Eisuke Sasaki

Heat shock protein 70 (hsp70) as a major target of the antibody response in patients with pulmonary cryptococcosis

Cryptococcus neoformans causes infection in individuals with defective T cell function, such as AIDS, as well as without underlying disease. It has been suggested that humoral as well as cellular immunity might play an important role in the immune response to C. neoformans infection. We have recently shown, using immunoblotting, that the 70‐kD hsp family of C. neoformans was the major target molecule of the humoral response in murine pulmonary cryptococcosis. In this study we also used immunoblotting to define the antibody responses in the sera of 24 patients with pulmonary cryptococcosis: 21 proven and three suspected diagnoses. Anti‐C. neoformans hsp70 antibody was detected in 16 of 24 (66.7%) patients with pulmonary cryptococcosis. Fourteen of 17 (82.3%) patients with high antigen titres (≥ 1:8) and two of seven (28.6%) patients with low titres (≤ 1:4) had detectable levels of anti‐hsp70 antibody. Sera from patients positive for anti‐hsp70 antibody showed high titres in the Eiken latex agglutination test for the detection of serum cryptococcal antigen. Our results indicate that the 70‐kD hsp family from C. neoformans appears to be a major target molecule of the humoral response, not only in murine pulmonary cryptococcosis, but also in human patients with pulmonary cryptococcosis.

Epidemiology and Clinical Features of Pulmonary Nontuberculous Mycobacteriosis in Nagasaki, Japan

Background and Objectives Recent reports indicate that the incidence of nontuberculous mycobacterial-lung disease (NTM-LD) is increasing. This study aimed to investigate the epidemiology and clinical features of NTM-LD patients in Nagasaki prefecture, Japan to identify the negative prognostic factors for NTM-LD in Japan. Methods The medical records of patients newly diagnosed with NTM-LD in eleven hospitals in Nagasaki prefecture between January 2001 and February 2010 were reviewed. Data regarding the annual population of each region and the incidence of all forms of tuberculosis were collected to assess geographic variations in NTM-LD incidence, isolates, and radiological features. Results A total 975 patients were diagnosed with NTM-LD. The incidence increased over the study period and reached 11.0 and 10.1 per 100,000 population in 2008 and 2009, respectively. M. intracellulare was the most common pathogen in the southern region, and M. avium most common in other regions. The most common radiographic pattern was the nodular-bronchiectatic pattern. Age >60 years, body mass index <18.5 kg/m2, underlying lung disease, and cavitary pattern were the negative prognostic factors at the 1-year follow-up. Conclusions The incidence of NTM-LD has been increasing in Nagasaki prefecture. The isolates and radiographic features of patients vary markedly by region.

Effects of macrophage colony-stimulating factor (M-CSF) on anti-fungal activity of mononuclear phagocytes against Trichosporon asahii

Trichosporon asahii is an emerging opportunistic pathogen in immunocompromised patients. Little is known about the mechanisms of host defence against T. asahii. We investigated the fungicidal activity of human peripheral blood monocytes and murine peritoneal macrophages against T. asahii isolates, and the effects of M‐CSF on the anti‐fungal activity of mononuclear phagocytes. We also established a neutropenic mouse model of disseminated trichosporonosis with T. asahii. M‐CSF enhanced the phagocytic fungicidal activity of mononuclear cells, and infected mice treated with human M‐CSF at 10 × 106 U/kg showed a significant improvement in survival rate, with fewer fungal colony counts in the lung compared with control mice. Mice treated with human M‐CSF showed higher concentrations of tumour necrosis factor‐alpha (TNF‐α) in the lung and plasma compared with control mice. The survival rate was significantly reduced in mice treated with anti‐mouse TNF‐α. Our results showed that M‐CSF enhanced the fungicidal activity of mononuclear phagocytes partly by production of TNF‐α, and suggest that the administration of M‐CSF to patients with disseminated trichosporonosis may be a useful adjunct to conventional anti‐microbial therapy and prophylaxis.

