Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile.

BACKGROUND: Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by surfactant accumulation, and is caused by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling. Abnormalities in CSF2 receptor alpha (CSF2RA) were reported to cause pediatric hereditary PAP. We report here the first case of CSF2RA-mutated, elderly-onset hereditary (h) PAP. CASE PRESENTATION: The patient developed dyspnea on exertion, and was diagnosed with PAP at the age of 77 years, based on findings from chest computed tomography scan and bronchoalveolar lavage. She tested negative for GM-CSF autoantibodies, with no underlying disease. Her serum GM-CSF level was elevated (91.3 pg/mL), indicating GM-CSF signaling impairment and genetic defects in the GM-CSF receptor. GM-CSF-stimulated phosphorylation in signal transducer and activator of transcription 5 (STAT5) was not observed, and GM-CSF-Rα expression was defective in her blood cells. Genetic screening revealed a homozygous, single-base C > T mutation at nt 508-a nonsense mutation that yields a stop codon (Q170X)-in exon 7 of CSF2RA. High-resolution analysis of single nucleotide polymorphism array confirmed a 22.8-Mb loss of heterozygosity region in Xp22.33p22.11, encompassing the CSF2RA gene. She was successfully treated with whole lung lavage (WLL), which reduced the serum levels of interleukin (IL)-2, IL-5, and IL-17, although IL-3 and M-CSF levels remained high. CONCLUSIONS: This is the first known report of elderly-onset hPAP associated with a CSF2RA mutation, which caused defective GM-CSF-Rα expression and impaired signaling. The analyses of serum cytokine levels during WLL suggested that GM-CSF signaling might be compensated by other signaling pathways, leading to elderly-onset PAP.

PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates.

The nontuberculous mycobacteria (NTM) cause miscellaneous disorders in humans, especially in the lungs, which present with a variety of radiological features. To date, knowledge of the pathogenic role of the Mycobacterium avium-intracellulare complex (MAC) in the human lung and the definitive criteria for initiating multidrug therapy are still lacking. However, there is little doubt that clarithromycin is the most efficacious drug among the various treatment regimens for lung NTM. In this study, with the use of a bridged nucleic acid (BNA) probe a detection system based on a real-time PCR (BNA-PCR) for the identification of the point mutations at position 2058 or 2059 in domain V of the 23S rRNA gene responsible for clarithromycin resistance was developed and has been assessed using MAC isolates from clinical samples. Out of 199 respiratory specimens, the drug susceptibility test demonstrated 12 strains resistant to clarithromycin, while the BNA-PCR showed 8 strains carrying the point mutation at position 2058 or 2059 of the 23S rRNA gene. This system revealed that there were mycobacterial strains resistant to clarithromycin which do not carry previously identified resistance genes. This paper documents a novel system for detecting clarithromycin-resistant strains and demonstrates that although these mutations are tacitly assumed to account for >90% of the reported resistant mutants, there is a significant fraction of resistant mutants that do not harbor these mutations. Therefore, unknown mechanisms affecting clarithromycin resistance remain to be elucidated.

Eosinophil infiltration in the upper gastrointestinal tract of patients with bronchial asthma.

BACKGROUND: Eosinophilic esophagitis (EoE) is related to allergic diseases such as bronchial asthma (BA), atopic dermatitis, and allergic rhinitis. The aim of this study was to examine the eosinophil infiltration in the upper gastrointestinal (GI) tract in patients with BA using esophagogastroduodenoscopy. METHODS: Patients with BA who had upper GI tract symptoms were enrolled. Patients who received systemically administered steroids were excluded. Eosinophil infiltrations in the esophagus, stomach, and duodenum were examined with regard to the endoscopic findings and pathological findings of biopsy specimens (UMIN000010132). RESULTS: Ninety patients were enrolled from October in 2012 to September in 2014. Thirty-six were male, 54 were female, and the mean age was 57.5 years. Eighty-one (90%) used inhaled corticosteroids. Fourteen patients (15.6%) had reflux esophagitis, 8 of whom had grade A and 6 had grade B. No patient with EoE was observed. One female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic gastroenteritis, but endoscopy showed only mucosal edema in the antrum. Another female patient who had marked eosinophil infiltration in the esophagus, stomach, and duodenum was diagnosed as having eosinophilic granulomatosis with polyangiitis, and endoscopy showed erosions in the antrum and the duodenum. Three patients had eosinophil infiltration in the stomach, but none of them had severe symptoms. CONCLUSIONS: Patients with asthma who had upper gastrointestinal symptoms rarely had eosinophilic gastrointestinal disorders. Biopsy specimens are of high importance in the diagnosis of eosinophilic gastrointestinal disorders even if there is no remarkable endoscopic finding.

