Masaki Fujimura

Comparison of atopic cough with cough variant asthma: is atopic cough a precursor of asthma?

Background: We have described a group of patients who present with isolated chronic bronchodilator resistant non-productive cough with an atopic constitution, eosinophilic tracheobronchitis, and airway cough receptor hypersensitivity without bronchial hyperresponsiveness, which we have termed “atopic cough”. Although cough variant asthma (in which the cough responds to bronchodilators) is recognised as a precursor of typical asthma, it is not known whether atopic cough is also a precursor of asthma. Methods: Eighty two patients with atopic cough were retrospectively examined for onset of typical asthma and compared with 55 patients with cough variant asthma (20 untreated patients and 35 treated with long term inhaled beclomethasone dipropionate (BDP), 218–467 μg/day). The median follow up period for patients with atopic cough and cough variant asthma was 4.8 (1–11.5) years and 3.7 (1–12.4) years, respectively. Results: Onset of typical asthma occurred in only one of the patients with atopic cough. In patients with cough variant asthma, typical asthma developed in two of 35 patients taking BDP and six of 20 untreated patients (difference 24.3%, 95% CI 2.8 to 45.8, p<0.02). Conclusions: These findings suggest that cough variant asthma is a precursor of typical asthma but that atopic cough is not. Treatment with inhaled steroids may prevent the transformation of cough variant asthma into typical asthma.

The Japanese Respiratory Society guidelines for management of cough.

Cough is one of the most frequent complaints for which patients seek medical care throughout the world. The exact prevalence of cough in Japan is unknown, but in the UK, 10–15% of the entire population have a daily cough, and in the USA, over 100 million dollars are spent each year on treatment of cough. The aetiology of cough ranges from the selfresolving common cold to life-threatening cardiac disease and lung cancer. Even if the underlying disease has a good prognosis, the energy expended due to cough decreases patient quality of life (QOL). In addition to being a discomfort for patients, cough due to severe acute respiratory syndrome (SARS) and tuberculosis spreads the risk of infection to family, friends and associates. The presence of rhonchi or rales on physical examination or abnormal findings on CXR makes the diagnosis of cough relatively easy, but in the absence of these findings, many patients may complain of a cough for several weeks without a diagnosis. A recent increase in patients with unexplained cough has been noted both by generalists and specialists in pulmonary medicine. Physicians often focus on symptomatic treatment of cough, but suppression of a productive cough with copious sputum production or cough due to aspiration may worsen the patient’s condition. For this reason, the Japanese Respiratory Society has decided to publish the ‘Cough Guidelines’. These guidelines broadly define cough based on duration as acute cough lasting less than 3 weeks, prolonged cough lasting 3–8 weeks and chronic cough lasting longer than 8 weeks. The guidelines are also divided into general and special topics. The special topics include acute cough, prolonged and chronic cough and cough in specific populations (paediatric patients, elderly patients and patients with underlying disease). The authors include paediatricians, internists and ENT specialists. Figure 1.1 shows the incidence of aetiology of cough for each period defined in the guidelines. The most common cause of acute cough is respiratory tract infection, whereas prolonged and chronic coughs of longer duration are more likely due to a non-infectious cause. A consensus report on cough published in the USA has been used in Japan, but many clinicians believe that underlying disease prevalence differs between patients with cough in Japan and Western countries. For example, of the three main causes of chronic cough in Western countries, cough-variant asthma, postnasal drip and gastroesophageal reflux disease (GERD), the latter two are not as prevalent in Japan. Therefore, these guidelines are not necessarily based on reports from Western countries, but are rather designed specifically for Japan. Cough is a common symptom, and the true value of these guidelines is that they are intended not only for pulmonary specialists, but also for the many generalist physicians who provide front-line care for most of these patients. For disorders presenting with persistent or chronic cough, these guidelines offer both simplified diagnostic criteria that can be used in general clinics where special tests are not needed, as well as more stringent diagnostic criteria requiring special tests that can only be performed in larger general or university hospitals with departments of pulmonary medicine. These guidelines are aimed at the differential diagnosis and treatment of common disorders seen in clinical practice. They are not all-inclusive of some

Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids.

