Significance of Self-Injectable Biologics in Japanese Patients with Severe Allergic Diseases: Focusing on Pen-Type Devices and Copayment.

Patients and Methods: A questionnaire survey was administered to 18, 14, and 3 patients introduced to home self-injection of dupilumab or mepolizumab using a pen-type device for atopic dermatitis, asthma alone, and asthma plus chronic rhinosinusitis with nasal polyps, respectively. Results: All but one participant wished to continue self-injection. Most participants affirmed the reduction in copayment (88.6%) and saving time and labor for hospital visits (88.6%). Six patients who received dupilumab complained of side effects, but all, except for one, continued the treatment. Of the 13 patients who had previously used a syringe-type device, 10 preferred the pen type because of its ease of use, while 3 (23%) preferred the syringe type because of the self-adjustable injection speed for pain control. Conclusion: Administration of biologics using pen-type devices is easier, and the introduction of home self-injection leads to a reduction in outpatient visits and copayment.

Prognostic value of forced expiratory volume in 1 second/forced vital capacity in idiopathic pulmonary fibrosis.

Emphysema on high-resolution computed tomography of the chest is the recent focus in the general practice in idiopathic pulmonary fibrosis (IPF). However, adequate attention has not been paid to obstructive disorder. Therefore, we retrospectively evaluated the association between the degree of airway obstruction and longevity in IPF subjects, with a hypothesis that lower forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) has an impact on prognosis. One hundred and fourteen consecutive IPF subjects who had been diagnosed with IPF and had undergone evaluation including pulmonary function test from January 2008 to May 2013 were included in the study. The relationship between baseline data and survival was examined. FEV1/FVC was widely distributed, ranging from 48.6% to 100%. On both univariate and multivariate Cox's regression analyses, lower FEV1/FVC was significantly associated with better survival (hazard ratio of 1.07 and 1.04 and 95% confidential interval of 1.03-1.10 and 1.01-1.08, respectively). Even on analysis with backward selection, FEV1/FVC remained a significant prognostic factor. FEV1/FVC is widely distributed and negatively predicts survival in IPF. A FEV1/FVC should be assessed in "real-world" general practice. Also, the effect of smoking on the clinical course of IPF should be investigated further.

Effect of a postoperative outpatient pulmonary rehabilitation program on physical activity in patients who underwent pulmonary resection for lung cancer.

AIM: Physical activity (PA) has been associated with an improvement in survival for individuals with cancer. However, little is known about the effect of postoperative pulmonary rehabilitation on PA after lobectomy in patients with lung cancer. The present study investigated the effect of outpatient rehabilitation on PA in patients with cancer after lung resection. METHODS: A total of 19 patients with lung cancer were recruited for this study and completed a preoperative rehabilitation program. One group of nine patients completed a postoperative outpatient pulmonary rehabilitation program (rehabilitation) and another group of 10 patients did not (control), but were similarly followed up. Preoperative lung function, assessed by forced expiratory volume in 1 s (FEV1 ), body mass index (BMI) and St. George's Respiratory Questionnaire (SGRQ) score were not different between groups. PA was measured before and 2 months after surgery using a three-axis accelerometer for 5-6 days. PA level (PAL) was defined as total energy expenditure divided by basal metabolic rate. RESULTS: Preoperative PAL was not different between groups. However, postoperative versus preoperative PAL was significantly lower in the control versus the rehabilitation group (P < 0.01), and PAL decline was less for the rehabilitation versus the control group (P < 0.001). A subgroup analysis showed improvement in postoperative PAL in rehabilitation patients aged <75 years and older. CONCLUSIONS: Two months after lung resection surgery, patients had not recovered to the preoperative PAL. However, compared with the control group, there was an improvement in the postoperative PAL in patients, including older patients, who underwent outpatient pulmonary rehabilitation. Geriatr Gerontol Int 2016; 16: 550-555.

Effect of ambulatory oxygen on exertional dyspnea in IPF patients without resting hypoxemia.

