Ryoichi Amitani

A pilot study of low-dose erythromycin in bronchiectasis

Patients with bronchiectasis suffer from sputum production, recurrent exacerbations, and progressive airway destruction. Erythromycin is effective in diffuse panbronchiolitis, another suppurative airway disorder, although its efficacy is unknown in idiopathic bronchiectasis. A double-blind placebo-controlled study was therefore conducted to evaluate the effects of 8-week administration of low dose erythromycin (500 mg b.i.d.) in steady-state idiopathic bronchiectasis. Patients in the erythromycin group (n=11, 8 female, mean age 50+/-15 yrs), but not the placebo group (n=10, 8 female, mean age 59+/-16 yrs) had significantly improved forced expiratory volume in one second, forced vital capacity and 24-h sputum volume after 8 weeks (p<0.05). There was no parallel improvement in sputum pathogens, leukocytes, interleukin (IL)-1alpha and IL-8, tumour necrosis factor-alpha, or leukotriene B4. The results of this pilot study show that low-dose erythromycin improves lung function and sputum volume in bronchiectasis. Further studies are indicated to evaluate the efficacy of long-term erythromycin therapy in bronchiectasis.

Airway remodelling in cough-variant asthma.

Subepithelial-layer thickening, a pathological feature of airway remodelling, is present in cough-variant asthma. In bronchial biopsy samples we found mean subepithelial-layer thickness was 7.1 (SE 0.4) microm in patients with cough-variant asthma, 8.6 (0.4) microm in patients with classic asthma with wheezing, and 5.0 (0.2) microm in healthy controls. Thickness was significantly higher in patients with asthma than in controls, and was significantly greater in those with classic asthma than in those with cough-variant asthma. Early anti-inflammatory treatment might, therefore, be beneficial in cough-variant asthma, as recommended in classic asthma.

Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility.

Macrophage-stimulating protein (MSP) is an 80-kD serum protein with homology to hepatocyte growth factor (HGF). Its receptor, RON tyrosine kinase, is a new member of the HGF receptor family. The MSP-RON signaling pathway has been implicated in the functional regulation of mononuclear phagocytes. However, the function of this pathway in other types of cells has not been elucidated. Here we show that in contrast to the HGF receptor, which was expressed at the basolateral surface, RON was localized at the apical surface of ciliated epithelia in the airways and oviduct. In addition, MSP was found in the bronchoalveolar space at biologically significant concentrations. MSP bound to RON on normal human bronchial epithelial cells with a high affinity (Kd = 0.5 nM) and induced autophosphorylation of RON. Activation of RON by MSP led to a significant increase in ciliary beat frequency of human nasal cilia. These findings indicate that the ciliated epithelium of the mucociliary transport apparatus is a novel target of MSP. Ciliary motility is critical for mucociliary transport. Our findings suggest that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and might be involved in the host defense and fertilization.

Aspergillus culture filtrates and sputum sols from patients with pulmonary aspergillosis cause damage to human respiratory ciliated epithelium in vitro

Aspergillus species frequently colonize lower respiratory tracts and lungs with localized underlying conditions (healed tuberculous cavity, cystic fibrosis, bronchiectasis, etc.) even in subjects without systemic predisposing factors. We investigated the in vitro effects of culture filtrates of Aspergillus species and sputum sols from patients with pulmonary aspergillosis on ciliary beat frequency (CBF) and epithelial integrity of human respiratory ciliated epithelium. Culture filtrates of 25 clinically isolated fungi (16 Aspergillus fumigatus, three Aspergillus niger, one Aspergillus flavus, three Candida albicans, and two Cryptococcus neoformans) were obtained by culturing the fungi in Medium-199 at 37 degrees C for 7 days, and five sputum sols were obtained from patients with pulmonary aspergillosis infected by A. fumigatus. During 6 h experiments using a photometric technique, 14 out of 16 A. fumigatus culture filtrates caused progressive and significant reduction in CBF associated with marked epithelial disruption, whilst the culture filtrates of A. niger and A. flavus caused minor epithelial damage without slowing of CBF, and Medium-199 alone (Control) showed neither epithelial damage nor slowing of CBF. All of the sputum sols also caused significant slowing of CBF as well as epithelial disruption. Culture filtrates of C. albicans and Cr. neoformans had no effects on human respiratory epithelium. We conclude that Aspergillus species, especially A. fumigatus release a factor (or factors) which causes damage to respiratory epithelium and slows CBF, and that these factors may contribute to the colonization of the lower respiratory tracts by the Aspergillus species and may possibly contribute to the further proliferation and spread of the lesions in pulmonary aspergillosis.

