Effect of inhaled corticosteroids on bone mineral density in patients with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are a safe treatment for asthma. However, at higher doses, ICS use has been reported to inhibit adrenocortical function. OBJECTIVE: This study aimed to evaluate the effect of ICS on bone mineral density (BMD) in adult patients with asthma. METHODS: Ultrasonic bone densitometry was performed in 40 patients (14 men, 26 women, mean age 61.2 years, mean duration of asthma 6.19 years) who were receiving ICS for asthma, and the whole bone density, thickness of cortical bone, and density of cancellous bone of the radius was measured. The age-matched mean was set as 100%. Lifetime cumulative dose of ICS was calculated using all past prescriptions. RESULTS: No significant correlations were observed between lifetime cumulative ICS dose and whole bone density (r² = 0.011), cortical bone thickness (r² = 0.022), and cancellous bone density (r² = 0.004). No significant differences were observed between lower and higher lifetime cumulative ICS dose among these BMD parameters (104% vs 97%, 103% vs 99%, and 106% vs 91%, respectively). No significant correlations or differences in lifetime cumulative ICS dose were observed by asthma severity, asthma duration, and pulmonary function. Also, serum markers of bone metabolism showed no significant correlations or differences with lifetime cumulative ICS dose. CONCLUSIONS: In the entire study population, long-term ICS use was safe and was not associated with an increased risk of osteoporosis.

The role of anti-elastin antibodies in a mouse model of asthma.

BACKGROUND: The role of anti-elastin antibody (Ab) in the lung is unclear, although they may be involved in chronic obstructive pulmonary disease (COPD). Recently, increased anti-elastin Ab levels were reported in asthma. OBJECTIVE: To elucidate the role of anti-elastin Ab in asthma, we created a murine asthma model. Anti-elastin Ab in the airway was neutralized by intratracheal administration of elastin peptide, and the inhibitory effects of anti-elastin Ab on airway remodeling were evaluated. METHODS: BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14. After immunization, the mice received booster OVA via inhalation twice per week for 9 weeks, and bronchoalveolar lavage fluid (BALF) and lung tissues were evaluated. RESULTS: In lung tissues, airway remodeling occurred after 9 weeks of OVA sensitization. Peak levels of anti-elastin Ab and eosinophils in BALF were detected after 3 weeks of OVA sensitization. Anti-elastin Ab and eosinophil levels in BALF were significantly reduced after 3 weeks by the neutralization of anti-elastin Ab. Peak transforming growth factor-ß1 levels in BALF were detected at 3 weeks after OVA sensitization and were significantly reduced by the neutralization of anti-elastin Ab. Airway remodeling in lung tissues was also significantly inhibited by the neutralization of anti-elastin Ab. CONCLUSIONS: In our murine asthma model, anti-elastin Ab was recruited to the airway by OVA-induced allergic inflammation. Airway remodeling was inhibited by the neutralization of anti-elastin Ab. Anti-elastin Ab may contribute to the progression of airway remodeling.

Elevation of anti-elastin antibody in patients with asthma.

BACKGROUND: It is often difficult to differentiate between asthma and chronic obstructive pulmonary disease (COPD), and useful biomarkers are needed for accurate diagnosis. OBJECTIVE: We evaluated anti-elastin antibody to identify useful biomarkers for differentiating between a diagnosis of asthma and COPD. METHODS: Patients with asthma (male to female ratio = 10/13; mean age, 67.3 years), COPD (16/0; 74.8 years) and controls (8/4; 72.3 years) were enrolled. Samples from sputum and serum were collected and levels of anti-elastin Ab were measured. RESULTS: The levels of anti-elastin Ab in sputum were significantly higher in asthma (11.4 ± 7.16 µg/mL) than in COPD (5.82 ± 5.16 µg/mL; P < 0.01), and serum levels in asthma (67.4 ± 29.7 µg/mL) were also significantly higher than in COPD or controls (45.0 ± 12.8 µg/mL; P < 0.05, 38.6 ± 10.4 µg/mL; P < 0.01, respectively). Anti-elastin Ab in sputum showed a positive correlation with smoking in asthma (r2 = 0.218, P < 0.05). However, no significant differences were observed in the levels of anti-elastin Ab and eosinophils, asthma phenotypes, inhaled corticosteroids, or severity in patients with asthma. Elastin was strongly expressed under the airway basement membrane in asthma compared with COPD or the healthy control. CONCLUSIONS: Anti-elastin Ab in sputum could be a useful biomarker for COPD and asthma in ever-smokers. In asthma, anti-elastin Ab was recruited to the airways by both airway allergic inflammation and smoking, and it may contribute to the progression of airway remodeling via autoimmune inflammation, but not emphysema, in COPD.