BACKGROUND Periostin, an extracellular matrix protein, contributes to subepithelial thickening in asthmatic airways, and its serum levels reflect airway eosinophilic inflammation. However, the relationship between periostin and the development of airflow limitation, a functional consequence of airway remodeling, remains unknown. OBJECTIVE We aimed to determine the relationship between serum periostin levels and pulmonary function decline in asthmatic patients on inhaled corticosteroid (ICS) treatment. METHODS Two hundred twenty-four asthmatic patients (average age, 62.3 years) treated with ICS for at least 4 years were enrolled. Annual changes in FEV1, from at least 1 year after the initiation of ICS treatment to the time of enrollment or later (average, 16.2 measurements over 8 years per individual), were assessed. At enrollment, clinical indices, biomarkers that included serum periostin, and periostin gene polymorphisms were examined. Associations between clinical indices or biomarkers and a decline in FEV1 of 30 mL or greater per year were analyzed. RESULTS High serum periostin levels (≥ 95 ng/mL) at enrollment, the highest treatment step, higher ICS daily doses, a history of admission due to asthma exacerbation, comorbid or a history of sinusitis, and ex-smoking were associated with a decline in FEV1 of 30 mL or greater per year. Multivariate analysis showed that high serum periostin, the highest treatment step, and ex-smoking were independent risk factors for the decline. Polymorphisms of periostin gene were related to higher serum periostin levels (rs3829365) and a decline in FEV1 of 30 mL or greater per year (rs9603226). CONCLUSIONS Serum periostin appears to be a useful biomarker for the development of airflow limitation in asthmatic patients on ICS.

Efficacy of Itraconazole in the Treatment of Patients with Chronic Cough Whose Sputa Yield Basidiomycetous Fungi—Fungus-Associated Chronic Cough (FACC)

Objectives. This controlled study was performed to clarify the therapeutic benefit of itraconazole for the treatment of patients with chronic cough, wherein a sputum culture yielded basidiomycetous (BM) fungi. Methods. Of the 171 patients who visited our hospital for the diagnosis and treatment of chronic cough, BM was detected in the sputum of 39 patients. Informed consents were obtained from 21 patients who were subsequently enrolled in this trial. After the administration of the standard therapy, all the patients were enrolled in a randomized placebo-controlled study with 2 weeks of treatment with a low dose of itraconazole (50 mg/day) (n = 10) in comparison with a corresponding period of treatment with matched placebo (ambroxol hydrochloride 45 mg/day) (n = 11). Coughing was assessed using subjective cough symptom scale and capsaicin cough challenging. Results. The treatment with itraconazole, but not placebo (p = 0.17), was associated with a significant improvement in the cough scale (p = 0.0051); moreover, the improvement achieved with itraconazole was significant (p < 0.001) when compared with that of the placebo. Conclusions. Low-dose itraconazole was shown to be an effective antitussive in patients with chronic cough in which sputum examination yielded BM fungi. The 21 patients described here entailed the following manifestations: (1) chronic cough; (2) the presence of environmental fungi, particularly basidiomycetous (BM) fungi, in the sputum; and (3) good clinical response to antifungal drugs. These clinical features may constitute a unique disease concept called fungus-associated chronic cough (FACC).

The importance of basidiomycetous fungi cultured from the sputum of chronic idiopathic cough:: A study to determine the existence of recognizable clinical patterns to distinguish CIC from non-CIC

BACKGROUND Recently we have reported 5 cases of allergic fungal cough (AFC), which is intractable and is characterized by sensitization to one of basidiomycetous fungus. Because AFC shows good clinical response to antifungal drugs, diagnosing AFC in patients with CIC may lead to the consequent management of CIC. Therefore, we determined the incidence of CIC among our hospital patients, and the frequency of BM fungi in sputum samples collected from patients with CIC. Furthermore we evaluated whether or not a recognizable clinical pattern that distinguishes CIC from non-CIC exists. METHODS The medical records of 70 patients complaining of chronic cough who were referred to our hospital for diagnosis and treatment were analyzed retrospectively. RESULTS The primary diagnoses were CIC (27.0%), cough-variant asthma (30.0%), atopic cough (24.3%), sinobronchial syndrome (8.6%), cough-predominant asthma (7.1%), gastro-esophageal reflux (1.4%), and others (1.4%). In CIC patients, the median age, proportion of females, and frequency of acute upper respiratory tract infection did not differ significantly from those in non-CIC patients. CIC patients had a longer median duration of cough (11.0 months vs. 3.5 months). The positive ratio of BM cultured from the sputa of CIC patients (62.5%) was significantly (p=0.0061) higher than that of non-CIC patients (16.7%). CONCLUSION The existence of BM fungi in induced sputum may be an important factor for distinguishing the clinical manifestation of CIC from that of non-CIC. The clinical approach from the aspect of fungal allergy may serve as a clue that may aid in the successful management of CIC.

