follow-up period in our previous study, we had reported that increased cough reflex sensitivity (CRS) may predict the efficacy of bronchial thermoplasty (BT) for treating asthma. Herein, we examined whether CRS predicts the efficacy of BT 2 years after the final BT treatment. We also investigated the influence of BT on CRS. We reviewed 10 patients 2 years after their final BT treatment. CRS, asthma-related symptoms, asthma exacerbations, and cough-related quality of life were assessed at baseline and 2 years after BT. Five patients responded positively to BT (BT responders) and their asthma control improved. No significant difference in CRS at baseline was detected between the BT responders and nonresponders. In contrast, BT responders exhibited significant improvements in CRS 2 years after BT. CRS at baseline could not predict the BT efficacy after 2 years. This is the first report demonstrating BT desensitized CRS in consecutive case series. J. Med. Invest. 70 : 271-275, February, 2023.

Primary ciliary dyskinesia with CCDC39 variants displaying specific ciliary ultrastructure and movement concordant with the genotype: A case report.

Primary ciliary dyskinesia (PCD) is a genetic disease with chronic airway infection and inflammation caused by ciliary ultrastructural defects and impairment in ciliary function. We present an adult case of PCD with compound heterozygous nonsense variants in CCDC39. The ciliary ultrastructure findings using electron microscopy and ciliary movement using high-speed video analysis matched the genotype. This is the first case report of PCD with CCDC39 variants in Japan demonstrating specific ciliary ultrastructure and movement related to the genotype.

Analysis of the clinical features of Japanese patients with primary ciliary dyskinesia.

OBJECTIVE: Primary ciliary dyskinesia (PCD) is a rare hereditary disease. Most reports of PCD in Japan are case reports, and clinical analysis has not been performed. Differences in the causative genes might affect the clinical features in different ethnic groups. The purpose of this study was to clarify the clinical features of Japanese patients with PCD. METHODS: We performed a retrospective chart review of PCD patients seen at Mie University Hospital and patients whose blood samples were sent to us for genetic analysis from 2011 to 2020. Data on the following items were collected and analyzed: age at first visit to the hospital, age at diagnosis of PCD, process of referral to our facility, chief complaint, situs status, PrImary CiliARy DyskinesiA Rule (PICADAR) score, nasal nitric oxide concentration, otoscopic findings, rhinoscopic findings, and paranasal computed tomography scan findings. RESULTS: Sixty-seven patients (24 male, 43 female) were diagnosed with PCD during the study period. Age at diagnosis ranged from 2 months to 69 years (median, 17 years). Respiratory symptoms (77%) were the most common complaint, followed by nasal (15%) and aural (8%) symptoms. Situs inversus was present in 17 (25%) cases. Only 2 cases had congenital cardiac anomalies. The mean PICADAR score was 7.3 (range, 3-14) points. Approximately 50% of tympanic membranes showed retraction, suggesting otitis media with effusion. The mean Lund-Mackay score was 12.8 (range, 7-17) points, suggesting that the radiographic findings were not always severe. There was no significant difference in the total Lund-Mackay score between patients with and without situs inversus (12.7 vs. 12.6, respectively). CONCLUSION: Situs inversus was present in 25% of Japanese PCD patients, which is much lower than observed in other countries. This is a result of differences in the major disease-causing genes. The general rule that "situs inversus is observed in approximately 50% of PCD patients" cannot be applied, at least, in Japanese PCD patients.

Two cases of chronic obstructive pulmonary disease evaluated by dynamic-ventilatory digital radiography for pulmonary function and assessment of treatment efficacy.

Spirometry is a crucial test used in the diagnosis and monitoring of patients with chronic obstructive pulmonary disease (COPD). Severe acute respiratory syndrome coronavirus 2 pandemic has posed numerous challenges in performing spirometry. Dynamic-ventilatory digital radiography (DR) provides sequential chest radiography images during respiration with lower doses of radiation than conventional X-ray fluoroscopy and computed tomography. Recent studies revealed that parameters obtained from dynamic DR are promising for evaluating pulmonary function of COPD patients. We report two cases of COPD evaluated by dynamic-ventilatory DR for pulmonary function and treatment efficacy and discuss the potential of dynamic DR for evaluating COPD therapy.