Suppressive effects of Aspergillus fumigatus culture filtrates on human alveolar macrophages and polymorphonuclear leucocytes.

Aspergillus spp., especially A. fumigatus (Af) can colonize the airways and the lungs with localized underlying conditions and further invade the surrounding lung tissues, even in subjects without systemic predisposing factors, presumably by escaping the local host defences. To clarify the mechanisms of colonization and invasion of Af, we investigated the in vitro effects of Af culture filtrates (ACFs) on the functions of human alveolar macrophages (AMs), and polymorphonuclear leucocytes (PMNs). ACFs were obtained by culturing clinically isolated Af in Medium-199 at 37 degrees C for 5 days. In the study of phagocytosis of Af conidia by human AMs, 52% of AMs ingested conidia during a 60 min incubation period in Medium-199. However, the percentage decreased to 24% when incubated with a final concentration of 30% ACF in Medium-199. With respect to the antichemotactic activity on human PMNs, 3% ACF was sufficient for significant suppression, and 30% ACF completely inhibited the migration of PMNs. In addition, phorbol myristate acetate (PMA)-induced O2- release from PMNs was significantly suppressed in Medium-199 which included 12.5% ACF or more. The antichemotactic activity of ACF was partially abolished by trypsin or chicken egg ovomacroglobulin. When ACF was separated into two fractions (molecular weight > 10 and < 10 kDa) by dialysis and centrifugation through CL-LGC filters, both fractions retained the antichemotactic activity. We conclude that Af produce several antiphagocytic factors, which can be responsible for the colonization of Af in the bronchopulmonary tissues and allow this species to invade surrounding lung tissues in pulmonary aspergillosis by suppressing local host defences.

Clinical profiles of Chinese patients with diffuse panbronchiolitis

BACKGROUND Diffuse panbronchiolitis (DPB), characterised by progressive sinobronchial sepsis, is well characterised in Japanese subjects but not in other ethnic groups. The experience with DPB in seven Chinese patients is described and the clinical profiles compared with those of Japanese subjects. METHODS Seven Chinese patients (three women; mean (SD) age 48(18.6) years, all never smokers) who attended a teaching hospital centre and fulfilled the diagnostic criteria for DPB were assessed prospectively for clinical, radiological, lung function, microbiological, and other “characteristic” laboratory parameters. RESULTS Lung function assessment showed a typical obstructive pattern (n = 5) and air trapping (n = 7). Typical bronchiolar infiltration by lymphocytes and plasma cells and accumulation of foamy macrophages in the intraluminal tissue were detected in open lung biopsy specimens (n = 2). Chest radiographs and high resolution computed tomographic scans revealed hyperinflation, diffuse nodules, bronchial thickening and dilatation, peripheral hypoattenuation, and bronchiolectasis. Radiological improvement, manifest as a reduction in nodular density and bronchial thickening, and persistence of other abnormalities such as air trapping were not accurately depicted by the classical Nakata or Akira classifications. The other “characteristic” features such as HLA-B54, IgG subclass deficiency, raised CD4/CD8 T lymphocyte ratio, cold haemagglutinaemia, raised IgA, IgG, and rheumatoid factor were not present. Treatment with erythromycin led to excellent responses in symptoms, lung function indices, and the radiological picture. A review of the non-Japanese cases in the literature reveals that this absence of typical “additional features” in DPB might also be applicable to non-Japanese patients. CONCLUSIONS We report the only series of non-Japanese Mongoloid patients with well characterised DPB who had uncharacteristic investigation profiles. This experience should help other clinicians in the investigation and management of DPB in non-Japanese patients.

Polypoid bronchial lesions due to Scedosporium apiospermum in a patient with Mycobacterium avium complex pulmonary disease.

A 69 yr old female was hospitalized for further examination of abnormal shadows on chest radiographs. She had a history of tuberculous pleurisy, rheumatoid arthritis and gold-induced interstitial pneumonia. On admission she still suffered from rheumatoid arthritis. A chest computed tomography scan on admission showed clusters of small nodules in subpleural regions of both lungs combined with bronchiectasis. Mycobacterium avium complex was cultured repeatedly from the sputum. Bronchoscopic examination disclosed white-yellow polypoid lesions in the orifice of the left B4 bronchus. Cultures of the brushing specimen of the polypoid lesions and bronchial aspirates from the B4 bronchus yielded smoky-grey mycelial colonies that were later identified as Scedosporium apiospermum. It was concluded that the polypoid bronchial lesions due to Scedosporium apiospermum were formed in the preexisting dilated bronchus caused by Mycobacterium avium complex pulmonary disease.

