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Pulmonary veno-occlusive disease is a rare subcategory of pulmonary arterial hypertension (WHO Group 1). The disease is poorly understood and difficult to diagnose; it has no definitive cure to date. These patients present with nonspecific symptoms, including dyspnea, exercise intolerance, and weakness. Chest x-rays sometimes differ from idiopathic pulmonary arterial hypertension and may demonstrate alveolar infiltrates and pleural effusions. High resolution computed tomography scans reveal ground glass opacities, interlobular septal thickening, and lymphadenopathy. Echocardiography can estimate the level of pulmonary artery pressures; right heart catheterization is needed for complete hemodynamic characterization of these patients. Lung biopsies demonstrate remodeling of the venules and small veins with intimal and adventitial fibrosis. This can result in total venous occlusion and subsequent recanalization. Similar changes occur in the small arteries and arterioles but are less pronounced than the venous changes. There is no effective medical therapy for these patients, and treatment with the pulmonary arterial hypertension specific medications often causes acute deterioration with pulmonary edema. The recent discovery of the biallelic mutations of the EIF2AK4 gene as an etiology for heritable form of pulmonary veno-occlusive disease increases our understanding of the disease pathogenesis and potentially identifies a future approach to treatment. Without definitive treatment, the prognosis is very poor, and the life expectancy of these patients is much shorter than patients with pulmonary arterial hypertension. These patients need early referral to transplantation centers., (Published by Elsevier Ltd.)

Invasive pulmonary aspergillosis is a well-recognized complication in immunocompromised patients, especially those with neutropenia. We report four cases of invasive pulmonary aspergillosis in patients whose main underlying disease was chronic obstructive pulmonary disease (COPD). Two patients had an acute fatal course, one had chronic necrotizing pulmonary aspergillosis ending in an acute fatal course, and the other had a semiacute disease that responded to amphotericin B. Autopsy on three patients showed invasive pulmonary aspergillosis in both lungs, and tissue invasion was documented by transbronchial biopsy in the patient who survived. Retrospective review of all cultures that grew Aspergillus species from bronchoscopic specimens showed no false-positive results, and this procedure proved to be the most useful maneuver in making the diagnosis. Invasive pulmonary aspergillosis should be in the differential diagnosis in patients with COPD and unexplained pulmonary infiltrates.

Since the clearance of Staphylococcus aureus from murine lungs after aerosol exposure depends only on regional defense processes and does not require the recruitment of neutrophils or other systemic factors, we used this model for pulmonary clearance to evaluate the effect of chronic glucocorticosteroid therapy on intrinsic pulmonary defense responses. Mice treated with oral prednisolone for 2 or more weeks had delayed clearance of S. aureus at both 6 and 22 h after aerosol exposure. Mice treated with prednisolone for 1 week had delayed clearance at 22h, and mice treated for 2 days had normal clearance. In mice that had been treated for 2 weeks, clearance returned to normal after 2 weeks off therapy, but not after 1 week. Prednisolone did not appear to alter the number of phagocytes in bronchoalveolar spaces or their ingestion capacity. These results suggest that chronic steroid therapy can alter pulmonary clearance functions independent of any effect on immune or inflammatory responses.

Several investigations of host and bacterial factors critical to staphylococcal clearance from lungs suggest that alveolar macrophages may not provide the principal defense against inhaled staphylococci. We evaluated possible contributions of extracellular bactericidal activities in lungs with a standard aerosol challenge model by using methods which allowed recovery of macrophages for in vitro bactericidal assays and recovery of intrapulmonary staphylococci for clearance studies. Macrophages recovered by a gentle lavage technique immediately after aerosol exposure contained 6.0 +/- 2.3 colony-forming units of viable staphylococci per 100 glass-adherent macrophages. These intracellular staphylococci were killed in vitro with a half-life of 10.8 +/- 2.1 h, which is identical to our results with a completely in vitro system for ingestion and killing. However, 99.4 +/- 0.2% and 94.9 +/- 1.5% of the viable cocci recovered in bronchoalveolar lavage at 0.5 and 6.0 h after aerosol exposure were sensitive to lysostaphin, a rapidly bactericidal enzyme with no demonstrable activity against intracellular organisms and therefore, presumably extracellular. Photomicrographs from lavage pellets obtained 0.5, 1.5, 3.0, and 5.5 h after aerosol exposure confirmed the presence of numerous extracellular cocci. These extracellular cocci were eliminated at the same rate as whole lung cocci (half-life = 3.07 and 3.14 h, respectively) and at a much faster rate than intracellular cocci. In summary, we found large numbers of extracellular staphylococci in bronchoalveolar spaces during the first 6 h after aerosol exposure that are inactivated at the same rate as the whole lung bacterial population. Since only a small number of staphylococci are ingested by macrophages and intracellular bactericidal activity appears too slow to explain intrapulmonary killing, we conclude that an as yet unidentified extracellular killing process contributed to staphylococcal clearance.