Late-onset programmed cell death protein-1 inhibitor-induced pneumonitis after cessation of nivolumab or pembrolizumab in patients with advanced non-small cell lung cancer: a case series.

Awareness of the immune-related adverse event of programmed cell death protein-1 (PD-1) inhibitor-induced pneumonitis is important. Herein, we report the clinical course of 3 patients suspected to have PD-1 inhibitor-induced pneumonitis after cessation of PD-1 inhibitor treatment. In case 1, a 62-year-old man was diagnosed with stage IVA adenocarcinoma. Nivolumab monotherapy was prescribed as second-line therapy and later discontinued due to financial reasons. Seven months after the final administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis. The patient was immediately prescribed prednisolone (1 mg/kg p.o. daily), and the pneumonitis resolved after 1.5 months. In case 2, a 68-year-old man was diagnosed with stage IVB squamous cell carcinoma. Nivolumab monotherapy was prescribed as fourth-line therapy. After the second administration of nivolumab, the patient developed what we diagnosed as nivolumab-induced pneumonitis; nivolumab was discontinued, and the patient was immediately prescribed prednisolone (1 mg/kg p.o. daily). Eight months after the final administration of nivolumab, the patient again developed nivolumab-induced pneumonitis. The pneumonitis resolved without additional medication. In case 3, a 69-year-old man was diagnosed with stage IVB adenocarcinoma. Pembrolizumab monotherapy was initiated as sixth-line therapy, and it was discontinued after 4 cycles due to disease progression. Four months after the final dose of pembrolizumab, the patient developed what we diagnosed as pembrolizumab-induced pneumonitis. The patient immediately received a high intravenous dose of methylprednisolone (1,000 mg per day for three days). The pneumonitis and respiratory failure progressed, and he died 8 weeks after the onset of the pneumonitis. We report pneumonitis after discontinuation of ICIs in 3 patients. We confirm that, although uncommon, PD-1 inhibitor-induced irAEs can develop after treatment discontinuation. Further accumulation of cases and clarification of the clinical features of patients with irAEs, such as the time of onset, imaging findings, and treatment outcomes are needed.

Fractional analysis of bronchoalveolar lavage in systemic sclerosis-associated interstitial lung disease.

BACKGROUND: The utility of bronchoalveolar lavage (BAL) in the evaluation of systemic sclerosis-associated interstitial lung disease (SSc-ILD) remains controversial. Fractional analysis of BAL (FBAL) is a technique that can analyze small airways and alveolar compartments separately and has proven informative in other ILDs. The aim of this study was to explore FBAL characteristics across the spectrum of SSc-ILD severity. METHODS: We retrospectively reviewed patients with SSc-ILD who underwent bronchoscopy with FBAL using three 50 mL aliquots of saline solution. These aliquots were analyzed separately for differential cell composition (FBAL-1, -2, and -3). We compared the FBAL cell composition to the progression of ILD and end-stages of ILD using Cox proportional hazards models. RESULTS: Sixty-eight patients with SSc-ILD were enrolled in this study. The percentage of neutrophils and eosinophils was lower in FBAL-3 compared to FBAL-1. In contrast, the percentage of macrophages and lymphocytes was higher in FBAL-3. Neutrophils in FBAL-2, -3, and the estimated total FBAL cell fraction (FBAL-total) were negatively correlated with the forced vital capacity % predicted (r=-0.420, -0.362, -0.409, respectively). Although FBAL-total was not linked to the progression and end-stage of ILD, a high percentage of neutrophils in FBAL-3 was significantly associated with the development of end-stage ILD (HR 1.093, 95% CI: 1.003-1.190). CONCLUSIONS: A higher percentage of neutrophils in FBAL-3 is correlated with development of end-stage ILD in SSc-ILD as well as mortality.