Elevated levels of β-chemokines in bronchoalveolar lavage fluid (BALF) of individuals infected with human T lymphotropic virus type-1 (HTLV-1)

Pulmonary complications are known to develop in HTLV‐1 carriers, including T lymphocytic alveolitis, and increased IL‐2 receptor α (CD25)‐bearing T cells have been found in BALF. Several chemokines may contribute to accumulation of T lymphocytes in the lungs of HTLV‐1 carriers. Here, we compared the distribution of T lymphocyte subsets and β‐chemokines, such as macrophage inflammatory peptide‐1α (MIP‐1α), regulated on activation normal T expressed and secreted (RANTES), and macrophage chemoattractant protein‐1 (MCP‐1), in BALF and peripheral blood between HTLV‐1 carriers and non‐infected healthy normal subjects. Flow cytometric analysis with MoAbs to cell surface antigens was used to identify T lymphocyte subsets in BALF samples from HTLV‐1 carriers (n = 13) and non‐infected healthy controls (n = 10). The levels of different β‐chemokines were estimated by ELISA. High percentages of CD3+ cells, CD3 expressing HLA‐DR antigen and CD3+CD25+ cells were detected in BALF of HTLV‐1 carriers compared with non‐infected controls. The concentration of MIP‐1α in BALF of patients was significantly higher than in non‐infected healthy controls and correlated well with the percentage of CD3+CD25+ cells. The level of RANTES in BALF was also significantly high in HTLV‐1 carriers, but did not correlate with the percentage of CD3+CD25+ cells. On the other hand, the level of MCP‐1 in BALF of HTLV‐1 carriers was not different from that of controls. Our results suggest a possible interaction between activated T cells bearing CD25 and β‐chemokines, especially MIP‐1α, which may contribute to the pulmonary involvement in HTLV‐1 carriers.

Development of imatinibmesylate-induced interstitial lung disease 2 weeks after discontinuation of the treatment: a case report

BackgroundImatinibmesylate (imatinib) is a small molecule tyrosine kinase inhibitor administered to patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. Although imatinib-associated interstitial lung disease is uncommon, a few cases have been reported so far. However, in all these cases interstitial lung disease developed during the use of imatinib. The present case is the first report of imatinib-induced interstitial lung disease developing after discontinuation of the drug.Case presentationA 51-year-old woman was administered oral imatinib for gastrointestinal stromal tumor. Ten weeks later, imatinib was discontinued because of facial edema. On this occasion, chest radiography showed no abnormal findings. However, 2 weeks after discontinuation of imatinib, she developed fever, dry cough, and dyspnea. Chest radiography and computed tomography showed diffuse interstitial infiltrates in both lungs. Examination of bronchoalveolar lavage fluid showed an increased proportion of lymphocytes. Imatinib-induced interstitial lung disease was suspected, because no other cause was evident. After administration of corticosteroids, her clinical condition and chest radiographic findings improved.ConclusionWe report a unique case of imatinib-induced interstitial lung disease that developed 2 weeks after discontinuation of the drug. Physicians should consider occurrence of imatinib-induced interstitial lung disease even after discontinuation of the drug.

Combination therapy with miconazole and flucytosine for deep-seated mycoses

This study evaluated combination therapy with miconazole and flucytosine for treating deep seated mycosis. Both mycological and clinical efficacy against candidemia and pulmonary cryptococcosis were satisfactory: All four isolatedCandida spp. were eradicated and all four patients with candidemia were cured, while six of nine patients with pulmonary cryptococcosis exhibited clinical improvement. The efficacy of combination therapy appeared to be low against aspergillosis, since only one of two patients with invasive pulmonary aspergillosis and two of five patients with pulmonary aspergilloma exhibited clinical improvement. Nevertheless, the clinical efficacy against aspergillosis was higher than that obtained with monotherapy in our previous study. Adverse reactions were observed in 36% (13 of 36) and abnormal laboratory findings in 22% (8 of 36) of patients treated with combination therapy; these rates were higher than those reported for monotherapy. These increases were not due to changes in serum concentrations of the two drugs due to simultaneous administration. The findings of this study suggest that combination therapy with miconazole and flucytosine may be an alternative therapy for refractory mycoses for carefully chosen patients.