We characterized the clearance of Candida albicans from the lung using a murine model for pulmonary aspiration. Swiss Webster mice uniformly survived intratracheally administered boluses of C. albicans (1 to 30 X 10(5) colony-forming units of yeast) which killed the majority of mice (more than 85%) when injected intravenously. Clearance studies, using quantitative cultures of lung homogenates, demonstrated rapid elimination of C. albicans from the lung after a 6-h delay; the residual fractions of viable fungi were 8.3 and 0.7% of the initial inoculums at 24 and 48 h, respectively, after inoculation. The number of leukocytes in the bronchoalveolar spaces increased twofold to threefold after deposition, and this primarily reflected a neutrophil influx. Histologic studies supported the bronchoalveolar lavage results and revealed a diffuse interstitial neutrophilic infiltrate and clusters of inflammatory cells in air spaces at 6 and 24 h after Candida deposition. Examination of lavage pellets demonstrated that both neutrophils and macrophages ingested C. albicans in vivo. Immunosuppression (orally administered prednisolone for 2 wk) delayed the clearance of C. albicans from the lung. However, evaluation of neutrophil migration into bronchoalveolar spaces and of the in vivo ingestion capacity of both macrophages and neutrophils did not identify differences that could explain this delayed clearance in steroid-treated mice. The fungicidal activity of pulmonary leukocytes was measured with in vitro assays and was similar in phagocyte cultures from control and steroid-treated mice. In summary, intrinsic pulmonary defense factors and recruited neutrophils rapidly and completely clear C. albicans from the lung after bolus deposition.(ABSTRACT TRUNCATED AT 250 WORDS)

Virus replication and interstitial pneumonia were studied in BALB/c mice inoculated intranasally with murine cytomegalovirus (MCMV). In normal mice MCMV replicated in lung tissue but did not produce any consistent histologic abnormalities through day 21. The addition of a single dose of cyclophosphamide (0.20 mg/g) 24 hr after virus inoculation resulted in a slight increase in lung virus titers on day 10. No histologic abnormalities were noted before day 10. However, 22 or 32 virus-infected mice treated with a single dose of cyclophosphamide but only two of 26 simultaneously mock-infected, cyclophosphamide-treated mice developed severe interstitial pneumonia 10-14 days after inoculation. In contrast, animals given cyclophosphamide (0.05 mg/g) every five days after the initial dose developed a 10-fold increase in lung virus titer, but interstitial pneumonia was not observed. These data suggest that the interstitial pneumonitis seen with MCMV pulmonary infection may be immunologically mediated rather than the result of direct viral damage to the lung.

Alkylating agents have several effects on cellular host defense responses which could increase either the frequency or the severity of pulmonary infections. In addition, some of these agents directly injure lung parenchyma and could have effects on intrapulmonary killing processes independent of any effect on phagocyte number and function. We have used a murine model for staphylococcal clearance to evaluate the effect of cyclophosphamide and mechlorethamine on intrinsic lung defenses. Single doses of mechlorethamine (40 micrograms IV) or of cyclophosphamide (150 mg/kg IP) reduce peripheral blood neutrophil counts and spleen weights on day 3 after injection; with the exception of neutrophil counts in mechlorethamine-treated mice, these parameters returned to normal by days 10-12. Both drugs reduced the number of alveolar macrophages recoverable by bronchoalveolar lavage on days 10-12 but not day 3. Mechlorethamine delayed the clearance of Staphylococcus aureus 502A from the lung on both days 3 and 12, but cyclophosphamide did not alter clearance on either day 3 or 10. The defect in clearance in mechlorenthamine-treated mice resolved by 3 wk after drug administration. These results demonstrate that alkylating agents do not have uniform effects on antibacterial processes in the murine lung. Since the mechlorethamine effect on staphylococcal elimination appears independent of its effect on macrophage numbers, these results suggest that staphylococcal clearance also depends on nonphagocytic host defense factors.

We used analytical electron microscopic techniques, including energy-dispersive X-ray analysis, to evaluate a patient with diffuse infiltrates and a history of silica exposure. We identified silica particles in digested bronchoalveolar lavage fluid, sectioned alveolar macrophages recovered by lavage, and parenchymal specimens obtained by transbronchial biopsy. This analysis confirmed our clinical suspicion (a sporadic case of accelerated silicosis) and eliminated the need for additional, more complicated, diagnostic procedures.

To further delineate the mechanisms underlying murine pulmonary defenses against bacterial infection, we studied the effects of antioxidant enzymes and hydroxyl radical scavengers on pulmonary clearance processes. Intratracheal injection of catalase and superoxide dismutase resulted in prolonged intraalveolar residence of the enzymes, but caused no decrease in rates of clearance of either Staphylococcus aureus 502A or Pseudomonas aeruginosa PAO1. In contrast, dimethylsulfoxide and dimethylthiourea caused significant depression of clearance of P. aeruginosa without altering clearance of S. aureus. These results provide further differentiation between clearance processes affecting gram-negative and gram-positive bacteria and suggest that murine clearance of gram-negative organisms may be in part mediated by reactions which generate hydroxyl anion. In vivo administration of agents which inhibit hydrogen peroxide-, superoxide-, or hydroxyl anion-mediated reactions do not alter normal clearance of S. aureus.