Effects of Low-Dose and Long-Term Treatment with Erythromycin on Interleukin-17 and Interleukin-23 in Peripheral Blood and Induced Sputum in Patients with Stable Chronic Obstructive Pulmonary Disease.

OBJECTIVE: To study the effects of low-dose and long-term treatment with erythromycin on IL-17 and IL-23, in peripheral blood and induced sputum, in patients with stable chronic obstructive pulmonary disease (COPD). METHODS: Patients were randomly divided into placebo-treated group, group A (12 months of additive treatment with erythromycin, N = 18), and group B (6 months of additive treatment with erythromycin followed by 6 months of follow-up, N = 18). Inflammatory cells in induced sputum, pulmonary function, and the 6-minute walk distance (6MWD) were analyzed. Concentrations of IL-17 and IL-23 in peripheral blood and sputum were measured using enzyme-linked immunosorbent assays. RESULTS: After treatment, sputum and peripheral blood concentrations of IL-17 and IL-23 significantly decreased in groups A and B compared with placebo-treated group. There were no significant differences after erythromycin withdrawal at months 9 and 12 in group B compared with placebo-treated group. An increase in 6MWD was observed after treatment. CONCLUSIONS: Erythromycin was beneficial and reduced airway inflammation in COPD patients. Underlying mechanisms may involve inhibition of IL-17 and IL-23 mediated airway inflammation. COPD patients treated with erythromycin for 6 months experienced improved exercise capacity. Finally, treatment for 12 months may be more effective than treatment for 6 months.

Differences in clinical characteristics and prognosis of Penicilliosis among HIV-negative patients with or without underlying disease in Southern China: a retrospective study.

BACKGROUND: The incidence of Penicillium marneffei infection has recently increased. This fungus can cause fatal systemic mycosis in both immunocompetent and immunocompromised patients without HIV infection. METHODS: We retrospectively analysed Penicilliosis patients between January 1, 2003 and August 1, 2014 at the First Affiliated Hospital of Guangxi Medical University. HIV-negative patients with Penicilliosis were divided into two groups: patients with underlying disease (Group D) and patients without underlying disease (Group ND). HIV-positive patients were excluded. The relationships between overall survival and the study variables were assessed using univariate and multivariate analyses. RESULTS: During 11 years, Penicillium marneffei infection was diagnosed in 109 patients. Sixty-six (60.55 %) patients were HIV-positive and excluded from these cases. Forty-three patients were HIV-negative were enrolled. Among these patients, 18 (41.86 %) patients were in Group D, and 25 (58.14 %) were in Group ND. The most common underlying disease was diabetes. There were no statistically significant differences between the two groups in clinical characteristics, except for immune state and prognosis. Group ND had higher lymphocyte cell counts, CD4 cell counts, and CD4 T-cell percentages than Group D (P < 0.05). Patients in Group D had higher recurrence and mortality rates than Group ND (P < 0.05). In the univariate analysis, only underlying disease, CD4 cell percentage, and T lymphocyte cell percentage were significantly associated with overall survival. CONCLUSIONS: Penicillium marneffei can infect HIV-negative patients and can cause fatal systemic mycosis. There were no clear differences in clinical manifestations among HIV-negative patients with and without underlying disease. However, Penicillium marneffei in HIV-negative patients in with underlying diseases may cause immune function decline and a deficiency in T-cell-mediated immunity. Underlying disease, CD4 cell percentage, and T lymphocyte cell percentage may be potential risk factors affecting prognosis. Timely, effective, and longer courses of antifungal treatments are important in improving prognoses.

Dendritic Cells Promote Treg Expansion but Not Th17 Generation in Response to Talaromyces marneffei Yeast Cells.

BACKGROUND: Dendritic cells (DCs) with both proinflammatory and tolerogenic properties have been implicated in modulation of CD4+ T cell responses in many fungal diseases. However, the role of DC in the context of Talaromyces marneffei (T. marneffei) infection has not been determined. In this study, we aimed to study the effect of the yeast form of T. marneffei yeasts on DCs, as well as the role of DCs in modulating T helper 17 (Th17) and regulatory T (Treg) cell responses to the pathogen. METHODS: Mouse bone marrow-derived DCs were stimulated with T. marneffei yeasts for 24 h. Frequencies of CD80 and CD86 expression on DCs and the levels of IL-6, IL-10 and TGF-ß in the culture supernatant of yeast-stimulated DCs were detected by flow cytometry and ELISA, respectively. In co-culture experiments, CD4+ T lymphocytes of mice were isolated from the spleen using magnetic beads and co-cultured with T. marneffei yeasts, with or without DCs for 24 h. The proportions of Th17 and Treg cells in co-culture were detected by flow cytometry. The mRNA levels of RORγt and Foxp3 were detected by RT-PCR. Levels of IL-10 and TGF-ß in the co-culture supernatant were detected by ELISA. RESULTS: The expressions of CD80 and CD86 on DCs were increased, as well as IL-6, IL-10 and TGF-ß levels in the culture supernatant of T. marneffei-stimulated DCs were higher than those in DCs cultured without T. marneffei. In co-culture experiments, in the presence of DCs, T. marneffei promoted Treg expansion and Foxp3 up-regulation but limited Th17 and downregulated RORγt. Levels of IL-10 and TGF-ß were higher in the co-culture containing DCs than without DCs. CONCLUSION: Our findings demonstrated that the interaction between DCs and T. marneffei could promote Treg expansion but not Th17 generation. These findings provide a mechanism by which DCs may promote immune tolerance in T. marneffei infection.

