Citations

Abstract Pulmonary eosinophilic granuloma is characterized by infiltration of the lungs with fibronodular lesions containing specialized Langerhans' cells. In some patients, progressive pulmonary fibrosis leads to significant respiratory impairment. Transforming growth factor-beta1 (TGF-beta1) promotes fibrosis by enhancing the synthesis of extracellular matrix components. The role of TGF-beta1 in promoting fibrosis in the setting of pulmonary eosinophilic granuloma is currently unknown. We used immunohistochemistry to evaluate the extent and distribution of TGF-beta1 and the extracellular matrix components type I collagen and decorin, a TGF-beta1-binding proteoglycan. Lung biopsies from 11 patients with pulmonary eosinophilic granuloma were evaluated. In biopsies with active inflammatory lesions containing Langerhans' cells, hyperplastic type 2 pneumocytes and alveolar macrophages within and surrounding the fibronodular lesions contained abundant TGF-beta1. Langerhans' cells were consistently devoid of immunoreactive TGF-beta1. Active inflammatory lesions also exhibited staining for decorin, in a loosely organized distribution. Advanced fibrotic lesions of eosinophilic granuloma, containing minimal inflammatory cells and few or no Langerhans' cells, exhibited weak or absent staining for TGF-beta1 within either hyperplastic type 2 pneumocytes or alveolar macrophages. The fibroconnective tissues of these advanced fibrotic lesions consistently revealed dense staining for decorin. Through their actions on extracellular matrix protein accumulation, TGF-beta1 and the TGF-beta1-binding proteoglycan decorin may modulate fibrotic repair accompanying pulmonary eosinophilic granuloma.

Abstract Acute eosinophilic pneumonia is characterized by acute respiratory insufficiency, hypoxemia, fever, diffuse radiographic infiltrates, and eosinophilia in bronchoalveolar lavage fluid (BALF) or lung biopsies in the absence of infection, atopy, or asthma. A rapid response to corticosteroids is characteristic. We reviewed our experience with nine cases of acute lung disease with histologic features of acute and organizing diffuse alveolar damage and prominent interstitial and alveolar eosinophils in order to determine whether this pathology was characteristic of acute eosinophilic pneumonia. The mean age of the patients (four men and five women) was 53 yr (range: 33 to 71 yr). They presented with 2 to 21 d of dyspnea, cough, myalgias, and fever. All were hypoxic and had bilateral infiltrates on chest radiographs. Peripheral blood eosinophilia was present in four of eight patients (peripheral blood count unavailable for one patient). All patients were treated with high-dose corticosteroids with a mean time to symptomatic and radiographic improvement of 4 d. Seven of the nine patients enrolled in the study are alive without relapse; one patient has a mild deficit in diffusing capacity, and one patient died of a myocardial infarct while improving on therapy. The presence of eosinophils in cases of acute respiratory insufficiency due to diffuse alveolar damage (DAD) should suggest the diagnostic possibility of acute eosinophilic pneumonia. Acute eosinophilic pneumonia should be distinguished from other causes of DAD because of important differences in natural history.

Abstract Cyclophosphamide-induced lung toxicity may be difficult to recognize because of the presence of confounding variables such as concomitant use of other cytotoxic drugs, opportunistic infections, diffuse pulmonary malignancy, radiation pneumonitis, and oxygen toxicity. The purpose of this retrospective analysis was to identify the clinical spectrum of pulmonary toxicity of cyclophosphamide. In our review of case records, we sought to identify patients in whom cyclophosphamide was the only identifiable etiologic factor for lung toxicity. In a 20-yr period six patients were identified with cyclophosphamide-induced lung disease, including five men and one woman ranging in age from 42 to 78 yr. Clinical features of toxicity include dyspnea, fever, cough, new parenchymal infiltrates, gas exchange abnormalities on pulmonary function tests, and pleural thickening on chest roentgenogram. Two patterns of cyclophosphamide-induced lung toxicity were identified. A single patient presented with early-onset pneumonitis and responded to discontinuation of the drug. Five patients with late-onset pneumonitis developed progressive pulmonary fibrosis associated with bilateral pleural thickening. Patients with late-onset pneumonitis showed no response to cessation of cyclophosphamide and institution of corticosteroid therapy. Three of these patients died of respiratory failure. Careful review of the individual cases reported in the literature as cyclophosphamide lung toxicity revealed only 12 cases in whom none of the additional confounding factors could be identified. These could easily be divided in the same two categories. Early-onset pneumonitis is reversible and may respond to corticosteroid therapy. Late-onset pneumonitis, frequently associated with pleural thickening, is clinically distinct from idiopathic pulmonary fibrosis but has a chronically progressive course. It appears unresponsive to corticosteroid therapy.