BACKGROUND AND OBJECTIVE: The effects of ambulatory oxygen for idiopathic pulmonary fibrosis (IPF) patients without resting hypoxemia have not been elucidated. The purpose of this study was to assess the effect of ambulatory oxygen on dyspnea in IPF patients without resting hypoxemia but with desaturation on exertion. METHODS: This was a double-blind, placebo-controlled, randomized crossover trial of ambulatory oxygen versus ambulatory air. Patients with IPF who had a partial pressure of arterial oxygen (PaO2) between 60 mm Hg and 80 mm Hg at rest, and desaturation of 88% or less in a room-air 6-min walk test were eligible. Patients underwent a standardized 6-min walk test and a 6-min free walk test under each ambulatory gas. Oxygen and air were provided at 4 L/min intranasally. Dyspnea was evaluated immediately, 1, and 2 min after the tests. RESULTS: Twenty patients (16 men), with a mean age of 73.5 (SD 4.1) years, % predicted forced vital capacity (FVC) of 71.0 (13.3) %, % predicted diffusion capacity for carbon monoxide (DLco) of 57.0 (13.3) %, and PaO2 of 72.5 (5.4) mm Hg were recruited. No significant differences in dyspnea were observed between ambulatory oxygen and air at each time point. However, some patients showed improvement in dyspnea with oxygen on an individual basis. CONCLUSIONS: Since oxygen provides no additional benefit over air in terms of exertional dyspnea for IPF patients without resting hypoxemia, routine prescription of ambulatory oxygen is not recommended. However, assessment on an individual basis is necessary. Trial registration. UMIN Clinical Trial Registry; No.:UMIN000005098; URL:http://www.umin.ac.jp/ctr/.

The regulation of amiloride-sensitive epithelial sodium channels by tumor necrosis factor-alpha in injured lungs and alveolar type II cells.

Alveolar liquid clearance, which mainly depends on sodium transport in alveolar epithelial cells, is an important mechanism by which excess water in the alveoli is reabsorbed during the resolution of pulmonary edema. In this study, we examined the regulation of epithelial sodium channel (ENaC), the main contributor to sodium transport, during acute lung injury and the direct impact of tumor necrosis factor-alpha (TNF-alpha), one of the important cytokines in acute lung injury, on the ENaC regulation. During the development of pulmonary edema, the increases in the number of neutrophils and the levels of TNF-alpha in blood and bronchoalveolar lavage were seen. In parallel, the mRNA expression of the alpha-, beta- and gamma-ENaC subunits in the whole lung tissue was inhibited to 72.0, 47.8 and 53.9%, respectively. The direct exposure of rat alveolar type II cells to TNF-alpha inhibited the mRNA expression of alpha- and gamma-ENaC to 64.0 and 78.0%, but not that of the beta-ENaC. TNF-alpha also inhibited the ENaC function as indicated by the reduction of amiloride-sensitive current (control 4.4, TNF-alpha 1.9 microA/cm(2)). These data suggest that TNF-alpha may affect the pathophysiology of acute lung injury and pulmonary edema through the inhibition of alveolar liquid clearance and sodium transport.

The possible role of hematopoietic cell kinase in the pathophysiology of COPD.

BACKGROUND: Hematopoietic cell kinase (Hck) is a myeloid cell-specific tyrosine kinase, which is known to induce neutrophil infiltration to the lungs. Although the overexpression of Hck causes emphysema-like histologic changes in mice, its expression and activity in patients with COPD are unclear. METHOD: The aim of this study was to clarify the expression and activity of Hck in neutrophils from COPD patients, and to investigate the association between the degree of Hck expression and the lung function parameters in COPD patients. Peripheral blood neutrophils were isolated from 22 patients with COPD and 9 healthy subjects (HSs). The protein levels of Hck and phosphorylated Hck were assessed, and the correlation with various background characteristics was evaluated. RESULTS: The Hck protein level was significantly higher in neutrophils from COPD patients compared with HSs (COPD patients, 1.094; HSs, 0.801; p < 0.05). A significant positive correlation was observed between the protein level of Hck and the surface expression of the integrin molecule CD-11b (r = 0.540; p < 0.01) or CXC chemokine receptor-1 (r = 0.432; p < 0.05). In contrast, there was no difference in the phosphorylation of the Hck protein between COPD patients and HSs. CONCLUSION: The Hck protein level in peripheral blood neutrophils was increased in COPD patients, suggesting that Hck might have an important role in the neutrophil function and play a key role in the pathophysiology of COPD.

