Deleterious impact of trivial to severe interstitial pneumonia and emphysema on mortality and acute exacerbation of interstitial pneumonia in patients with lung cancer: a retrospective cohort study.

BACKGROUND: Interstitial pneumonia and emphysema may complicate patients with lung cancer. However, clinical significance of trivial and mild pulmonary abnormalities remains unclear. In this study, we aimed to investigate whether trivial and mild interstitial pneumonia and emphysema, in addition to their advanced forms, impact the prognosis and lead to acute exacerbation of interstitial pneumonia (AEIP) in patients with lung cancer. METHODS: This retrospective cohort study was conducted at a tertiary hospital and included patients with lung cancer. Computed tomography images were evaluated using the interstitial lung abnormality (ILA) score for interstitial pneumonia, which included no ILA, equivocal ILA, ILA, interstitial lung disease (ILD), and the Goddard score for emphysema. Cox analyses were performed using the ILA and Goddard scores as the main explanatory variables, adjusting for multiple covariates. RESULTS: Among 1,507 patients with lung cancer, 1,033 had no ILA, 160 had equivocal ILA, 174 had ILA, and 140 had ILD. In total, 474 patients (31.5%) exhibited interstitial pneumonia and 638 (42.3%) showed emphysema. The log-rank trend test showed that survival probability was significantly better in patients with no ILA, followed by those with equivocal ILA, ILA, and ILD (P < 0.001). After adjustment, the ILA and Goddard scores remained significant variables for increased hazard ratios (HR) for mortality: no ILA (HR, 1.00: reference), equivocal ILA (HR, 1.31; 95% confidence interval [CI], 1.18-1.46; P < 0.001), ILA (HR, 1.71; 95% CI, 1.39-2.12; P < 0.001), ILD (HR, 2.24; 95% CI, 1.63-3.09; P < 0.001), and Goddard score (HR, 1.03; 95% CI, 1.01-1.06; P < 0.010). Moreover, both scores were associated with increased cause-specific HRs for AEIP. CONCLUSION: Our results revealed that approximately one-third of patients with lung cancer had interstitial pneumonia when incorporating trivial and mild cases. Because interstitial pneumonia and emphysema, ranging from trivial to severe, significantly impact mortality and AEIP in patients with lung cancer, we should identify even trivial and mild cases of these pulmonary abnormalities among patients with lung cancer in addition to the advanced ones.

Findings of virtual bronchoscopic navigation can predict the diagnostic rate of primary lung cancer by bronchoscopy in patients with peripheral lung lesions.

BACKGROUND: Despite being minimally invasive, bronchoscopy does not always result in pathological specimens being obtained. Therefore, we investigated whether virtual bronchoscopic navigation (VBN) findings were associated with the rate of diagnosis of primary lung cancer by bronchoscopy in patients with peripheral lung lesions. METHODS: This study included patients with suspected malignant peripheral lung lesions who underwent bronchoscopy at St. Luke's International Hospital between October 2013 and March 2020. Patients diagnosed with primary lung cancer were grouped according to whether their pathology could be diagnosed by bronchoscopy, and their clinical factors were compared. In addition, the distance between the edge of the lesion and the nearest branch ("distance by VBN") was calculated. The distance by VBN and various clinical factors were compared with the diagnostic rates of primary lung cancer. RESULTS: The study included 523 patients with 578 lesions. After excluding 55 patients who underwent multiple bronchoscopies, 381 patients were diagnosed with primary lung cancer. The diagnostic rate by bronchoscopy was 71.1% (271/381). Multivariate analysis revealed that the lesion diameter (odds ratio [OR] 1.107), distance by VBN (OR 0.94) and lesion structure (solid lesion or ground-glass nodule; OR 2.988) influenced the risk of a lung cancer diagnosis. The area under the receiver operating characteristic curve for diagnosis based on lesion diameter and distance by VBN was 0.810. CONCLUSION: The distance by VBN and lesion diameter were predictive of the diagnostic rates of primary lung cancer by bronchoscopy in patients with peripheral lung lesions.