Change in bronchial responsiveness and cough reflex sensitivity in patients with cough variant asthma: effect of inhaled corticosteroids

BackgroundCough variant asthma (CVA) is a cause of chronic cough and a precursor of typical asthma. We retrospectively examined the longitudinal change in bronchial responsiveness and cough reflex sensitivity in CVA patients with respect to the effect of long-term inhaled corticosteroids (ICS).MethodsProvocative concentration of methacholine causing a 20% fall in forced expiratory volume in one second (PC20-FEV1) and provocative concentration of capsaicin eliciting 5 or more coughs (C5) were measured before treatment and during a follow up period following relief of cough (median; 2.0 (range; 0.5 to 8.0) years after the initial visit) in a total of 20 patients with CVA (7 males and 13 females, mean ± SD age of 49.9 ± 12.9 years).ResultsThree of 8 patients not taking long-term ICS developed typical asthma compared to none of 12 patients taking ICS (p = 0.0171). PC20-FEV1 significantly (p < 0.0001) increased from 1.80 (GSEM, 1.35) to 10.7 (GSEM, 1.63) mg/ml in patients taking ICS but did not change in patients not taking ICS [2.10 (GSEM, 1.47) compared to 2.13 (GSEM, 1.52) mg/ml]. Cough threshold did not change in patients whether taking or not taking ICS.ConclusionLong-term ICS reduces bronchial hyperresponsiveness in CVA as recognized in typical asthma. Cough reflex sensitivity is not involved in the mechanism of cough in CVA.

Integrating longitudinal information on pulmonary function and inflammation using asthma phenotypes.

From the Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; the Clinical Research Directorate/CMRP, Leidos Biomedical Research (formerly SAIC-Frederick), Frederick National Laboratory for Cancer Research, Frederick, Md; the Division of Allergy and Immunology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; the Clinical Center and the Department of Laboratory Medicine, National Institutes of Health, Bethesda, Md; and the Department of Internal Medicine, Virginia Commonwealth University, Richmond, Va. E-mail: jdmilner@ niaid.nih.gov. Or: twilson@mail.nih.gov. Supported by National Institutes of Health (NIH) U19AI77435, and in part by grants from Food Allergy Research and Education (formerly the Food Allergy and Anaphylaxis Network [FAAN], the Food Allergy Project [FAP], and the Food Allergy Initiative [FAI]), the Buckeye Foundation, and the Campaign Urging Research for Eosinophilic Diseases (CURED) Foundation. This project has been funded in part with federal funds from the National Cancer Institute, NIH, under contract no. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the NIAID. Disclosure of potential conflict of interest: N. Jones has received a grant from LEIDOS. J. P. Abonia has received grants from the National Institutes of Health (NIH), Food Allergy Research and Education (FARE), the Food Allergy & Anaphylaxis Network, the Buckeye Foundation, and the Campaign Urging Research for Eosinophilic Diseases Foundation. M. E. Rothenberg has received research support from the NIH, the CURED Foundation, FARE, and the Buckeye Foundation; is a board member of the International Eosinophil Society Steering Committee and the APFED Medical Panel; has consultant arrangements with Immune Pharmaceuticals, Pluristem Pharmaceuticals, Receptos, and Novartis; is an inventor on patents submitted and owned by Cincinnati Children’s Hospital Medical Center; receives royalties from Teva Pharmaceuticals; and has stock/stock options in Immune Pharmaceuticals and Receptos. L. B. Schwartz is on the board of directors for the Clinical Immunology Society and the Asthma and Allergy Foundation of America; has consultant arrangements with Sanofi Aventis, Dyax, and Viropharma; has received grants from CSL Behring and Dyax; receives royalties for licensing arrangements through VCU Tech Transfer; and receives honorarium as Associate Editor of the Journal of Clinical Immunology. The rest of the authors declare that they have no relevant conflicts of interest.