Poor sensitivity of symptoms in early detection of COPD.

The prevalence of chronic obstructive pulmonary disease (COPD) has been increasing. However, COPD is often underdiagnosed. The objective of this study was to determine how many outpatients had persistent airflow limitation and could be diagnosed as COPD by post-bronchodilator spirometry. We also evaluated whether the newly diagnosed patients had any symptoms. All outpatients with liver or general diseases over 40 years old who regularly visited to our hospital were tested for pulmonary function by spirometry. Patients with airflow limitation by the first screening spirometry had further examinations including post-bronchodilator spirometry and chest radiograph by pulmonary specialists. A total of 288 patients accepted a first spirometry. The most common chronic diseases of these patients were chronic hepatitis (33.7%), fatty liver (26.4%), liver cirrhosis (8.3%), diabetes (3.5%) and hypertension (3.1%). Approximately half of the patients had a smoking history. 44 of 288 patients (15.3%) showed airflow limitation by pre-bronchodilator spirometry. Of these, 8 patients did not show airflow limitation by a repeat pre-bronchodilator spirometry nor did 5 patients by post-bronchodilator spirometry. The rest were diagnosed as COPD (80.6%), asthma (16.1%) and bronchiectasis (3.2%). The prevalence of COPD was 8.7%. Approximately half of the patients (13/25, 52.0%) diagnosed as COPD had never complained of any respiratory symptoms. Because symptoms such as dyspnea on exertion, cough and sputum are less sensitive for the diagnosis of COPD, the propagation of spirometry in a general practice/setting should be recommended for establishing the diagnosis rate of COPD rather than relying on the presence of respiratory symptoms.

Prevalence of COPD in primary care clinics: correlation with non-respiratory diseases.

BACKGROUND AND OBJECTIVE: Various extrapulmonary effects and comorbidities have been noted to contribute to the burden of chronic obstructive pulmonary disease (COPD). However, the relationship between the prevalence of COPD and non-respiratory diseases has not been well investigated. The aim of the present study was to determine whether or not COPD is different among patients already suffering from other diseases. METHODS: Spirometry was performed by patients aged >or=40 years old with non-respiratory diseases who visited primary care clinics. Four hundred eighty-one patients performed spirometry and 7 patients were excluded because of poor spirometry maneuvers, resulting in 474 patients that were eligible for the current study. In subjects showing abnormalities in their spirograms, precise diagnoses were made using a questionnaire and chest X-ray examination. RESULTS: Among the 474 patients, airflow limitation (FEV(1)/FVC<70%) was observed in 53 patients (11.2%). Forty-nine patients (10.3%) were diagnosed as COPD and 4 patients (0.8%) as bronchial asthma. Among the various diseases, the prevalence of COPD was significantly higher only in the patients with liver diseases, which was 18.8% (12 of 64 patients). The odds ratio adjusted by both the amount of smoking and age was 2.66 (95%CI 1.06-6.63, p=0.037). CONCLUSIONS: The prevalence of COPD was different according to the type of disease, and patients with liver diseases had a higher prevalence of COPD.

Overexpression of CD-11b and CXCR1 on circulating neutrophils: its possible role in COPD.