Elevated plasma levels of Krebs von den Lungen-6 and geographic appearance on high-resolution computed tomography are associated with diffuse alveolar damage in autopsy cases of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Although diffuse alveolar damage (DAD) is a histopathological hallmark of acute respiratory distress syndrome (ARDS), its detection without lung biopsy is challenging. In patients with ARDS, the specificity of the Berlin definition to diagnose DAD as a reference standard is not adequately high, making it difficult to adequately diagnose DAD. The purpose of this study was to investigate the relationship between DAD and clinical findings, including KL-6 and geographic appearance, in ARDS patients and to identify more specific diagnostic criteria for DAD. METHODS: Among all adult autopsy cases at a tertiary hospital in Japan between January 2006 and March 2021, patients with ARDS who met the Berlin definition criteria were included. The patients' conditions were classified according to histopathological patterns as DAD or non-DAD, and clinical characteristics, laboratory data, and high-resolution computed tomography (HRCT) findings were compared between the two groups. RESULTS: During the study period, 27 met the Berlin definition (median age: 79 years, 19 men), of whom 18 (67%) had DAD and 9 (33%) did not. In the non-DAD group, histopathologic findings revealed organizing pneumonia in seven patients and pulmonary hemorrhage in two patients. On HRCT at onset, patients with DAD had more geographic appearance than those without DAD (89% vs. 44%). In patients with geographic appearance and elevated KL-6 (> 500 U/mL), the sensitivity and specificity for DAD diagnosis were 56% and 100%, respectively. All three patients with no geographic appearance and normal KL-6 did not have DAD. CONCLUSIONS: Geographic appearance on HRCT combined with KL-6 levels may predict the presence of DAD in patients with ARDS.

[Safety of pemetrexed according to the duration of vitamin B12 and folic acid supplementation prior to the first dose of pemetrexed].

OBJECTIVE: Administration of vitamin B12 and folic acid for 7 days prior to the administration of the first dose of pemetrexed is recommended. However, vitamin supplementation rarely is initiated less than 7 days prior to the first dose of pemetrexed. Therefore, we analyzed the safety of pemetrexed with vitamin supplementation for less than 7 days prior to the first dose of pemetrexed. METHODS: Patients were classified into 2 groups according to the duration of vitamin supplementation prior to the first dose of pemetrexed: group A received vitamin supplementation for 7 days or more, and group B received vitamin supplementation for less than 7 days. We analyzed adverse effects, such as myelosuppression, rash, and diarrhea, after 1 cycle of pemetrexed therapy. RESULTS: A total of 70 patients were administered pemetrexed; 40 patients were men and 30 were women with a median age of 64.5 years(range, 43-86 years). A total of 57 patients were classified into group A and 13 into group B; 33 patients were administered pemetrexed as a first-line treatment. Neutropenia of Grade 3 or more was observed in 4/49(8.2%)patients in group A and 2/13(15.4%)patients in group B(p=0.60). There were no significant differences in the rates of occurrence of neutropenia, rash, and diarrhea. CONCLUSION: This retrospective study indicated that patients could be safely treated with pemetrexed if vitamin supplementation is initiated for less than 7 days prior to the first administration of pemetrexed. However, further studies are needed because of a lack of statistical power and adjustment for confounding factors.

Successful thoracoscopic operative approach for refractory pneumothorax in interstitial lung disease under local anaesthesia.

Refractory pneumothorax associated with interstitial lung disease (ILD) remains a challenging condition due to the patient's tolerability and lung compliance that restrict the feasibility of aggressive interventions. Additionally, many cases recur after improvement with treatment, and reports of successful management for this complicated condition are limited. Herein, we report the case of a 60-year-old man with ILD, utilizing home oxygen therapy, who experienced a successful recovery from a surgical intervention under local anaesthesia for pneumothorax. This case highlights the potential for operative intervention under local anaesthesia as a viable option for patients who do not respond to internal approaches.

Antimicrobial therapy for nontuberculous mycobacterial pulmonary disease improved hearing loss and normalized myeloperoxidase-anti-neutrophil cytoplasmic antibody level: A case report.

