Timothy J. Harkin

Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis.

OBJECTIVE To determine whether linezolid is safe and well tolerated in the treatment of extensively drug-resistant tuberculosis (XDR-TB). MATERIALS AND METHODS The was conducted in a specialized tuberculosis ward for multidrug-resistant tuberculosis (MDR-TB) on the Chest Service of Bellevue Hospital Center, which is a 768-bed public hospital in New York City. Seven patients with confirmed MDR-TB or XDR-TB who were still culture positive despite appropriate directly observed therapy were treated with a regimen containing linezolid and at least one other active agent. RESULTS The linezolid-containing regimen led to sustained negative conversion of sputum cultures and radiographic improvement in all patients. Long-term therapy (longest duration of therapy, 28 months) was well tolerated in most patients. Neutropenia developed in three patients, but was reversible, and peripheral neuropathy developed in two patients. CONCLUSIONS Linezolid remains a promising possible addition to our therapeutic armamentarium against XDR-TB. Linezolid is associated with side effects that can be adequately managed. Further studies to define the mechanism of action and optimum dose should be performed.

Dehydroepiandrosterone inhibits the spontaneous release of superoxide radical by alveolar macrophages in vitro in asbestosis

Asbestosis is characterized by an alveolar macrophage alveolitis with injury and fibrosis of the lower respiratory tract. Alveolar macrophages recovered by bronchoalveolar lavage spontaneously release exaggerated amounts of oxidants including superoxide anion and hydrogen peroxide that may mediate alveolar epithelial cell injury. Dehydroepiandrosterone (DHEA) is a normally occurring adrenal androgen that inhibits glucose-6-phosphate dehydrogenase, the initial enzyme in the pentose phosphate shunt necessary for NADPH generation and superoxide anion formation. In this regard, we hypothesized that DHEA may reduce asbestos-induced oxidant release. DHEA added in vitro to alveolar macrophages lavaged from 11 nonsmoking asbestos workers significantly reduced superoxide anion release. DHEA was measured in bronchoalveolar lavage and found to be similar to serum concentrations. DHEA is an antioxidant and potential anticarcinogenic agent that may have a therapeutic role in reducing the increased oxidant burden in asbestos-induced alveolitis of the lower respiratory tract.

Elevated interleukin-8 in the alveolitis of individuals with asbestos exposure

Asbestosis is a fibrotic and inflammatory interstitial lung disease occurring after chronic occupational exposure to asbestos. An alveolitis has been described with activated alveolar macrophages and increased neutrophils as sampled by bronchoalveolar lavage (BAL). Animal models and in vitro studies demonstrate that asbestos can stimulate alveolar macrophages to release neutrophil chemotactic factor. We performed BAL on 18 nonsmoking individuals with asbestos exposure and observed a twofold increase in percent neutrophils recovered. Alveolar macrophages cultured in vitro from the asbestos-exposed individuals spontaneously released significant amounts of the neutrophil chemotaxin, interleukin-8 (IL-8). In addition, the alveolar macrophages expressed a 2.7-fold increase in steady state mRNA levels compared to unexposed normal controls utilizing the reverse transcriptase/polymerase chain reaction. In vitro experiments confirmed that crocidolite or chrysotile asbestos could stimulate the release of IL-8 from mononuclear phagocytes in a dose-dependent fashion. We conclude that asbestos exposure causes a mild neutrophilic alveolitis, and that IL-8 is one potential mediator capable of contributing to this inflammation in the lower respiratory tract.

Mechanisms of colchicine effect in the treatment of asbestosis and idiopathic pulmonary fibrosis.

AbstractThe objective of this study was to evaluate the mechanisms of colchicine action in pulmonary fibrosis. The study included 10 patients with pulmonary fibrosis (idiopathic pulmonary fibrosis 5, asbestosis 4, and scleroderma 1) who had been admitted to Bellevue Hospital Center, a tertiary care public hospital in New York City. We administered colchicine 0.6 mg orally for 12 weeks to patients with pulmonary fibrosis. Symptoms, high resolution CT scans, pulmonary function tests, and bronchoalveolar lavage parameters were compared prior to and after treatment. Results showed declines in dyspnea index, selective improvement in several CT scans, but no statistically significant change in BAL cells, cytokines, fibronectin, or hydroxyproline. However, there was a decline in hydroxyproline in the BAL fluid in 8/10 patients. We concluded that colchicine has a mild antifibrotic effect which may be in inhibiting collagen formation since there was no effect on the inflammation that accompanies fibrosis.

Transbronchial needle aspiration (TBNA) in patients infected with HIV

Transbronchial needle aspiration (TBNA) of intrathoracic lymph nodes has been shown to be useful in the diagnosis and staging of bronchogenic carcinoma. With the exception of sarcoidosis, the usefulness of TBNA has not been widely investigated in other clinical settings. We investigated the utility of TBNA with a 19-gauge histology needle in HIV-infected patients with mediastinal and hilar adenopathy at Bellevue Hospital Center. We performed 44 procedures in 41 patients. Adequate lymph node sampling was obtained in 35 of 44 (80%), and diagnostic material was obtained in 23 of 44 (52%) procedures. TBNA was the exclusive means of diagnosis in 13 of 41 (32%) patients. Of the 44 procedures, 23 (52%) were performed in patients with mycobacterial disease, with TBNA providing the diagnosis in 20 of 23 (87%). In these patients, positive TBNA specimens included smears of aspirated materials for acid-fast bacilli in 11, mycobacterial culture in 14, and histology in 15. In other diseases, TBNA diagnosed sarcoidosis with noncaseating granulomata in 2 of 4 patients and non-small cell lung cancer in 1 of 2 patients. TBNA was not helpful in other diseases including Pneumocystis carinii pneumonia, infection with Cryptococcus or Nocardia, bacterial pneumonia, viral pneumonia, and Kaposis sarcoma. No pulmonary diagnosis was established in five patients. No complications of TBNA occurred. We conclude that TBNA through the flexible bronchoscope is safe and effective in the diagnosis of intrathoracic adenopathy in HIV-infected patients, and is particularly efficacious in the diagnosis of mycobacterial disease. Furthermore, TBNA may provide the only diagnostic specimen in almost one-third of HIV-infected patients, thereby sparing these patients more invasive procedures such as mediastinoscopy.