BACKGROUND: It has been shown that the beta2-integrin molecule is up-regulated in circulating neutrophils in COPD subjects. However, little has been reported about the expression of the cell surface molecules in such patients and their relationship with pulmonary function. The aim of the present study was to investigate the surface expression of molecules in circulating neutrophils and to clarify their possible role in the airflow limitation of COPD. METHODS: The surface expression of Mac-1 cells (ie, CD-11b and CD-18 cells) and CXC chemokine receptor (CXCR) 1 and CXCR2 of circulating neutrophils obtained from COPD patients and healthy subjects (HSs) was measured by flow cytometry analysis. The serum levels of interleukin (IL)-8 were measured by enzyme-linked immunosorbent assay. RESULTS: Both CD-11b and CXCR1 expression were significantly higher in COPD patients than in HSs (mean [+/- SE] CD-11b concentration: HSs, 9.7 +/- 1.0; COPD patients, 14.2 +/- 1.8 [p < 0.05]; mean CXCR1 concentration: HSs, 9.6 +/- 0.5; COPD patients, 11.9 +/- 0.4 [p < 0.01]). Although aging was positively correlated with the expression of CXCR1 (r = 0.440; p < 0.01), none of the other background factors, including smoking and body mass index, showed a correlation with the expression of the molecules. Although serum IL-8 levels were higher in patients with COPD than in HSs, no significant correlation between serum IL-8 levels and the expression of any molecule was seen. The expression of CD-11b (r = -0.317) and CXCR1 (r = -0.383) showed a significant negative correlation with the severity of airflow limitation (both p < 0.05). CONCLUSIONS: The overexpression of CD-11b and CXCR1 in circulating neutrophils may be associated with the development of airflow limitation in COPD patients.

Agents against cytokine synthesis or receptors.

Various cytokines play a critical role in pathophysiology of chronic inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). The increasing evidence of the involvement of these cytokines in the development of airway inflammation raises the possibility that these cytokines may become the novel promising therapeutic targets. Studies concerning the inhibition of interleukin (IL)-4 have been discontinued despite promising early results in asthma. Although blocking antibody against IL-5 markedly reduces the infiltration of eosinophils in peripheral blood and airway, it does not seem to be effective in symptomatic asthma, while blocking IL-13 might be more effective. On the contrary, anti-inflammatory cytokines themselves such as IL-10, IL-12, IL-18, IL-23 and interferon-gamma may have a therapeutic potential. Inhibition of TNF-alpha may also be useful in severe asthma or COPD. Many chemokines are also involved in the inflammatory response of asthma and COPD through the recruitment of inflammatory cells. Several small molecule inhibitors of chemokine receptors are now in development for the treatment of asthma and COPD. Antibodies that block IL-8 reduce neutrophilic inflammation. Chemokine CC3 receptor antagonists, which block eosinophil chemotaxis, are now in clinical development for asthma therapy. As many cytokines are involved in the pathophysiology of inflammatory lung diseases, inhibitory agents of the synthesis of multiple cytokines may be more useful tools. Several such agents are now in clinical development.

Angioimmunoblastic lymphadenopathy with dysproteinaemia accompanied by pleural effusion.

Angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) is a rare lymphoproliferative disorder characterized by systemic lymphadenopathy, hepatosplenomegaly, loss of body weight, fever, skin eruption, and polyclonal hypergammaglobulinaemia. Occasionally, pulmonary involvement, including pleural effusion, has also been observed. Two cases of AILD accompanied by pleural effusion are reported here. When thoracentesis was performed, an exudative effusion was obtained and there was an increase in soluble interleukin-2 receptor and immunoglobulin G, A, and M in the pleural fluid. Cytologically, atypical plasma cells, and T-cell predominant lymphocytes were also present. These findings are likely to be characteristic of pleural effusions associated with AILD and may prove to be a useful marker for diagnosis.

Modulation of Na+ transport and epithelial sodium channel expression by protein kinase C in rat alveolar epithelial cells.