Several case reports have indicated that nontuberculous mycobacterial pulmonary disease is associated with anti-neutrophil cytoplasmic antibody-associated vasculitides. However, the effect of the treatment for nontuberculous mycobacterial pulmonary disease on anti-neutrophil cytoplasmic antibody-associated vasculitides remains unclear. An asymptomatic 80-year-old woman presented with nodular bronchiectasis. After 1 year, she developed a productive cough. Mycobacterial culture of the respiratory specimen revealed Mycobacterium avium. She was diagnosed with nontuberculous mycobacterial pulmonary disease based on the criteria proposed by the American Thoracic Society. Concurrently, she had hearing loss, tinnitus, and weight loss. A blood test showed an elevated level of myeloperoxidase-anti-neutrophil cytoplasmic antibody (107 IU/mL, normal level: <3.5 IU/mL). Bilateral otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis was diagnosed based on the diagnostic criteria proposed by the Japan Otological Society. After starting antimicrobial agents for the nontuberculous mycobacterial pulmonary disease, her pulmonary symptoms and hearing loss improved, and the level of myeloperoxidase-anti-neutrophil cytoplasmic antibody normalized. No immunosuppressive treatment was administered. The present case suggests that nontuberculous mycobacterial pulmonary disease can cause otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitides, and antimicrobial treatment for the nontuberculous mycobacterial pulmonary disease may resolve otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitides.

Investigating Viral Involvement in Immunocompromised Patients Using Comprehensive Infectious Disease Testing Including FilmArray Respiratory Panel 2.1 on Bronchoscopy: A Retrospective Study.

Introduction Reports are rare on the usefulness of the FilmArray Respiratory Panel 2.1 (FARP) using lower respiratory tract specimens. This retrospective study assessed its use, as part of a comprehensive infectious disease panel, to detect the viral causes of pneumonia using bronchoalveolar lavage samples from immunosuppressed patients. Methods This study included immunocompromised patients who underwent bronchoalveolar lavage or bronchial washing by bronchoscopy between April 1, 2021, and April 30, 2022. The collected samples were submitted for comprehensive testing, including FARP test; reverse transcription polymerase chain reaction (RT-PCR) for cytomegalovirus, varicella-zoster virus DNA, and herpes simplex virus; PCR for Pneumocystis jirovecii DNA; antigen testing for Aspergillus and Cryptococcus neoformans; and loop-mediated isothermal amplification method for Legionella. Results Out of 23 patients, 16 (70%) showed bilateral infiltrative shadows on computed tomography and three (13%) were intubated. The most common causes of immunosuppression were anticancer drug use (n=12, 52%) and hematologic tumors (n=11, 48%). Only two (9%) patients tested positive for severe acute respiratory syndrome coronavirus 2 and adenovirus by FARP. Four patients (17%) tested positive for cytomegalovirus by RT-PCR, but no inclusion bodies were identified cytologically. Nine (39%) patients tested positive for Pneumocystis jirovecii by PCR, but cytology confirmed the organism in only one case. Conclusions Comprehensive infectious disease testing, performed using bronchoalveolar lavage samples collected from lung lesions in immunosuppressed patients, showed low positive detection by FARP. The viruses currently detectable by FARP may be less involved in viral pneumonia diagnosed in immunocompromised patients.

Progressive pulmonary fibrosis due to diffuse alveolar damage in a COVID-19-infected autopsy case.

We encountered a patient with severe coronavirus disease 2019 (COVID-19)-related pneumonia, who died of progressive respiratory acidosis after 2 months of treatment with mechanical ventilation. The autopsy revealed diffuse alveolar damage (DAD) without any active signs of fungal or bacterial infections, suggesting prolonged and over-activated immune responses against COVID-19 infection. When COVID-19 patients develop acute respiratory distress syndrome, it is essential to remember that the infection can progress to DAD a few months after the disease onset.

Bronchoscopy for the diagnosis of nontuberculous mycobacterial pulmonary disease: Specificity and diagnostic yield in a retrospective cohort study.