Mycobacterium gordonae-induced humidifier lung.

BACKGROUND: Nontuberculous mycobacteria are well known to be a cause of hot tub lung, however, to our knowledge, there exists no case report of humidifier lung induced by mycobacteria. CASE PRESENTATION: A case of a nonimmunocompromised female patient with Mycobacterium gordonae-induced humidifier lung is described. She spontaneously recovered after discontinuing ultrasonic humidifier use. When subjected to a provocation test, she demonstrated acute respiratory distress with signs and symptoms, consistent with hypersensitivity pneumonitis. Before and after the provocation test, water in the humidifier reservoir revealed only Mycobacterium gordonae by the microbiologic analyses. CONCLUSION: To our knowledge, this is the first report of humidifier lung induced by nontuberculous mycobacteria. Although nontuberculous mycobacteria are well-known to be agents of hot tub lung or metal working fluid lung, physicians should also consider the pathogen as a cause of hypersensitivity lung reaction associated with humidifier use.

Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks.

OBJECTIVE: To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis (RA) despite treatment with disease-modifying antirheumatic drugs (DMARDs). METHODS: A total of 316 patients were randomised to receive subcutaneous injections every 4 weeks of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3); group 1 crossed over to golimumab 50 mg at week 16. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 14. ACR50 and ACR70 response rates were also measured. Adverse events (AEs) were monitored throughout the study. RESULTS: Demographics were similar across groups; the mean age was 52 years and 81.8% of patients (252/308) were female. Week 14 ACR20 response rates were significantly greater in groups 2 (51/101 (50.5%)) and 3 (60/102 (58.8%)) than in group 1 (20/105 (19.0%); p<0.0001 for both), as were ACR50 and ACR70 response rates. After placebo crossover at week 16, week 24 ACR response rates were similar in groups 1 and 2. Through week 16, 63.8% of patients in group 1, 62.4% in group 2 and 60.8% in group 3 had AEs and 1.9%, 1.0% and 2.0% had serious AEs. After week 16, one malignancy was reported (breast cancer, group 3). Infections were the most common AEs. No deaths or cases of tuberculosis were reported through week 24. CONCLUSIONS: Golimumab monotherapy (50 and 100 mg) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment.

Omalizumab attenuates airway inflammation and interleukin-5 production by mononuclear cells in patients with severe allergic asthma.

BACKGROUND: Omalizumab, an anti-immunoglobulin E monoclonal antibody, has shown an inhibitory effect on airway inflammation, which may be associated with clinical improvement of severe asthma. This study evaluated changes in airway inflammation and cytokine release by the peripheral blood mononuclear cells (PBMCs) of Japanese patients with severe asthma after administration of omalizumab. METHODS: Sixteen Japanese patients with severe asthma who were allergic to house-dust mites were enrolled in this study. Eight received omalizumab every 2 or 4 weeks for 16 weeks, and 8 control subjects were treated with conventional drug treatment. Changes in clinical scores for sputum eosinophils and levels of fraction of exhaled nitric oxide (FeNO) were measured at the time of enrollment and at week 16. Cytokines from PBMCs stimulated by house-dust mite (Dermatophagoides farinae) or ionomycin/phorbol myristate acetate (PMA) were measured at baseline and at week 16. RESULTS: In the omalizumab-treated group, decreases in sputum eosinophils and FeNO were observed following treatment. Furthermore, the ex vivo production of interleukin (IL)-5 by PBMCs in response to both mite allergen and ionomycin/PMA decreased significantly. In contrast, interferon (IFN)-γ production was unchanged. There were no changes in any of the parameters observed in the control group. CONCLUSION: Omalizumab exerts inhibitory effects on airway inflammation in Japanese patients with severe allergic asthma. This treatment attenuates production of IL-5 by PBMCs stimulated with both a specific allergen and a nonspecific activator. Reduction of the Th2 inflammatory cascade likely contributes to clinical benefits; however, further studies are required to clarify these results due to the small sample size in this study.