Abstract Intraluminal airway pressure and pharyngeal muscle activity are widely recognized as major determinants of the size and collapsibility of the upper airway. In addition, changes in the volume or pressure of tissue surrounding the pharyngeal airway may significantly influence its size. The present study used fast computed tomography (CT) to determine the effects of changes in central venous pressure (CVP) on upper airway size. Ten awake male patients with obstructive sleep apnea (OSA) were studied. Scans were performed at functional residual capacity (FRC) and at the end of a tidal inspiration (VTei) under three conditions of CVP: (1) at baseline (CVP nl) with patients lying supine; (2) at decreased CVP (CVP-) by inflating blood pressure cuffs to 40 mm Hg on both legs; and (3) at increased CVP (CVP+) by elevating both legs to 33 degrees. At FRC, changes in CVP had no significant effect on either mean or minimum cross-sectional area (CSA) of the upper airway. In contrast, an analysis of variance (ANOVA) indicated that alterations in CVP were associated with changes in mean CSA (p = 0.03) and to a lesser extent in minimum CSA (p = 0.07) at VTei. With the legs elevated (CVP+), neither mean nor minimum CSA showed any significant change with tidal breathing. However, after leg-cuff inflation (CVP-), highly significant increases in both mean (163 +/- 22 to 218 +/- 19 mm2, p = 0.001) and minimum (48 +/- 8 to 85 +/- 12 mm2, p = 0.02) CSA were detected. Changes in mean and minimum CSA with tidal breathing at baseline (CVP nl) were intermediate. These results indicate that changes in CVP significantly alter the response of the upper airway to tidal breathing. They further suggest that increases in upper airway size with tidal breathing may be related to reduction in venous blood volume in pharyngeal and neck tissues as the generation of negative intrathoracic pressure during inspiration increases venous return to the chest.

Abstract The early stage of idiopathic pulmonary fibrosis (IPF) is thought to involve a smaller number of alveoli and to be characterized predominantly by cellularity and minimal fibrosis, whereas advanced disease involves a large number of alveoli and is characterized predominantly by fibrosis with minimal cellularity. In addition, correlative studies have indicated that prognosis and response to therapy is determined in part by the extent of fibrosis and cellularity. This study was undertaken to determine whether pulmonary function assessment would help distinguish between the cellular and fibrotic phases of this disorder, as determined by a semiquantitative pathology scoring system that comprised four factor scores: fibrosis, cellularity, granulation/connective tissue, and desquamation. Ninety-six untreated patients with biopsy-confirmed IPF (27 never smokers, 32 current smokers, and 37 ex-smokers) were evaluated. In the group as a whole, there was no significant relationship between the fibrosis or the connective/granulation tissue factor scores and any of the physiologic parameters. The Dl co correlated with the “desquamation” and the total pathology scores, whereas the TLC and FVC correlated with the cellularity factor score. In the current smokers, the coefficient of elastic retraction, Dl co/Va, and FEV1/FVC ratio were significantly lower than in never smokers and ex-smokers, and TLC and FVC were higher than in never smokers. Also, the mean cellularity and granulation/connective tissue factor scores were significantly lower, and the desquamation factor score was significantly higher than those in never smokers and ex-smokers. Both age and smoking status were significant for the cellularity factor score, whereas for the connective/granulation tissue factor score, age was not significant but smoking status was. For the desquamation factor score, age was significant but smoking status was not. There were significant differences between never smokers and ever smokers in the relationship between the pathology factors and measurements of respiratory function, and this may explain some of the difficulty in assessing structure-function correlation in patients with IPF. In the never smokers, the correlations between structure and function were likely the direct result of IPF per se. In the current smokers, bronchiolar and/or emphysematous changes associated with cigarette smoking may have complicated the pathologic alterations caused by IPF, as well as influencing the functional derangements.

Abstract Chronic eosinophilic pneumonitis (CEP) is characterized by longstanding respiratory symptoms accompanied by a massive pulmonary eosinophil infiltration. We hypothesized that cytokine(s) produced in the disease sites are implicated in the pathophysiology of CEP. We studied peripheral blood and bronchoalveolar lavage fluids (BALF) obtained from two lung segments of a patient with CEP. Seventy times more eosinophils were found in the BALF from an involved lung segment (showing patchy opacification on a chest roentgenogram) than from an uninvolved segment. The eosinophil-active cytokines interleukin-5 (IL-5), IL-6, and IL-10 were strikingly elevated in the BALF from the involved lung segment, whereas no or minimal levels of these cytokines were detectable in the BALF from the uninvolved segment or serum, respectively. Leukocytes in the involved lung segment, but not those in peripheral blood, expressed messenger ribonucleic acid (mRNA) for IL-5, IL-6, and IL-10. In contrast, IL-2, IL-3, IL-4, interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-alpha) were not detected in any sample. These findings suggest that increased production of several cytokines, such as IL-5, IL-6, and IL-10, in the involved lung segment, but not in the uninvolved lung segment or peripheral blood, is a critical pathophysiologic feature of CEP.