The role of rapidly growing mycobacteria (RGM) as pulmonary pathogens has been unclear. We identified 154 cases of lung disease caused by RGM using the microbiologic and radiographic criteria of the American Thoracic Society (ATS) and availability of the causative organism for study. More than one third of patients had positive lung biopsy cultures. Patients were predominantly white (83%), female (65%) nonsmokers (66%), and they had prolonged periods from onset of symptoms to diagnosis of their disease. Cough was an almost universal presenting symptom, whereas constitutional symptoms became more important with progression of disease. Upper lobe infiltrates were most common (88%), with 77% of patients developing bilateral disease. Cavitation was present in only 16% of the patients. Specific underlying diseases were infrequent, but they included previously treated mycobacterial disease (18%), coexistent Mycobacterium avium complex (8%), cystic fibrosis (6%), and gastroesophageal disorders with chronic vomiting (6%). The majority of isolates (82%) were M. abscessus (formerly M. chelonae subsp. abscessus). Effective treatment for M. fortuitum long disease was accomplished with drug therapy, whereas surgical resection of localized disease was the only effective long-term therapy for M. abscessus. Although the disease was generally slowly progressive, 21 of 154 (14%) patients died as a consequence of progressive RGM lung disease and respiratory failure. RGM should be recognized as a cause of chronic mycobacterial lung disease, and respiratory isolates should be assessed carefully.

In this study the incidence and course of pleural effusions (parapneumonic effusions) in patients with acute bacterial pneumonia were prospectively evaluated. Bilateral decubitus chest x-ray films were obtained within 72 hours of admission in 203 patients with an acute febrile illness, purulent sputum and an infiltrate evident on the chest film. Ninety of the 203 patients (44 percent) had pleural effusions. Parapneumonic effusions, which required chest tubes for resolution and/or on which the pleural fluid cultures were positive, were classified as complicated parapneumonic effusions. The 10 patients with complicated parapneumonic effusions had clinical characteristics similar to the remainder of the group and could be separated from the 80 with uncomplicated effusions only by pleural fluid analysis. A pleural fluid pH below 7.00 and/or a glucose level below 40 mg/100 ml are indications for immediate tube thoracostomy. In patients with pleural fluid pH between 7.00 and 7.20 or lactic dehydrogenase (LDH) above 1,000 IU/1,000 ml, tube thoracostomy should be considered, but each case should be individualized; serial studies of the pleural fluid are useful in some of these cases. Patients with pleural fluid pH above 7.20 and pleural fluid LDH below 1,000 mg/100 ml rarely have complicated parapneumonic effusions and do not require serial therapeutic thoracenteses.

Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.

The potential importance of pleural fibrin deposition in the pathogenesis of pleural injury is supported by both clinical and experimental observations. We hypothesized that the local equilibrium between procoagulant and fibrinolytic activities is disrupted to favor fibrin deposition in exudative pleuritis. To test this hypothesis, we characterized procoagulant and fibrinolytic activities in pleural exudates from patients with pneumonia, lung cancer, or empyema and transudates from patients with congestive heart failure. Procoagulant activity was generally increased in exudative processes and was due mainly to tissue factor. All effusions contained antithrombin III and inhibited factor Xa and thrombin, but endogenous prothrombinase or thrombin activities were variably detected. Pleural fluid fibrinolytic activity was increased in congestive heart failure and was due to both tissue plasminogen activator and urokinase. Depressed fibrinolytic activity was found in pleural exudates despite increased concentrations of plasminogen, mainly glu-1-plasminogen, and was due to inhibition of plasminogen activation by plasminogen activator inhibitors 1 and 2 and of plasmin, in part by alpha 2-antiplasmin. Concentrations of PAI-1 in exudative pleural fluids were increased up to 913-fold, compared with normal pooled plasma. Exudative pleural effusions are characterized by increased procoagulant and depressed fibrinolytic activity, favoring fibrin deposition in the pleural space. The balance of these activities is reversed and favors fibrin clearance in congestive heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermediate results of the first 50 patients treated with clarithromycin (CLARI) regimens for Mycobacterium avium-intracellulare (MAI) lung disease were evaluated. Patients were HIV negative, and pretreatment isolates were susceptible to CLARI. Patients received CLARI 500 mg twice daily, ethambutol, rifampin (RMP), or rifabutin (RBT) and initial streptomycin, and they were treated until culture-negative 1 yr. Eleven of 50 patients (22%) were dropped in the first 3 mo. Of the remaining 39 patients, 36 (92%) converted their sputa to negative, and 32 (82%) remain culture negative to date. This includes 11 of 16 (69%) with prior drug therapy and 21 of 23 (91%) with no prior therapy. One or more companion drugs were discontinued in 16 of 39 (41%) of patients because of adverse events. Isolates from six of 39 patients (15%) became CLARI-resistant. Of 23 patients who are alive and were culture-negative a mean of 12.0 mo while receiving therapy, all remain culture-negative without therapy a mean of 19.1 mo. Despite reduced CLARI serum levels in patients also receiving RMP, 10 of 13 patients (77%) receiving this regimen were successfully treated. Although not directly compared with previous regimens, the success of this regimen strongly suggests it is superior to previous non-CLARI-containing regimens.

We studied the role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Expression of the activating receptors NKp30, NKp46, and NKG2D were enhanced on NK cells by exposure to M. tuberculosis-infected monocytes, whereas expression of DNAX accessory molecule-1 and 2B4 was not. Anti-NKG2D and anti-NKp46 inhibited NK cell lysis of M. tuberculosis-infected monocytes, but Abs to NKp30, DNAX accessory molecule-1, and 2B4 had no effect. Infection of monocytes up-regulated expression of the NKG2D ligand, UL-16 binding protein (ULBP)1, but not expression of ULBP2, ULBP3, or MHC class I-related chain A or chain B. Up-regulation of ULBP1 on infected monocytes was dependent on TLR2, and anti-ULBP1 abrogated NK cell lysis of infected monocytes. The dominant roles of NKp46, NKG2D, and ULBP1 were confirmed for NK cell lysis of M. tuberculosis-infected alveolar macrophages. We conclude that NKp46 and NKG2D are the principal receptors involved in lysis of M. tuberculosis-infected mononuclear phagocytes, and that ULBP1 on infected cells is the major ligand for NKG2D. Furthermore, TLR2 contributes to up-regulation of ULBP1 expression.

No abstract

We previously showed that human NK cells used the NKp46 receptor to lyse Mycobacterium tuberculosis H37Ra-infected monocytes. To identify ligands on H37Ra-infected human mononuclear phagocytes, we used anti-NKp46 to immunoprecipitate NKp46 from NK cells bound to its ligand(s) on H37Ra-infected monocytes. Mass spectrometry analysis identified a 57-kDa molecule, vimentin, as a putative ligand for NKp46. Vimentin expression was significantly up-regulated on the surface of infected monocytes, compared with uninfected cells, and this was confirmed by fluorescence microscopy. Anti-vimentin antiserum inhibited NK cell lysis of infected monocytes, whereas antiserum to actin, another filamentous protein, did not. CHO-K1 cells transfected with a vimentin construct were lysed much more efficiently by NK cells than cells transfected with a control plasmid. This lysis was inhibited by mAb-mediated masking of NKp46 (on NK cells) or vimentin (on infected monocytes). ELISA and Far Western blotting showed that recombinant vimentin bound to a NKp46 fusion protein. These results indicate that vimentin is involved in binding of NKp46 to M. tuberculosis H37Ra-infected mononuclear phagocytes.