Effect of formoterol on eosinophil trans-basement membrane migration induced by interleukin-8-stimulated neutrophils.

BACKGROUND: Neutrophils are often increased in the airways of either chronic severe asthma or acute exacerbations. Neutrophils that have migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of patients with asthma and possibly aggravate the disease. In this study, we investigated whether formoterol modified the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8. METHODS: Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. Eosinophil TBM was examined using a modified Boyden's chamber technique. Neutrophils were preincubated with or without formoterol (0.1 µM) at 37°C for 30 min. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium containing preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After a 90-minute incubation, the eosinophils that had migrated into the lower chamber were calculated using eosinophil peroxidase assays. RESULTS: A combination of neutrophils and IL-8 significantly induced the eosinophil TBM; formoterol alone had no effect. However, formoterol modestly but significantly attenuated the TBM of eosinophils stimulated with neutrophils and IL-8. CONCLUSION: These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent, severe asthma. The effect of formoterol likely involves the inhibition of neutrophil activation.

Dopamine D1-like receptor antagonist attenuates Th17-mediated immune response and ovalbumin antigen-induced neutrophilic airway inflammation.

Allergic airway inflammation is generally considered a Th2-type immune response. Recent studies, however, demonstrated that Th17-type immune responses also play important roles in this process, especially in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We previously reported that dendritic cells release dopamine to naive CD4(+) T cells in Ag-specific cell-cell interaction, in turn inducing Th17 differentiation through dopamine D1-like receptor (D1-like-R). D1-like-R antagonist attenuates Th17-mediated diseases such as experimental autoimmune encephalomyelitis and autoimmune diabetes. However, the effect of antagonizing D1-like-R on Th17-mediated airway inflammation has yet to be studied. In this study, we examined whether D1-like-R antagonist suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice and then elucidated the mechanism of action. DO11.10 mice were nebulized with OVA or PBS, and some mice received D1-like-R antagonist orally before OVA nebulization. D1-like-R antagonist significantly suppressed OVA-induced neutrophilic airway inflammation in DO11.10 mice. It also inhibited the production of IL-17 and infiltration of Th17 cells in the lung. Further, D1-like-R antagonist suppressed the production of IL-23 by lung CD11c(+) APCs. In contrast, D1-like-R antagonist did not increase Foxp3(+) regulatory T cells in the lung. D1-like-R antagonist neither suppressed nonspecific LPS-induced neutrophilic airway inflammation nor OVA-induced eosinophilic airway inflammation. These results indicate that D1-like-R antagonist could suppress Th17-mediated neutrophilic airway inflammation, raising the possibility that antagonizing D1-like-R serves as a promising new strategy for treating neutrophil-dominant severe asthma.

[A case of lung paragonimiasis superinfection with hookworm presenting difficulty in discrimination].

