Kensuke Fukumitsu

Serum Periostin as a Biomarker for Comorbid Chronic Rhinosinusitis in Patients with Asthma

Rationale: Periostin is a matricellular protein that is involved in the pathophysiology of allergic rhinitis, chronic rhinosinusitis, and asthma. Associations of serum periostin with systemic and airway eosinophilic inflammation and comorbid chronic rhinosinusitis in patients with asthma have been demonstrated. Although serum periostin is positioned as a marker of helper T cell 2 immune responses, its implication regarding the presence of comorbid upper airway diseases in patients with asthma remains unclear. Objectives: To investigate the utility of serum periostin as a diagnostic biomarker for upper airway disease in patients with asthma. Methods: We prospectively enrolled 65 patients with stable asthma, 20 without upper airway disease, 22 with rhinitis, and 23 with chronic rhinosinusitis (13 with nasal polyps, 10 without). Serum periostin, eotaxin, total IgE, fractional exhaled nitric oxide, and blood and sputum eosinophil levels were measured and compared between upper airway disease subtypes. We evaluated the utility of each biomarker in detecting upper airway disease, associations among the biomarkers, and severity of upper airway disease as measured by the Lund‐Mackay score for sinus computed tomography. Results: Serum periostin levels were higher in patients with asthma who had chronic rhinosinusitis (109.6 ± 47.4 ng/ml) than in those without upper airway disease (83.2 ± 22.9 ng/ml) (P = 0.04). Serum periostin levels in patients with asthma who had chronic rhinosinusitis and nasal polyps were significantly higher (130.0 ± 46.6 ng/ml) than in those without nasal polyps (87.9 ± 37.7 ng/ml) (P = 0.001). Serum periostin levels were not associated with the presence or the severity of rhinitis. In contrast, receiver operating characteristic curve analyses showed moderate diagnostic accuracy for detecting chronic rhinosinusitis (area under the curve, 0.71; P = 0.01) and high accuracy for chronic rhinosinusitis with nasal polyps (area under the curve, 0.86; P = 0.0002). When we compared patients with asthma who had comorbid chronic rhinosinusitis and nasal polyps with patients with asthma without these comorbidities, we found serum periostin to be the sole biomarker among those tested for detecting the presence of nasal polyps. Serum periostin was also the sole biomarker that significantly correlated with Lund‐Mackay score in patients with chronic rhinosinusitis (r = 0.44; P = 0.04). Conclusions: Serum periostin is useful for detecting chronic rhinosinusitis with nasal polyps and predicting radiological chronic rhinosinusitis severity in patients with asthma. Clinical trial registered with the UMIN Clinical Trials Registry (UMIN000017533).

A suspected case of inflammatory bronchial polyp induced by bronchial thermoplasty but resolved spontaneously

Bronchial thermoplasty (BT) is a novel treatment for patients with severe asthma (1). Although respiratory adverse events such as asthma attack, atelectasis, and pneumonia are widely known as complications following BT (1), endobronchial organic lesions such as inflammatory bronchial polyps are not generally recognized as such by clinicians. We experienced a suspected case of an inflammatory bronchial polyp induced by BT that showed a spontaneous resolution. Written patient consent was obtained for this case report.

Combined measurements of fractional exhaled nitric oxide and nasal nitric oxide levels for assessing upper airway diseases in asthmatic patients