BACKGROUND: Bronchoscopy is a recognized method for obtaining specimens for the diagnosis of nontuberculous mycobacterial pulmonary disease (NTM-PD). However, its diagnostic properties remain to be elucidated. The aim of this study was to determine the specificity of bronchoscopy for the diagnosis of NTM-PD, and to examine the diagnostic yield of bronchoscopy for detecting nontuberculous mycobacteria (NTM) when patients cannot expectorate sputum with NTM. METHODS: This retrospective cohort study included 2657 patients who underwent bronchoscopy and mycobacterial culture between January 2004 and June 2018 in a tertiary care center in Tokyo, Japan. To examine the specificity of bronchoscopy, the first cohort comprised patients who underwent bronchoscopy for the diagnosis of lung cancer and mycobacterial culture. To investigate the diagnostic yield, patients with nodular bronchiectasis who underwent bronchoscopy for the diagnosis of NTM-PD were enrolled into the second cohort. RESULTS: In total, 919 patients were diagnosed with lung cancer, 19 patients showed positive culture for NTM, and 14 patients showed findings for NTM-PD. Accordingly, the specificity was calculated as 900/905 (99.4%). In addition, NTM-PD was suspected before bronchoscopy in 199 patients; the diagnostic yield was 105/199 (52.8%). Four factors were associated with NTM-PD: upper lobe examination, absence of specific bacteria, absence of connective tissue disease, and a higher total computed tomography score. CONCLUSIONS: Bronchoscopy has a high specificity for the diagnosis of NTM-PD. In addition, even when NTM is undetected in sputum, bronchoscopy may detect mycobacteria in approximately half of the patients suspected of having NTM-PD.

A case of a thoracic mass negative on thoracentesis diagnosed by cryobiopsy from the visceral pleura.

Thoracoscopy under local anaesthesia is recommended for malignant tumours with negative pleural effusion cytology. Cryobiopsy from the visceral pleura by thoracoscopy under local anaesthesia can provide more diagnostic options for patients with thoracentesis-negative malignant effusions. Here we present the first case in which this technique was used. The patient had a pleural metastasis that could not be diagnosed even with rapid cytology of the parietal pleura biopsy. Indications, technical pitfalls, and safety tips are discussed.

Steroid resistance and rebound phenomena in patients with COVID-19.

BACKGROUND: In patients with coronavirus disease (COVID-19) pneumonia, corticosteroids reduce progression to respiratory failure and death. Some patients, however, remain unresponsive to this treatment, or experience a rebound after termination. METHODS: This retrospective cohort study included COVID-19 patients treated with systemic corticosteroids in a Japanese hospital between June 1, 2020, and January 17, 2021. Patients were categorized into three groups: success, rebound, and refractory, and clinical characteristics and outcomes were compared. RESULTS: A total of 319 COVID-19 patients were admitted to our hospital and 113 patients met inclusion criteria. The success group had 83 patients (73.5%), the rebound group had nine patients (8.0%), and the refractory group had 21 patients (18.6%). Compared with the success group, the rebound group received corticosteroids earlier, for a shorter duration, and stopped them sooner. The median time from symptom onset to rebound was 12 days. There was no rebound after 20 days. Compared with the success group, the hazard ratio for the number of days from corticosteroid onset to an improvement of two points on a seven-point ordinal scale was 0.29 (95% confidence interval [CI], 0.14-0.60, P < .001) for the rebound group versus 0.13 (95% CI, 0.07-0.25, P < .001) for the refractory group. CONCLUSIONS: COVID-19 patients treated with corticosteroids were classified into three response groups: success, rebound, and refractory, between which recovery time and prognosis differed. It was found that corticosteroid administration may prevent rebound phenomena if administered at least two weeks from symptom onset.

Identification of patients with COVID-19 who are optimal for methylprednisolone pulse therapy.

BACKGROUND: Corticosteroids have been reported to reduce the mortality rates in patients with coronavirus disease 2019 (COVID-19). Additionally, the role of high-dose methylprednisolone pulse therapy in reducing mortality in critically ill patients has also been documented. The purpose of this study is to identify patients with COVID-19 who are suitable for methylprednisolone pulse therapy. METHODS: This was a retrospective study that included patients with COVID-19 receiving methylprednisolone pulse therapy (≥250 mg/day for 3 days) with subsequent tapering doses at our hospital between June 2020 and January 2021. We examined the differences in background clinical factors between the surviving group and the deceased group. RESULTS: Out of 156 patients who received steroid therapy, 17 received methylprednisolone pulse therapy. Ten patients recovered (surviving group) and seven patients died (deceased group). The median age of the surviving and deceased groups was 64.5 years (range, 57-85) and 79 years (73-90), respectively, with a significant difference (p=0.004). Five of the deceased patients (71%) had developed serious complications associated with the cause of death, including pneumothorax, pneumomediastinum, COVID-19-associated pulmonary aspergillosis, cytomegalovirus infection, and bacteremia. On the other hand, out of the 10 survivors, only one elderly person had cytomegalovirus infection and the rest recovered without complications. CONCLUSION: Administration of methylprednisolone pulse therapy with subsequent tapering may be an effective treatment in patients with COVID-19 up to the age of early 70s; however, severe complications may be seen in elderly patients.