Although the amiloride-sensitive epithelial sodium channel (ENaC) plays an important role in the modulation of alveolar liquid clearance, the precise mechanism of its regulation in alveolar epithelial cells is still under investigation. Protein kinase C (PKC) has been shown to alter ENaC expression and activity in renal epithelial cells, but much less is known about its role in alveolar epithelial cells. The objective of this study was to determine whether PKC activation modulates ENaC expression and transepithelial Na+ transport in cultured rat alveolar epithelial cells. Alveolar type II cells were isolated and cultured for 3 to 4 d before they were stimulated with phorbol 12-myristate 13-acetate (PMA 100 nmol/L) for 4 to 24 h. PMA treatment significantly decreased alpha, beta, and gammaENaC expression in a time-dependent manner, whereas an inactive form of phorbol ester had no apparent effect. This inhibitory action was seen with only 5-min exposure to PMA, which suggested that PKC activation was very important for the reduction of alphaENaC expression. The PKC inhibitors bisindolylmaleimide at 2 micromol/L and Gö6976 at 2 micromol/L diminished the PMA-induced suppression of alphaENaC expression, while rottlerin at 1 micromol/L had no effect. PMA elicited a decrease in total and amiloride-sensitive current across alveolar epithelial cell monolayers. This decline in amiloride-sensitive current was not blocked by PKC inhibitors except for a partial inhibition with bisindolylmaleimide. PMA induced a decrease in rubidium uptake, indicating potential Na+-K+-ATPase inhibition. However, since ouabain-sensitive current in apically permeabilized epithelial cells was similar in PMA-treated and control cells, the inhibition was most probably related to reduced Na+ entry at the apical surface of the cells. We conclude that PKC activation modulates ENaC expression and probably ENaC activity in alveolar epithelial cells. Ca2+-dependent PKC is potentially involved in this response.

A case of primary lung cancer producing alpha-fetoprotein.

A case of lung carcinoid showing elevated plasma alpha-fetoprotein (AFP) level is reported. A 44-year-old man who complained of the development of bloody sputum had a left hilar lung mass on chest radiograph. The serum level of AFP was markedly increased to 8438 ng/mL. After resection, it was diagnosed as an atypical carcinoid, and the tumour cells were positive for cytoplasmic AFP. AFP is one of the most useful tumour markers for the diagnosis of hepatic cell carcinoma or germ cell tumours. It has also been reported that some primary lung tumours produce AFP. However, these tumours are mainly poorly differentiated adenocarcinomas or large cell carcinomas. A lung carcinoid that produces AFP is extremely rare.

Downregulation of ENaC activity and expression by TNF-alpha in alveolar epithelial cells.

Sodium absorption by an amiloride-sensitive channel is the main driving force of lung liquid clearance at birth and lung edema clearance in adulthood. In this study, we tested whether tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine involved in several lung pathologies, could modulate sodium absorption in cultured alveolar epithelial cells. We found that TNF-alpha decreased the expression of the alpha-, beta-, and gamma-subunits of epithelial sodium channel (ENaC) mRNA to 36, 43, and 16% of the controls after 24-h treatment and reduced to 50% the amount of alpha-ENaC protein in these cells. There was no impact, however, on alpha(1) and beta(1) Na(+)-K(+)-ATPase mRNA expression. Amiloride-sensitive current and ouabain-sensitive Rb(+) uptake were reduced, respectively, to 28 and 39% of the controls. A strong correlation was found at different TNF-alpha concentrations between the decrease of amiloride-sensitive current and alpha-ENaC mRNA expression. All these data show that TNF-alpha, a proinflammatory cytokine present during lung infection, has a profound influence on the capacity of alveolar epithelial cells to transport sodium.

A case of pulmonary intravascular lymphomatosis diagnosed by thoracoscopic lung biopsy.