ABSTRACT Background: Despite the close linkage between rhinitis, chronic rhinosinusitis (CRS) and asthma, relevant biomarkers of both upper and lower airway inflammation are rare. Methods: Patients with asthma (without upper airway disease [UAD; n = 24], with rhinitis [n = 25], CRS [n = 24], and nasal polyps [n = 2]), isolated rhinitis (n = 13), isolated CRS (n = 13), and 10 healthy controls were prospectively recruited. Fractional exhaled nitric oxide (NO) levels at 50 mL/s (FeNO50), nasal NO levels, Lund–Macay-scores of sinus computed tomography and an asthma control questionnaire (ACQ) were evaluated. Results: Asthma was associated with higher FeNO50 levels irrespective of the UAD category. FeNO50 levels were higher in asthmatics with CRS (median: 54.0 ppb) than those with rhinitis (35.2 ppb, p = 0.02) and those without UAD (34.3 ppb, p = 0.002). Nasal NO levels were higher in rhinitis patients than other UAD categories, irrespective of the asthma concomitance. Nasal NO levels were higher in asthmatics with rhinitis (112.8 ppb) than those without UAD (67.2 ppb, p = 0.001) and those with CRS (57.6 ppb, p < 0.0001). A receiver-operating-characteristic curve analysis for detecting comorbid allergic rhinitis (AR) in asthmatics showed a high area under the curve (0.87). Nasal NO levels were positively correlated with FeNO50 levels (ρ = 0.56, p = 0.003) in asthmatics with rhinitis. In contrast, they were negatively correlated with the Lund–Macay (ρ = −0.46, p = 0.03) and ACQ scores (ρ = −0.52, p = 0.009) in asthmatics with CRS. Conclusions: Higher nasal NO levels reflect the presence of AR, irrespective of asthma concomitance. Higher FeNO50 levels reflect the presence of CRS and asthma. These NO measurements are useful for assessing comorbid UAD in asthmatics.

TTF-1 Expression Predicts the Merit of Additional Antiangiogenic Treatment in Non-squamous Non-small Cell Lung Cancer

Background/Aim: To investigate whether TTF-1 expression predicts a beneficial response of non-squamous non-small-cell lung cancer (NS-NSCLC) patients to bevacizumab. Patients and Methods: We retrospectively screened 118 advanced NS-NSCLC patients who were treated with pemetrexed plus platinum derivatives alone (Bev(−)) or with bevacizumab (Bev(+)), and investigated the relationship between expression of TTF-1 and treatment outcomes. Results: Among the 92 TTF-1-positive patients, clinical outcomes in the Bev(+) group were significantly better than those in the Bev(−) group (response rate, 51.4% vs. 27.3%, p=0.027; median progression-free survival, 216 days vs. 137 days, p=0.012). Overall survival in the Bev(+) group tended to be longer than that in the Bev(−) group. However, the addition of bevacizumab to the standard treatment of 26 TTF-1-negative patients offered no clinical benefit. Conclusion: TTF-1 expression may serve as a predictive marker to identify patients who may benefit from the addition of bevacizumab to platinum doublet therapy.