A 40-year-old woman, who was born in Thailand and moved to Japan 20 years previously, was admitted to our university hospital because of eosinophilia and abnormal chest radiography findings over a 6-month period. The chest CT showed multiple cavitary nodules in the subpleural area and a tubular structure that extended from each cavity to the pleura. Immunological examination revealed an elevation of antibody titers against Ancylostoma duodenale, Paragonimiasis miyazakii and Paragonimiasis westermanii based on an ELISA assay. In addition, hookworm eggs were found in the stool. We firstly administered pyrantel pamoates, following which the eggs become undetectable. Nevertheless, eosinophilia and abnormal chest CT findings persisted. We diagnosed the patient as having a superinfection with paragonimiasis and hookworm, then administered praziquantel. Subsequently, the number of eosinophils returned to a normal level and the abnormal shadow in the chest CT images diminished without scarring. The final diagnosis was a superinfection of paragonimiasis and hookworm.

[Rapid specific IgE assay (ImmunoCAP® RAPID) and skin prick test in the diagnosis of allergic disease].

BACKGROUND: ImmunoCAP® Rapid is a rapid test kit to measure the allergen-specific IgE to the eight major inhalation allergen (cat, mite, orchard grass, ragweed, wormwood, dog, cockroach, Japan cedar). METHODS: We performed ImmunoCAP® Rapid 83 patients with allergic disease (26 males, 57 females, median aged 43 years, 53 of asthma, 43 of allergic rhinitis) in our allergy center. ImmunoCAP® Rapid results were compared with those of skin prick test (SPT). RESULTS: Although total positive allergens of SPT were higher than that of ImmunoCAP® Rapid (26.5% vs 22.5%, p<0.05), there was no significantly difference of each positive allergen between two tests. The rate of ImmunoCAP® Rapid to Japan cedar was almost equivalent to SPT in all patients (68.7% vs 55.4%, p=0.07). In contrast, the rate of ImmunoCAP® Rapid to Japan cedar was higher than SPT in patients with rhinitis (90.4% vs 71.4%, p<0.05). Efficiency between ImmunoCAP® Rapid and SPT was 86.4%, sensitivity was 66.9%, and specificity was 93.4%. The reactivity of ImmunoCAP® Rapid to allergens significantly correlated with sizes of SPT (erythema: r=0.645, urticaria: r=0.657). CONCLUSION: Although identification rate in the screening ImmunoCAP® Rapid slightly inferior to SPT, this test system was useful for diagnosis of Japan cedar and mite.

Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea.

STUDY OBJECTIVES: Poor adherence to continuous positive airway pressure (CPAP) has been a critical issue in treating obstructive sleep apnea. Because long-term CPAP adherence may be established shortly after treatment begins, early intervention is essential. This study aimed to identify the potential factors affecting CPAP therapy adherence during diagnostic polysomnography and auto CPAP titration polysomnography. METHODS: This retrospective observational study included 463 patients with obstructive sleep apnea who underwent consecutive diagnostic polysomnography and titration polysomnography. We recorded their demographic, anthropometric, and lifestyle factors and obtained self-reported comments regarding their sleep status following both polysomnography evaluations. CPAP adherence was evaluated following 3 months of treatment. RESULTS: A total of 312 patients (67.4%) fulfilled the criteria for good adherence. Each patient's CPAP adherence was categorized as "poor" (< 4 hours/night or <70% of nights), "good" (≥ 4 hours/night and ≥ 70% of nights), or "excellent" (≥ 6 hours/night and ≥ 80% of nights). There were no significant differences in arterial oxyhemoglobin saturation measured by pulse oximetry and apnea-hypopnea index during diagnostic polysomnography among 3 groups. The polysomnographic evaluations indicated that patients with better adherence displayed more significant improvements in sleep parameters, including apnea-hypopnea index, sleep efficacy, sleep latency, and sleep architecture, which were correlated with an improvement in self-reported sleep quality. CONCLUSIONS: Polysomnographic evaluations enabled CPAP adherence prediction and a comparison of self-reported sleep quality with and without CPAP; CPAP adherence led to improvements in polysomnographic parameters. Our findings suggest that titration polysomnography and self-reported sleep improvement with CPAP could be used for adherence prediction in clinical practice. CITATION: Shirahata T, Uchida Y, Uchida T, et al. Improvement of sleep parameters by titration polysomnography could predict adherence to positive airway pressure therapy in obstructive sleep apnea. J Clin Sleep Med. 2023;19(8):1465-1473.

Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study.

OBJECTIVE: To assess the efficacy and safety of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). METHODS: 269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6-8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1. RESULTS: The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively. CONCLUSION: In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns.

[Effects of educational guidance on airway inflammation of patients with severe persistent asthma].

BACKGROUND: Airway inflammation is a fundamental feature of bronchial asthma. We examined whether educational guidance using a text on pathophysiology and management of asthma modify airway inflammation of severe asthma. METHODS: Eighteen severe persistent asthmatics were enrolled in this study. Evaluation on asthma control using Asthma Control Test (ACT), Asthma Health Questionnaire (AHQ)-Japan), FEV1, percentages of eosinophils and neutrophils in induced sputum were analyzed before and 4 weeks after patient education process. RESULTS: Following educational guidance, ACT and FEV1 did not improve, but AHQ score significantly improved. Furthermore, percentage of eosinophils in sputum significantly reduced. On the contrary, the percentage of neutrophils in sputum was not changed. In accordance with this lack of the change in neutrophil numbers, neutrophil chemoattractants including IL-8 or CXCR3 in the induced sputum did not change before and after patient guidance. CONCLUSION: Educational guidance using a text on pathophysiology and management of asthma provides some effects on quality of life in asthmatic patients and eosinophilic inflammation, however, this procedure does not modify the control status of asthma and neutrophilic inflammation seen with severe asthma.

IFN-γ-inducible protein of 10 kDa upregulates the effector functions of eosinophils through ß2 integrin and CXCR3.

BACKGROUND: Eosinophils play an important role in the pathogenesis of bronchial asthma and its exacerbation. Recent reports suggest the involvement of IFN-γ-inducible protein of 10 kDa (IP-10) in virus-induced asthma exacerbation. The objective of this study was to examine whether CXCR3 ligands including IP-10 modify the effector functions of eosinophils. METHODS: Eosinophils isolated from the blood of healthy donors were stimulated with CXCR3 ligands and their adhesion to rh-ICAM-1 was then measured using eosinophil peroxidase assays. The generation of eosinophil superoxide anion (O2-) was examined based on the superoxide dismutase-inhibitable reduction of cytochrome C. Eosinophil-derived neurotoxin (EDN) release was evaluated to determine whether CXCR3 ligands induced eosinophil degranulation. Cytokine and chemokine production by eosinophils was examined using a Bio-plex assay. RESULTS: Eosinophil adhesion to ICAM-1 was significantly enhanced by IP-10, which also significantly induced eosinophil O2- generation in the presence of ICAM-1. Both the enhanced adhesion and O2- generation were inhibited by an anti-ß2 integrin mAb or an anti-CXCR3 mAb. Other CXCR3 ligands, such as monokine induced by IFN-γ (Mig) and IFN-inducible T cell α chemoattractant (I-TAC), also induced eosinophil adhesion and O2- generation in the presence of ICAM-1. IP-10, but not Mig or I-TAC, increased the release of EDN. IP-10 increased the production of a number of cytokines and chemokines by eosinophils. CONCLUSIONS: These findings suggest that CXCR3 ligands such as IP-10 can directly upregulate the effector functions of eosinophils. These effects might be involved in the activation and infiltration of eosinophils in the airway of asthma, especially in virus-induced asthma exacerbation.

[A case of bronchial asthma caused by occupational exposure to trichophyton].

A case involved a 39-year-old female nurse in a health-care facility for elderly individuals requiring long-term care, who presented with insufficient control of bronchial asthma. Although she did not have tinea, she had opportunities for contact with patients who did. Careful interview of history suggested a relationship between asthma exacerbation and workplace, so we measured the specific IgE antibody to Trichophyton and confirmed a positive result. As occupational exposure to Trichophyton was considered as a cause of asthma exacerbations, avoidance of Trichophyton as well as anti-asthma treatment was conducted and symptoms improved. Identification and avoidance of specific allergens is essential for successful long-term management of asthma. However, measurement of specific IgE antibody to Trichophyton is not routinely performed, although this fungus could induce not only tinea, but also asthma. The possibility that occupational exposure to trichophyton could exacerbate asthma symptoms needs to be kept in mind, particularly in the case of nurses who may be in contact with elderly individuals with tinea.