Specific IgE response to Trichophyton and asthma severity.

BACKGROUND Sensitization to Trichophyton, a major dermatophyte, has been associated with asthma. Whether such sensitization is generally associated with the severity of asthma, like other molds such as Alternaria, is unknown. METHODS We compared 258 patients with asthma, which was classified by severity as mild (n = 123), moderate (101), or severe (34), and 114 healthy control subjects, with regard to specific IgE titers against Trichophyton rubrum and other common allergens such as mixed molds, house-dust mite, cat dander, dog dander, Japanese cedar pollen, mixed Graminea pollens and mixed weed pollens. RESULTS Positive rate of Trichophyton-specific IgE was higher in the patients with moderate asthma (15.8%) than in the control subjects (7.0%, p = 0.04) and patients with mild asthma (4.9%, p < 0.006), and it was also higher in the patients with severe asthma (32.4%) than in control subjects (p = 0.0001), and patients with mild asthma (p < 0.0001) and moderate asthma (p = 0.04), but it did not differ between the control subjects and patients with mild asthma. The positive rates of mixed molds, cat dander, and dog dander were almost invariably higher in patients in all asthma subgroups than in the control subjects but did not differ among patients in the three asthma subgroups. The positive rates of other allergens were not different in all groups. Reanalysis of positive rate of Trichophyton-specific IgE after excluding 52 subjects with positive results for mixed molds showed a similar statistical trend to that of the original cohort. This may negate the potential effect of cross-reactivity to these molds. Multivariate analysis of asthma subgroups identified positive IgE results for Trichophyton as an independent determinant of asthma severity. CONCLUSIONS Specific IgE response to Trichophyton may be associated with more severe asthma.

Chronic Eosinophilic Pneumonia: Treatment with Inhaled Corticosteroids

Background: Chronic eosinophilic pneumonia (CEP) is highly sensitive to systemic corticosteroids, but frequently relapses if the dose is tapered or treatment discontinued. Long-term usage of systemic corticosteroids may cause side effects. Alternative treatments are therefore desired. Objectives: We evaluated the response of CEP to monotherapy with inhaled corticosteroids (ICS). Methods: Four patients who had CEP without spontaneous resolution were studied. Patients received inhaled beclomethasone dipropionate (BDP) at a dose of 0.8 mg/day in 1 patient and 1.6 mg/day in 3 patients for 2 weeks. Treatment was continued if a patient showed improvement in at least 1 of the following indices: radiological findings, symptoms, and blood eosinophilia. Results: After the initial 2 weeks of treatment with BDP, the blood eosinophil count increased in 2 patients and decreased in 2. Symptoms worsened in 2 and improved in 2. Infiltrates on chest radiography increased in 3 and showed little change in 1. In the 2 patients with worsening of all 3 outcome indices, oral prednisolone was started; the indices improved. In the remaining 2 patients, BDP alone was continued. One patient had worsening of CEP after 2 months of treatment, and another had relapse of CEP at 3.5 years while receiving 1.6 mg/day of BDP. All patients thus finally had worsening or relapse of CEP during treatment with BDP. Conclusions: ICS may not be effective when given as monotherapy in patients with CEP.

Inflammatory bronchial polyps associated with asthma: resolution with inhaled corticosteroid

In a 50 year old man who complained of cough and sputum, a small endobronchial tumour was found in the left main bronchus and was biopsied via bronchoscopy. The histological diagnosis was inflammatory polyp with marked infiltration of eosinophils. Six years later, the patient developed asthma. At the same time, another polyp was found in the posterior basal bronchus of the right lower lobe. The appearance of the first polyp was unchanged endoscopically and histologically. Inhalation of beclomethasone dipropionate, 200 micrograms b.i.d., was started and symptoms of asthma soon subsided. In addition, the two polyps regressed and eventually disappeared after one year of treatment. Inhaled corticosteroids, being noninvasive and relatively safe, appear to be a possible therapeutic option in inflammatory bronchial polyps, especially in cases where the patient has asthma as an underlying condition, or the polyps are small and their management is not urgent.