Lymphoid interstitial pneumonia: clinical features, associations and prognosis.

Lymphoid interstitial pneumonia (LIP) is rare and its clinical course incompletely described. The aim of this study was to examine the clinical features, associations and prognosis of surgical lung biopsy-proven LIP. The study group consisted of 15 subjects encountered over a 14-yr period. The majority of subjects were females (n = 11) and the mean age was 47 yrs (range 17-78 yrs). Underlying systemic immune disorders were frequent, including Sjögren's syndrome (n = 8), rheumatoid arthritis, systemic lupus erythematosus, polymyositis, common variable immunodeficiency and dysproteinaemia. Only three patients were classified as "idiopathic". Presenting symptoms were dominated by dyspnoea and cough. Restrictive physiology, reduced diffusion capacity (62.5+/-18.4% predicted) and bronchoalveolar lavage lymphocytosis (30.5+/-29.1% pred) were noted. Thirteen patients received corticosteroid therapy. Of the nine whose response could be assessed, four showed clinical improvement and four were stable. Overall, median survival was 11.5 yrs. Of the seven patients who died, respiratory problems were the primary cause of death in three. Conversion to lymphoma was not identified. In conclusion, histopathological lymphoid interstitial pneumonia is commonly associated with immune system dysregulation, with idiopathic lymphoid interstitial pneumonia being extremely rare. Clinical stability or improvement with corticosteroids can be expected; however, survival remains impaired.

Obliterative bronchiolitis: varying presentations and clinicopathological correlation.

In obliterative bronchiolitis, inflammation and fibrosis lead to narrowing or occlusion of bronchiolar lumina. To determine how bronchiolar structural alterations relate to lung physiology, 19 patients with a pathological diagnosis of obliterative bronchiolitis were studied. The bronchiolar inflammatory and fibrotic features were correlated to the clinical presentation, and lung function tests. Eleven patients demonstrated airflow limitation, one had a restrictive pattern and one had a mixed pattern, two had isolated gas trapping, but four had normal spirometry. Mild-to-moderate bronchiolar inflammation was invariably present. It involved 60% of bronchioles subepithelially and 54% in the adventitia. Subepithelial fibrosis was observed in 15 patients and adventitial in 12. Adventitial bronchiolar inflammation correlated with forced expiratory volume in one second and forced vital capacity and inversely correlated with residual volume. Subepithelial fibrosis inversely correlated with subepithelial and adventitial inflammation. High-resolution computed tomography in 10 patients revealed inspiratory (five out of 10) and expiratory air trapping (five out of five), ground glass opacities (seven out of 10), bronchial wall thickening (five out of 10), bronchiectasis (two out of 10) and centrilobular nodules (two out of 10). The present study suggests that inflammation and fibrosis occurs in bronchioles at different time points in the disease process, or that there is no transition between these types of pathology in the same patient. No correlation was observed between the degree of bronchiolar fibrosis and the degree of airflow limitation.

Acute eosinophilic pneumonia in AIDS.

A 39-year-old man with AIDS presented with acute respiratory distress and diffuse bilateral infiltrates seen on a chest radiograph. Acute eosinophilic pneumonia (AEP) was diagnosed by thoracoscopic lung biopsy. There was no evidence of an infectious etiology, and the patient rapidly improved with corticosteroid therapy. Several of the idiopathic interstitial pneumonias have been reported in adult patients with AIDS. To our knowledge, this case represents the first tissue-confirmed case of AEP associated with adult AIDS.

Hypoxemia explained 36 years later.

A 37-year-old man who had an atrial septal defect (ASD) corrected as an infant was found to be hypoxemic with a 22% shunt. An MRI scan revealed that the patient's inferior vena cava drained into his left rather than his right atrium, a previously undetected complication of his ASD repair 36 years before.

Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality.