Salbutamol modulates the balance of Th1 and Th2 cytokines by mononuclear cells from allergic asthmatics.

BACKGROUND: There is evidence that excessive use of inhalational beta(2)-agonists induces the deterioration of asthma. Although the exact mechanism of this remains to be elucidated, overuse of beta(2)-agonists may impair the Th1/Th2 balance in asthmatic airways. The aim of the present study was to evaluate whether salbutamol, a representative inhalational beta(2)-agonist, modifies the production of Th1- and Th2-type cytokines by mononuclear cells separated from patients with asthma and healthy volunteers. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from 8 healthy volunteers and 10 patients with mild persistent asthma allergic to house dust mites were treated with either salbutamol or medium alone. PBMCs were then stimulated with either medium alone, house dust mite (Dermatophagoides farina, Df) allergen or a combination of ionomycin plus phorbol 12-myristate 13-acetate ester (PMA). Concentrations of IFN-gamma, IL-13, TNF-alpha and RANTES in the cell supernatants were measured using ELISA. RESULTS: In PBMCs from healthy volunteers, salbutamol did not modify IFN-gamma production, but increased the spontaneous production of IL-13. In contrast, salbutamol significantly inhibited the spontaneous and ionomycin- plus PMA-stimulated production of IFN-gamma by PBMCs from asthmatics. Salbutamol significantly enhanced both spontaneous and Df-induced production of IL-13 by PBMCs from asthmatics. Salbutamol did not modify the production of TNF-alpha. Finally, salbutamol enhanced the production of RANTES induced by Df allergen in asthmatics. CONCLUSIONS: Salbutamol inhibits IFN-gamma and enhances IL-13 production by PBMCs from asthmatics. These effects would promote a Th1/Th2 imbalance in the airways and may therefore contribute to the deterioration of asthma.

Changes in airway inflammation and hyperresponsiveness after inhaled corticosteroid cessation in allergic asthma.

BACKGROUND: Most patients with asthma are currently controlled by pharmacotherapeutic means such as inhaled corticosteroid (ICS). However, whether ICS actually induces remission of asthma remains unknown. The present study evaluates changes in airway inflammation and hyperresponsiveness in adult patients with asthma after stopping ICS. METHODS: We enrolled 11 patients with allergic asthma (7 males and 4 females; mean age, 52.3 years) who had been asymptomatic and had no exacerbation by low-dose ICS. Airway hyperresponsiveness (AHR) was assessed using methacholine challenge, and induced sputum was evaluated before and every 3 months after ICS cessation during the 1-year follow-up. RESULTS: Among the 11 asthmatics, AHR increased in 10 (90.9%) and asthma clinically relapsed in 4 (36.4%) within 1 year of ICS cessation. AHR increased in all 7 asthmatics that were sensitized to Dermatophagoides farinae and asthma clinically relapsed in 4 (57.1%) of them. Furthermore, eosinophil numbers and IL-4 concentrations in the sputum significantly increased after ICS cessation. CONCLUSIONS: Remission with normal airway response to methacholine (no AHR) might be rare in adult patients with allergic asthma, and sensitization to house dust mites appears to play an important role in relapse. Therefore, ICS cessation should be carefully considered in patients sensitive to house dust mites. Serial determination of eosinophil counts or IL-4 concentrations in sputum might be appropriate for monitoring and preventing asthma relapse in adults.

[Questionnaire for determining relationship between nasal and asthma symptoms].