A mathematical model to predict protein wash out kinetics during whole-lung lavage in autoimmune pulmonary alveolar proteinosis.

Whole-lung lavage (WLL) remains the standard therapy for pulmonary alveolar proteinosis (PAP), a process in which accumulated surfactants are washed out of the lung with 0.5-2.0 l of saline aliquots for 10-30 wash cycles. The method has been established empirically. In contrast, the kinetics of protein transfer into the lavage fluid has not been fully evaluated either theoretically or practically. Seventeen lungs from patients with autoimmune PAP underwent WLL. We made accurate timetables for each stage of WLL, namely, instilling, retaining, draining, and preparing. Subsequently, we measured the volumes of both instilled saline and drained lavage fluid, as well as the concentrations of proteins in the drained lavage fluid. We also proposed a mathematical model of protein transfer into the lavage fluid in which time is a single variable as the protein moves in response to the simple diffusion. The measured concentrations of IgG, transferrin, albumin, and ß2-microglobulin closely matched the corresponding theoretical values calculated through differential equations. Coefficients for transfer of ß2-microglobulin from the blood to the lavage fluid were two orders of magnitude higher than those of IgG, transferrin, and albumin. Simulations using the mathematical model showed that the cumulative amount of eliminated protein was not affected by the duration of each cycle but dependent mostly on the total time of lavage and partially on the volume instilled. Although physicians have paid little attention to the transfer of substances from the lung to lavage fluid, WLL seems to be a procedure that follows a diffusion-based mathematical model.

Cough variant and cough-predominant asthma are major causes of persistent cough: a multicenter study in Japan.

OBJECTIVE: Persistent cough is a frequent cause of doctor and hospital visits, and its incidence may be increasing. However, diagnosis of the cause of cough remains difficult. Because different causes of cough have different treatments, accurate diagnosis of the cause of cough is critical. To gain a better understanding of the causes of cough in Japan, we performed a multicenter epidemiological study of Japanese patients. METHODS: The study involved seven institutions in five different areas of Japan, and was conducted over 1 year from March 2009. Patients aged ≥16 years attending the participating centers for the first time complaining of cough persisting for ≥3 weeks were eligible. Patients with chest X-ray abnormalities responsible for cough, fever or blood-stained sputum were excluded, while those with wheeze or shortness of breath were included. Frequency and severity of cough were assessed using questionnaires, and laboratory tests were performed to enable differential diagnoses. RESULTS: Among the 313 patients evaluated, mean duration of cough symptoms was 192.1 ± 558.4 days. Cough variant asthma (CVA) was the most common cause of prolonged/chronic cough (42.2%), followed by cough-predominant asthma (CPA) (28.4%), atopic cough (7.3%) and chronic obstructive pulmonary disease (6.7%). Patients with an unclear diagnosis were treated with tulobuterol, a transdermal ß2-agonist preparation, for 1-2 weeks. Transdermal tulobuterol improved assessments of cough in patients with CVA or CPA, enabling rapid diagnosis of these diseases. CONCLUSIONS: These findings show that CVA and CPA are the main causes of cough persisting for ≥3 weeks.

Molecular biological analysis in a patient with multiple lung adenocarcinomas.

The utility of molecular biological analysis in lung adenocarcinoma has been demonstrated. Herein we report a rare case presenting as multiple lung adenocarcinomas with four different EGFR gene mutations detected in three lung tumors. After opacification was detected by routine chest X-ray, the patient, a 64-year-old woman, underwent chest computed tomography which revealed a right lung segment S4 ground-glass nodule (GGN). Follow-up computed tomography revealed a 42 mm GGN nodule with a 26 mm nodule (S6) and a 20 mm GGN (S10). Histopathology of resected specimens from the right middle and lower lobes revealed all three nodules were adenocarcinomas. Four EGFR mutations were detected; no three tumors had the same mutations. Molecular biological analysis is a promising tool for the diagnosis of primary tumors in patients with multiple lung carcinomas of the same histotype, enabling appropriate treatment.

Risk factors for disseminated intravascular coagulation in patients with lung cancer.