Intravascular lymphomatosis with primary pulmonary lesion is an extremely rare disease. Although the major clinical symptoms include fever, cough, dyspnea and loss of body weight, these are not diagnostic. Chest radiograph findings are also nonspecific and include bilateral reticular shadow, reticulonodular shadow, ground-glass opacity or wedge-shaped subpleural opacities. Therefore, the antemortem diagnosis is relatively difficult. It is considered that intravascular lymphomatosis is a high-grade malignant lymphoma. However, it has been shown recently that a good response and long-term survival may possibly be obtained through systemic combination chemotherapy. We report a case of intravascular lymphomatosis with primary pulmonary lesion where an early diagnosis was obtained through thoracoscopic lung biopsy and subsequent systemic chemotherapy proved to be quite effective. Because the clinical symptoms or chest radiograph findings are usually nonspecific, it was thought that thoracoscopic lung biopsy could be a useful procedure for early and reliable diagnosis of primary pulmonary intravascular lymphomatosis and that it might contribute to an improved prognosis.

[A case of pulmonary actinomycosis with recurrent hemoptysis].

A 68-year-old man was admitted to our hospital because of hemoptysis in September 1999. Chest CT scans showed a nodular shadow with infiltration in the right S 7. Bronchial arteriography showed vascularization in the right S 7, and bronchial artery embolization was performed. However, in April and October 2000 hemoptysis recurred, and bronchial arteriography showed recurrence of vascularization in the same area, so embolization was performed again. Then, the patient was admitted in March 2001 because of recurrent hemoptysis. CT scans showed growth of the nodular shadow. Right lower lobectomy was performed, and the microscopic findings in the tissue from the resected lobe showed branching filamentous bacteria, and pulmonary actinomycosis was diagnosed. We concluded that pulmonary actinomycosis should be considered in the differential diagnosis of nodular shadows with recurrent hemoptysis.

The impact of phorbol ester on the regulation of amiloride-sensitive epithelial sodium channel in alveolar type ii epithelial cells.

Amiloride-sensitive sodium channel (ENaC) plays an important role in recovery from pulmonary edema. Recently, it has been shown that an activation of protein kinase C (PKC) could affect the mRNA expression of ENaC in rat parotid gland cells and A6 distal nephron epithelial cells. To determine whether an activation of PKC would regulate the mRNA expression or the function of ENaC, we stimulated rat alveolar type II epithelial cells with phorbol 12-myristate 13-acetate (PMA), a potent PKC activator, at a concentration of 100 nM. The mRNA expression of alpha-, beta-, and gamma-ENaC subunits and amiloride-sensitive current were measured. PMA inhibited the mRNA expression of all 3 ENaC subunits (alpha-ENaC: 56.0% +/- 12.1%; beta-ENaC: 62.6% +/- 15.9%; gamma-ENaC: 68.5% +/- 10.6%, respectively) and amiloride-sensitive current (control = 7.0 +/- 1.5 microA/cm(2); PMA = 1.7 +/- 0.9 microA/cm(2)) significantly at 24 hours. On the other hand, 4alpha-phorbol didecanoate 4alpha-PDD, inactive form of PMA, had no inhibitory effect on alpha- and gamma-ENaC expression or amiloride-sensitive current. However, no significant difference was seen in beta-ENaC expression between PMA and 4alpha-PDD. GF 109203X, a wide-range PKC inhibitor, blocked the inhibitory effect of PMA on all ENaC subunits mRNA expression. These results suggest that an activation of PKC may play an important role in the regulation of ENaC mRNA expression and function.

Severe gustatory disorder caused by cisplatin and etoposide.

A 48-year-old woman with small-cell lung cancer received combined chemotherapy consisting of cisplatin (CDDP) and etoposide (Vp-16). Although the gustatory threshold in the glossopharyngeal nerve area was normal (14 dB) before chemotherapy, it rose to 22 dB on day 8 of chemotherapy, and it could not be measured, because of severe gustatory disorder, from day 15 to day 29. In the chorda tympani nerve area, the threshold was normal until day 15, but it could not be measured on day 29. This gustatory disorder continued for 2 more months, until the time of the patient's discharge. Although gustatory disorder caused by anticancer drugs has been reported as a rare side effect, this may be because it has been reported as appetite loss, and it may happen more frequently than reported cases would suggest. As gustatory disorder reduces the patient's quality of life, the presence of this side effect should be given more serious consideration.