BACKGROUND: The interaction between allergic rhinitis and bronchial asthma is well known. However, there is little epidemiological data on the relationship between nasal diseases and asthma, especially in Japan. METHODS: We administered a questionnaire to 126 patients to examine the frequency of associations between nasal and asthma symptoms in patients with both nasal disease and asthma. We also investigated in which type of patients the asthma symptoms were affected by changes in nasal symptoms. RESULTS: Thirty-eight patients (30%) were aware that their asthma was worsened by exacerbated nasal disease, and nasal treatment improved asthma in 28 patients (22%). The influence of changes in nasal symptoms on asthma symptoms was stronger in patients lacking good asthma control. The relationship between nasal and asthma symptoms tended to be stronger in patients with sinusitis. CONCLUSION: About 30% of patients with nasal disease and asthma reported an association between their nasal and asthma symptoms. Nasal treatment is considered to be important for asthma control, especially in patients with asthma symptoms. These results suggested the important role of comprehensive allergy care in controlling both nasal disease and asthma.

Eosinophil superoxide anion generation induced by adhesion molecules and leukotriene D4.

RATIONALE: Eosinophils preferentially accumulate at sites of inflammation in the asthmatic airway. Participation of circulating eosinophils in the airway inflammation in asthma involves their interaction with adhesion molecules expressed on the endothelial cell surface and exposure to inflammatory mediators, such as cysteinyl leukotrienes (cysLTs). OBJECTIVE: To investigate whether interaction of eosinophils with adhesion molecules modifies the functions of these cells induced by cysLTs. METHODS: Eosinophils were isolated from the blood of healthy donors, incubated in the EIA plates coated with adhesion proteins, and then exposed to LTD4. The generation of superoxide anion (O2-), adhesion to the plates, and release of eosinophil-derived neutrotoxin (EDN) were evaluated. RESULTS: Neither VCAM-1 nor LTD4 (100 nM) independently induced eosinophil O2- generation, however, combined exposure to the two molecules synergistically induced eosinophil O2- generation. ICAM-1 by itself induced eosinophil O2- generation, which was enhanced by LTD4. On the contrary, P-selectin did not induce O2- generation, either in the presence or absence of LTD4. LTD4 significantly enhanced eosinophil adhesion to rh-VCAM-1 and rh-ICAM-1, but not to rh-P-selectin. Finally, we observed that combined exposure of eosinophils to LTD4 and VCAM-1 induced the release of EDN. CONCLUSION: Combined exposure to VCAM-1 or ICAM-1 and cysLT effectively induces the effector functions of eosinophils. Eosinophil adhesion to and migration across endothelial cells via these specific adhesion proteins and subsequent exposure to cysLTs may be mechanisms underlying activation of the effector functions of eosinophils in the asthmatic airway.

Neutrophilic inflammation and CXC chemokines in patients with refractory asthma.

BACKGROUND: There is evidence that eosinophils and neutrophils are simultaneously increased in the airways of some patients with chronic refractory asthma. The mechanisms by which neutrophils accumulate in the airways of asthmatics remain to be elucidated, however, chemoattractants for neutrophils such as CXC chemokines may affect either the accumulation or functional status of neutrophils in such patients. The objective of the present study was to identify the CXC chemokine responsible for the neutrophilic and possibly eosinophilic inflammation observed in the airways of patients with refractory asthma. METHODS: Following the inhalation of hypertonic saline, induced sputum was obtained from 14 healthy controls, 16 patients with mild well-controlled nonrefractory asthma, and 14 patients with refractory asthma. Concentrations of CXC chemokines and differential inflammatory cell counts were determined. RESULTS: The percentages of induced sputum eosinophils were significantly higher both in patients with nonrefractory asthma and in patients with refractory asthma. On the other hand, the percentages of neutrophils were increased only in sputum from patients with refractory asthma. The concentration of IL-8, but not ENA-78 or GRO-alpha, was also significantly increased in induced sputum from patients with refractory asthma. The concentration of IL-8 correlated significantly with the percentages of neutrophils. CONCLUSIONS: The results of the present study suggest that IL-8, but not ENA-78 or GRO-alpha, may contribute to the observation of neutrophilic inflammation in patients with refractory asthma.