BACKGROUND: The mortality rate from disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in non-lung cancer patients. Moreover, the prevalence of DIC varies among the pathologic types of lung cancer. This study analyzed the relationship between coagulation factors and the pathologic types of lung cancer. METHODS: Twenty-six patients with progressive, inoperable stage IIB or higher lung cancer (20 men, 6 women; mean age 71 years; 11 Adeno, 10 squamous cell carcinoma, and 5 small cell carcinoma) and five healthy volunteers without respiratory disease (3 men, 2 women; mean age 72 years) were enrolled in the study. Blood samples were collected at lung cancer diagnosis, before treatment. RESULTS: White blood cell count, platelet count, serum C-reactive protein, fibrin/fibrinogen degradation products, fibrinogen, thrombin-antithrombin complex, and D-dimer levels differed significantly between lung cancer patients and the control group, but not among the pathologic types of lung cancer. Thrombomodulin levels were significantly higher in patients with Adeno and squamous cell carcinoma than in those with small cell carcinoma (P < 0.05 and P < 0.01, respectively). Antithrombin levels were significantly lower in patients with squamous cell carcinoma than in those with Adeno (P < 0.05). CONCLUSION: Coagulation disorders may develop secondary to chronic inflammation in patients with progressive lung cancer. DIC in lung cancer may be attributed to changes in anticoagulation factors, such as thrombomodulin and antithrombin, but not in other coagulation factors.

Effect of adjusting the combination of budesonide/formoterol on the alleviation of asthma symptoms.

BACKGROUND: The combination of budesonide + formoterol (BFC) offers the advantages of dose adjustment in a single inhaler according to asthma symptoms. We analyzed the relationship between asthma symptoms in terms of peak expiratory flow (PEF) and dose adjustment by the patient. METHODS: Twenty-eight patients with asthma who used BFC for alleviation of their symptoms (12 men, 16 women; 60 years old) were instructed that the inhaled BFC dose could be increased to a maximum of 8 inhalations per day according to symptom severity. Patients measured and recorded PEF every morning and evening in their asthma diary along with their symptoms and the dose of drugs taken. RESULTS: Sixteen of the 28 patients increased their dose for asthma symptoms. The time to recovery from the asthma symptoms was significantly shorter when cough was the only symptom present compared with dyspnea or wheeze (1.4 vs. 5.3 or 6.6 days, p < 0.05) and when they had only one symptom compared with two or three symptoms (1.3 vs. 5.7 or 10.5, p < 0.01). The relationship between PEF (% of personal best) when the dose was increased (Y) and the days for the increased dose to achieve a PEF greater than PEF in the symptom-free state (X) was determined to be Y = - 0.591X + 89.2 (r2 = 0.299, p < 0.001). CONCLUSION: As a guide for increasing the BFC dose when patients with mild asthma have asthma symptoms, the dose should be increased when cough is present or PEF is decreased to 88.9% (i.e., X = 0.5).

Effect of Thrombomodulin Alfa on Disseminated Intravascular Coagulation in Patients with Lung Cancer.

Objective The mortality rate due to disseminated intravascular coagulation (DIC) is higher in patients with lung cancer than in those without. We examined the effect of treatment with thrombomodulin alfa (TM-α) for DIC in lung cancer patients. Methods Subjects were 57 patients with DIC (43 men, 14 women; mean age, 71.7 years), comprising 31 with lung cancer and 26 without. DIC patients with or without lung cancer did not differ significantly in their background characteristics. Results No significant difference was noted in the mortality rate between patients with lung cancer (61.3%) and those without (57.7%). However, the dose of TM-α was higher for survivors with lung cancer than for non-survivors (473.1 U/kg/day vs. 380.6 U/kg/day; p<0.01). Although no significant difference was noted in the DIC score between these four groups, the serum C-reactive protein level (6.9 mg/dL vs. 11.6 mg/dL; p<0.05) and prothrombin time-international normalized ratio (PT-INR; 1.10 vs. 1.52; p<0.05) were lower in survivors with lung cancer than in the non-survivors with lung cancer. The initial body temperature in non-survivors without lung cancer was lower than that in survivors without lung cancer (37.2°C vs. 37.9°C, p<0.01), and the platelet count and the time to recovery from DIC in patients without lung cancer showed a significant negative correlation (r2=0.438, p<0.05). Conclusion Our findings suggest that although 380 U/kg/day of TM-α is the recommended dose for DIC treatment, a higher dose may reduce the mortality rate of lung cancer patients with DIC. Furthermore, TM-α should be initiated before worsening of DIC parameters.