Pulmonary manifestations of anti-ARS antibody positive interstitial pneumonia – With or without PM/DM

BACKGROUND Autoantibodies against aminoacyl-tRNA synthetases (ARS) have been found to be highly specific for polymyositis and dermatomyositis (PM/DM) and to correlate strongly with complicating interstitial pneumonia (IP). The aim of the present study was to compare the clinical presentations of anti-ARS antibody-positive IP patients with or without manifestations of PM/DM. METHODS We retrospectively examined 36 IP patients with anti-ARS antibodies. Sixteen patients presented with and 20 without the features of PM/DM. They were divided into PM/DM-IP and idiopathic-IP (IIP) groups. Clinical symptoms, findings on physical examination, laboratory data, pulmonary function, computed tomography (CT), and bronchoalveolar lavage fluid (BALF) cell counts were compared. RESULTS Skin findings, myalgia, and elevation of serum creatinine kinase were found in the PM/DM-IP group. Features common to both groups included: volume loss in lower bilateral lobes; ground-glass opacities, reticular shadows and traction bronchiectasis on chest CT; high percentage of lymphocytes (IIP: 44.0% ± 21.0% (mean ± SD), PM/DM-IP: 50.5% ± 23.5%) and low CD4/8 ratios (IIP: 0.36 ± 0.34, PM/DM-IP: 0.44 ± 0.42) in BALF; decreased pulmonary function, including percentage of predicted vital capacity (VC) (IIP: 80.1% ± 15.4%, PM/DM-IP: 73.6% ± 16.4%), residual volume (RV) (IIP: 70.7% ± 21.7%, PM/DM-IP: 71.5% ± 17.1%), total lung capacity (TLC) (IIP: 73.4% ± 13.6%, PM/DM-IP: 71.6% ± 13.0%), and diffusing capacity DLco (IIP: 57.5% ± 26.7%, PM/DM-IP: 46.4% ± 10.3%). Both groups achieved good responses to initial corticosteroid or immunosuppressant therapy. CONCLUSION Patients with anti-ARS antibody-positive IP have common pulmonary manifestations regardless of the presence of PM/DM.

Effect of Pressure Stress Applied to the Airway on Cough-Reflex Sensitivity in Guinea Pigs

RATIONALE We hypothesized that cough stress of the airway wall results in a self-perpetuating cough-reflex cycle in which antigen-induced increase in cough-reflex sensitivity results in pathologic cough, and the cough in turn further amplifies cough-reflex sensitivity. OBJECTIVES To examine cough-reflex sensitivity in an experimental animal model. METHODS We developed an experimental guinea pig model in which airway collapse similar to that in cough was induced by rapid negative pressure applied to the airway of artificially ventilated animals. We examined the influence of this stimulus on cough-reflex sensitivity to inhaled capsaicin and bronchoalveolar lavage (BAL) cell components. After the termination of artificial ventilation, the number of coughs due to capsaicin was measured, and BAL was performed. MEASUREMENTS AND MAIN RESULTS Capsaicin cough-reflex sensitivity and the number of BAL neutrophils were increased 6 hours after stimulus application, decreasing to control levels by 24 hours. Cough-reflex sensitivity or BAL cell components were not changed in the absence of stimulus application. The number of BAL neutrophils correlated significantly with the number of coughs. Hydroxyurea inhibited the stimulus-induced increase in the number of coughs and airway neutrophil accumulation. CONCLUSIONS Our findings suggest that cough itself is a traumatic mechanical stress to the airway wall that induces neutrophilic airway inflammation and cough-reflex hypersensitivity. Cough stress to the airway wall results in a self-perpetuating cough-reflex cycle.

Ambroxol for the prevention of acute upper respiratory disease.

Although acute upper respiratory diseases (AURDs) such as common cold and influenza are common, few interventions have been proven to be effective in their prevention and treatment. The aim of this study was to assess the efficacy of ambroxol for preventing AURD. Fifty-four patients were randomly divided into 3 groups: a rebamipide (non-mucoactive drug) group (300 mg/day), carbocisteine group (1500 mg/day) and ambroxol group (45 mg/day). The study was divided into 2 terms, the first half-year (summer season) and the second half-year (winter season). In the preceding winter, only 19.5% of the patients had been vaccinated against influenza viruses (flu). The primary goal of this study was to evaluate the effectiveness of mucoactive drugs in decreasing the frequency of AURD. Treatment with ambroxol, but not carbocisteine, significantly reduced the median number of AURD episodes (P=0.0049 vs. rebamipide). Thirty-three patients without vaccination against flu were assessed especially during the second half-year. Treatment with ambroxol also significantly reduced the median number of AURD episodes in this assessment (P=0.0028 vs. rebamipide in the second half-year). In conclusion, ambroxol may be useful for preventing AURD.