Erythromycin Prevents Elastin Peptide-Induced Emphysema and Modulates CD4+T Cell Responses in Mice.

Purpose: Elastin peptides (EP) can induce lung inflammation and emphysema. Erythromycin has been shown to decrease acute exacerbation frequency and delay lung function decline in chronic obstructive pulmonary disease patients and ameliorate emphysema in murine models; however, the mechanism remains unclear. We aimed to observe the preventive and immunomodulatory effects of erythromycin in a mouse model of EP-induced emphysema. Methods: In the in vivo study, Balb/c mice were treated with EP intranasally on day 0, and then administered erythromycin (100 mg/kg) or vehicle orally on day 1, which was continued every other day. Mice exposed to cigarette smoke were used as an emphysema positive control. The severity of emphysema and inflammation in the lungs of EP-exposed mice with or without erythromycin treatment were observed on day 40 after EP administration. In the in vitro study, naïve CD4+T cells were isolated from healthy mice spleens and stimulated by EP with or without erythromycin incubation. Flow cytometry was used to measure the proportions of Th1, Th17, and Treg cells. ELISA was used to detect cytokine levels of IFN-γ, IL-17, IL-6, and TGF-ß. Transcript levels of Ifnγ, IL17a, and Foxp3 were evaluated by qRT-PCR. Results: After exposure to EP, Th1 and Th17 cell percentages and the levels of inflammatory cytokines increased in vivo and in vitro, while Treg cells decreased in vivo. Erythromycin reduced IFN-γ, IL-17, IL-6 inflammatory cytokines, MLI, and the inflammation score in the lungs of EP-exposed mice. In vitro, erythromycin also limited Th17 and Th1 cell differentiation and downregulated transcript levels of Ifnγ and IL17a in the EP-stimulated CD4+T cells. Conclusion: The Th1 and Th17 cell responses were increased in EP-induced emphysema. Prophylactic use of erythromycin effectively ameliorated emphysema and modulated CD4+T cells responses in EP-induced lung inflammation in mice.

Determinants of prognosis in Talaromyces marneffei infections with respiratory system lesions.

BACKGROUND: Little study has investigated the differences between Talatomyces marneffei (T. marneffei) respiratory infection and tuberculosis and the prognostic factors of such infection. This study investigated the characteristics and prognostic factors of T. marneffei infections with respiratory lesions and the causes of misdiagnosis. METHODS: Clinical characteristics and prognoses of patients with T. marneffei infections with respiratory system lesion were investigated. T. marneffei diagnosis followed isolation from clinical specimens using standard culture, cytology, and histopathology. Survival curves were estimated by using Kaplan-Meier analysis, with log-rank test to compare differences in survival rates between groups. Univariate and multivariate Cox regression analyses were also performed to assess significant differences in clinical characteristics of overall survival. RESULTS: Of 126 patients diagnosed with T. marneffei infections, 63 (50.0%) had T. marneffei respiratory system infections; 38.1% (24/63) were misdiagnosed as having tuberculosis. Human immunodeficiency virus (HIV) infection, CD4/CD8 < 0.5, percentage of CD4 T cells <42.8%, and length of time from onset to confirmation of diagnosis >105 days were potential risk factors for poor prognoses. Length of time from onset to confirmation of diagnosis persisted as an independent predictor of all-cause mortality in multivariate analysis (odds ratio: 0.083, 95.0% confidence interval: 0.021-0.326, P < 0.001). However, the size of the lung lesions, dyspnea, thoracalgia, mediastinal lymphadenopathy, and pleural effusion did not significantly predict overall survival. There was no significant difference in prognosis according to the type of treatment. CONCLUSIONS: T. marneffei infections involving the respiratory system are common. The critical determinants of prognosis are HIV infection, CD4/CD8, percentage of CD4 T cells, type of treatment, and the time range from onset to confirmation of diagnosis. Rapid and accurate diagnosis is crucial for improving prognosis.