Bereaved Family Members' Perceived Care at the End of Life for Patients with Noncancerous Respiratory Diseases.

Background: Data regarding the quality of end-of-life care for patients with noncancerous illnesses are lacking. Objective: This study aimed to evaluate end-of-life care for patients with noncancerous respiratory disease from the perspective of bereaved family members and explore the factors associated with the quality of patient death and care. Design: This cross-sectional study included patients who had died of noncancerous respiratory disease in general wards of pulmonary department in Japan between 2014 and 2016 and conducted an anonymous self-report questionnaire survey for the patients' bereaved family members. Measurements: We evaluated overall satisfaction with care and the quality of death and end-of-life care using the Good Death Inventory (GDI) and Care Evaluation Scale (CES), respectively. A multiple linear regression analysis was performed to explore the factors associated with these outcomes. Results: In total, 130 questionnaires were distributed, and the effective response rate was 38% and 50 patients were included (median age: 82 [range 58-101] years; 37 men [74%]). Primary diagnoses at death included 29 cases of pneumonia (58%), 15 interstitial lung disease (30%), and 3 chronic obstructive pulmonary disease (6%). Of the bereaved family members, 26 (52%) were spouses, and 19 (38%) were children (median age [range]: 68 [33-102] years, 15 men [30%]). The overall CES and GDI scores (mean ± standard deviation) were 77 ± 15 and 79 ± 15, respectively. The presence of dementia was an independent factor associated with high CES and GDI scores in the multiple linear regression analysis. Conclusions: In patients who died of noncancerous respiratory disease, the presence of dementia could be associated with the higher quality of patient death and care. In dementia, an understanding of the terminal nature of this condition may lead to an appropriate end-of-life care.

Pectoralis Muscle Mass on Chest CT at Admission Predicts Prognosis in Patients with Pneumonia.

Methods: A retrospective cohort study was performed in patients aged 18 years or older with pneumonia who underwent chest CT within 24 hours of admission between April 2014 and March 2019. We measured the thickness, area, and volume of the pectoralis major and minor muscles at the level of the aortic arch. Factors associated with mortality were examined using logistic regression analysis. Results: A total of 483 patients (mean age 77 ± 14 years, 300 men (62%)) were included, and fifty-one patients (11%) died during admission. In univariate analysis, decreased thickness, area, and volume of the pectoralis major and minor muscles were associated with higher in-hospital mortality. Multivariate analysis with adjustment for age, gender, serum albumin, and A-DROP revealed that thinner pectoralis major and minor muscles were independent factors of poor prognosis (odds ratio: 0.878, 95% confidence interval (CI): 0.783-0.985, P=0.026 and odds ratio: 0.842, 95% CI: 0.733-0.968, P=0.016, respectively). Approximately 25% of the patients died when the pectoralis minor muscle thickness was 5 mm or less, and no patients died when it was 15 mm or more. Conclusion: The pectoralis muscle mass may be an independent prognostic factor in hospitalized patients with pneumonia.

Reproducibility of peripheral branches in virtual bronchoscopic navigation using VINCENT and LungPoint software for peripheral lung lesions.

BACKGROUND: Recently, virtual bronchoscopic navigation (VBN) has become frequently used for the pathological specimen collection of peripheral lung lesions using various VBN software packages. Herein, we examined the reproducibility of peripheral branches in VBN software using LungPoint and VINCENT versions 4.0 and 5.5. METHODS: This study included patients suspected of malignant peripheral lung lesions who underwent bronchoscopy at our hospital from February 2016 to April 2017. Computed tomography was taken at a thickness of 1.25 mm in all cases, and VB images were created based on the computed tomography data using LungPoint, or VINCENT version 4.0 or 5.5. One observer read the program-generated VB images and compared how many branches could be visualized with the lobe bronchus as the primary branch. RESULTS: A total of 129 patients (n = 131 lesions) underwent bronchoscopy, with 82 cases of primary lung cancer. Pathological bronchoscopic diagnosis was done in 63 cases, resulting to a diagnostic rate of 76.8%. VB images generated by LungPoint, and VINCENT versions 4.0 and 5.5 reproduced an average of 4.3, 3.47, and 5.12 branches, respectively, with significant differences (p < 0.05) between them. CONCLUSIONS: VINCENT version 5.5 exhibits better reproducibility of peripheral branches than LungPoint for VBN.