Bronchial Thermoplasty for Severe Asthmatic Cough

Background: Bronchial thermoplasty is a novel treatment for severe asthma that reduces the volume of airway smooth muscles and the number of airway nerves and epithelial neuroendocrine cells (1). These reductions are associated with fewer asthma exacerbations. However, little is known about the efficacy of this therapy on cough. Objective: To describe a patient with severe, cough-predominant asthma whose cough was alleviated by bronchial thermoplasty. Case Report: A 35-year-old woman presented with a 2.5-year history of chronic cough. The patient was diagnosed with asthma 6 months earlier on the basis of wheezing on auscultation and the ability of inhaled salbutamol to increase FEV1 by 13.8% above baseline levels. The cough had worsened and was awakening the patient and disturbing conversation despite treatment with high-dose inhaled corticosteroids, long-acting 2-agonists, and leukotriene-receptor antagonists. A 7-day course of oral prednisolone, 20 mg/d, also had not improved the cough. The patient had a cough visual analogue scale score of 67 mm (range, 0 to 100 mm, with lower scores indicating less frequent cough) and a total Leicester cough questionnaire score of 9.1 (range, 3 to 21, with higher scores indicating better quality of life). These findings documented that the cough was frequent and severe. In addition, the patient had an asthma control test score of 16 (range, 5 to 25, with higher scores reflecting greater asthma control and scores>19 indicating well-controlled asthma). Blood eosinophil counts and levels of exhaled nitric oxide and serum IgE were normal, and we could not detect sensitization to inhaled aeroallergens (data not shown). On capsaicin cough sensitivity testing using the fixed-time inhalation method, an inhalation of the lowest capsaicin concentration (0.61 mcM) evoked 7 coughs (Table). Table. Time Course of the Number of Coughs in Response to Capsaicin* We began treatment with sustained theophylline, tiotropium, and erythromycin, but cough frequency, cough-specific quality of life, asthma control, and the number of capsaicin-induced coughs remained unchanged at 6-month follow-up (Figure). We used bronchial thermoplasty to treat all visible bronchi with heat energy at 65C for 10 seconds during 3 procedures at 3-week intervals for a total of 138 activations. The cough improved immediately after the first procedure. Three months after the final procedure, we documented improvements in cough frequency (cough visual analogue scale score, 36 mm), cough-related quality of life (Leicester cough questionnaire score, 14.6), and asthma control (asthma control test score, 19). The number of capsaicin-induced coughs also decreased, but measures of systemic eosinophilic and airway inflammation and pulmonary function remained unchanged. Figure. Clinical course of cough frequency, cough-specific quality of life, asthma control, and clinical indices. ACT= asthma control test; BT= bronchial thermoplasty; FeNO= fractional exhaled nitric oxide; LCQ= Leicester cough questionnaire; LLL= left lower lobe; LUL= left upper lobe; RLL= right lower lobe; RUL= right upper lobe; VAS= visual analogue scale. * Higher scores indicate better cough-related quality of life. The minimum clinically important difference is1.3. Lower scores indicate less frequent cough. Discussion: Some patients have asthmatic cough that is frequent and severe enough to justify the aggressive treatment that we used in this patient (2). Understanding how this treatment works would be comforting, but we can only speculate about the mechanism. Asthmatic cough is generally induced by bronchoconstriction via A- fibers of the airway smooth muscle (3), and acute bronchoconstriction promotes the capsaicin cough response (4). Airway neuronal dysfunction may therefore be a useful therapeutic target. Patients with stable asthma, particularly women and nonatopic patients, have a more pronounced cough response to capsaicin than healthy persons (5). This patients capsaicin cough response improved after bronchial thermoplasty, which suggests that this therapy may alter the expression of transient receptor potential vanilloid-1, the capsaicin receptor. This receptor is a nonselective cation channel that is activated by temperatures greater than 43C; acidic conditions; capsaicin, which is the irritating compound in hot chili peppers; and allyl isothiocyanate, which is the pungent compound in mustard and wasabi. Decreasing neuronal dysfunction and altering the capsaicin receptor may thus have contributed to this patients improvement. Whatever the explanation, we believe that other clinicians should consider bronchial thermoplasty for patients with severe asthmatic cough who have not responded to more conventional therapies.

Summer-type hypersensitivity pneumonitis in a patient with rheumatoid arthritis on methotrexate and tacrolimus: Hypersensitivity pneumonitis with RA

A 59‐year‐old woman receiving methotrexate and tacrolimus for rheumatoid arthritis (RA) was referred to our hospital following bilateral ground‐glass opacity observed in her chest X‐ray and elevated serum KL‐6. After methotrexate and tacrolimus cessation, shortness of breath developed and ground‐glass opacity observed in the chest computed tomography rapidly worsened. Bronchoalveolar lavage showed increased lymphocytes, and trans‐bronchial lung biopsy confirmed lymphocytic alveolitis. In addition, the patient had serum antibodies against Trichosporon asahii, a fungal pathogen. The mildew in her bathroom and washing machine which were the source of the fungus were removed, which resulted in no further relapse of the condition. In this patients case, methotrexate and tacrolimus may have masked and suppressed summer‐type hypersensitivity pneumonitis.