Left ventricular dysfunction in an idiopathic pulmonary fibrosis patient on nintedanib.

Nintedanib, a tyrosine kinase inhibitor, is approved for the treatment of idiopathic pulmonary fibrosis. We report a case of left ventricular dysfunction in a patient with idiopathic pulmonary fibrosis treated with nintedanib, which recovered after cessation of nintedanib. Nintedanib may induce left ventricular dysfunction, and early recognition is important since this condition is potentially reversible.

Eribulin-induced Interstitial Pneumonia: A Case Series and Retrospective Cohort Study.

Eribulin is a chemotherapeutic agent used for advanced breast cancer, but there are some reports of eribulin-induced lung injuries. Three of our patients experienced eribulin-related lung injuries. Radiology revealed organizing pneumonia in two cases and diffuse ground-glass shadows indicative of hypersensitivity pneumonitis in the third. A retrospective survey of patients treated with eribulin at our hospital identified no other cases of eribulin-induced lung injuries. Overall, drug-related lung injuries occurred in 2.8% of our eribulin-treated patients, which is similar to the rates reported for other anticancer drugs. The findings from these three cases provide guidance for the safe use of eribulin.

Bilateral Pleuritis as the Initial Symptom of Systemic Lupus Erythematosus: A Case Series and Literature Review.

We documented four cases of systemic lupus erythematosus (SLE) presenting with pleuritis as the initial disease manifestation. The diagnosis was challenging because, atypically, all patients were elderly and 3 of the 4 patients were men. Furthermore, SLE pleuritis, characterized by lymphocytic pleural effusion and high ADA activity, is difficult to differentiate from tuberculous pleurisy. A detailed physical examination, blood tests, and urinalysis are therefore indispensable to ensure an accurate diagnosis. We also reviewed the previously published case reports on SLE patients presenting with pleuritis and discussed the relevant findings.

Yellow Nail Syndrome Patients with Diffuse Panbronchiolitis-like Pulmonary Manifestation.

Yellow nail syndrome (YNS) is a rare clinical syndrome characterized by a triad of yellow thick nail, lymphedema and respiratory diseases. We experienced 2 cases of YNS with diffuse panbronchiolitis (DPB)-like pulmonary manifestation. Since YNS might be hidden to those who have been diagnosed with DPB, physicians should be alert to recognize nail signs of YNS in case of DPB refractory to macrolide therapy. We hereby review previous case reports of YNS and discuss its pulmonary manifestations.

Digital Clubbing Is Associated with Higher Serum KL-6 Levels and Lower Pulmonary Function in Patients with Interstitial Lung Disease.

Background: Although digital clubbing is a common presentation in patients with interstitial lung disease (ILD), little has been reported regarding its role in assessing patients with ILD. This study evaluated patients with ILD for the presence of clubbing and investigated its association with clinical data. Methods: We evaluated patients with ILD who visited the teaching hospital at which the study was conducted, between October 2014 and January 2015. Clubbing, evaluated using a Vernier caliper for individual patients, was defined as a phalangeal depth ratio > 1. We examined the association of clubbing with clinical data. Results: Of 102 patients with ILD, we identified 17 (16.7%) with clubbing. The partial pressure of oxygen in arterial blood was lower (65.2 ± 5.9 mmHg versus 80.2 ± 3.1 mmHg; p=0.03), serum Krebs von den Lugen-6 (KL-6) levels were higher (1495.0 ± 277.4 U/mL versus 839.1 ± 70.2 U/mL; p=0.001), and the percent predicted diffusing capacity of carbon monoxide was lower (50.0 ± 6.0 versus 73.5 ± 3.1; p=0.002) in these patients with clubbing. Conclusions: Patients with clubbing had lower oxygen levels, higher serum KL-6 levels, and lower pulmonary function than those without clubbing.