It is hypothesized that the extent and severity of fibrosis and cellularity found on lung biopsy determine the prognosis and response to therapy in idiopathic pulmonary fibrosis (IPF). The objective of this study was to determine which histopathologic features predict survival in IPF. We prospectively studied 87 patients with usual interstitial pneumonia (UIP) confirmed by surgical lung biopsy. Four pathologists independently graded the extent and severity of specific histopathologic features. We used Cox proportional-hazards models to assess the effect of histopathologic patterns on patients' survival. The effects of age, sex, and smoking were also included in the analysis. Sixty-three patients died during the 17-yr study period. Survival was longer in subjects with lesser degrees of granulation/connective tissue deposition (fibroblastic foci). The degree of alveolar space cellularity, alveolar wall fibrosis, and cellularity did not affect survival. A history of cigarette smoking, the level of dyspnea, and the degree of lung stiffness at presentation were also shown to be independent factors predicting survival. The extent of fibroblastic foci present on lung biopsy predicts survival in IPF. These findings support the hypothesis that the critical pathway to end-stage fibrosis is not "alveolitis" but rather the ongoing epithelial damage and repair process associated with persistent fibroblastic proliferation. Controlling these processes, rather than stopping inflammation, appears most important in preventing progressive disease and the fatal outcome common in IPF.

Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.

Our purpose was to identify clinical, radiological and physiological (CRP) determinants of survival and to develop a CRP scoring system that predicts survival in newly diagnosed cases of idiopathic pulmonary fibrosis (IPF). The study population consisted of 238 patients with biopsy confirmed usual interstitial pneumonia. For each patient, clinical manifestations, chest radiographs, and pulmonary physiology were prospectively assessed. We used Cox proportional-hazards models to assess the effect of these parameters on survival. The effects of age and smoking were included in the analysis. Survival was related to age, smoking status (longer in current smokers), clubbing, the extent of interstitial opacities and presence of pulmonary hypertension on the chest radiograph, reduced lung volume, and abnormal gas exchange during maximal exercise. A mathematical CRP score for predicting survival was derived from these parameters. We showed that this CRP score correlated with the extent and severity of the important histopathologic features of IPF, i.e., fibrosis, cellularity, the granulation/connective tissue deposition, and the total pathologic derangement. Using these models, clinicians are in a better position to provide prognostic information to patients with IPF and to improve the selection of the most appropriate patients for lung transplantation or other standard or novel therapeutic interventions.

Acute interstitial pneumonitis: current understanding regarding diagnosis, pathogenesis, and natural history.

Acute interstitial pneumonitis (AIP) is a fulminant disease culminating in acute respiratory failure and often death. Originally described in 1935 by the pathologists Hamman and Rich, this rare syndrome is characterized by rapidly progressive pulmonary fibrosis, leading to frequent confusion with idiopathic pulmonary fibrosis. In fact, the eponym Hamman-Rich syndrome became synonymous with idiopathic pulmonary fibrosis despite clear differences in clinical presentation, radiography, pathology, and survival. In 1986, Katzenstein described eight patients with acute respiratory failure of unknown etiology. On biopsy, organizing diffuse alveolar damage was present in all specimens. Given the idiopathic nature of the disease, Katzenstein coined the phrase acute interstitial pneumonitis to distinguish it from the fibroproliferative stage of the acute respiratory distress syndrome (ARDS), which has an identical pathology. Olson et al retrospectively examined Hamman and Rich's original cases, compared them to contemporary cases of AIP, and found the two identical. Since then, little progress into understanding this disease has been made. Many questions still linger regarding the epidemiology, pathogenesis, and outcome. We recently published our experience with AIP providing new information regarding natural history. This review summarizes the current literature on AIP emphasizing diagnostic criteria, pathogenesis, and natural history.

Acute interstitial pneumonitis. Case series and review of the literature.

Acute interstitial pneumonitis (AIP) is an acute, idiopathic interstitial lung disease characterized by rapidly progressive diffuse pulmonary infiltrates and hypoxemia requiring hospitalization. The case-fatality ratio is high. Previous reports suggested that survivors of the acute event have a favorable outcome. We undertook this study to examine the natural history of survivors. We had observed several patients who experienced recurrent episodes of AIP and chronic progressive interstitial lung disease. We sought to determine longitudinal survival in these patients and to compare our experience with that in the medical literature. Overall, we identified 13 biopsy-proven cases of AIP. The mean patient age was 54 years in our review, which is identical to previous reports. Twelve patients were hospitalized and all 12 required mechanical ventilation. Overall hospital survival was 67%. All patients demonstrated abnormalities in gas exchange at presentation. Radiographs typically demonstrated bilateral patchy densities that progressed to a diffuse alveolar filling pattern in nearly all cases. All biopsy specimens showed organizing diffuse alveolar damage. Longitudinal data were available for 7 patients. Two died of AIP recurrences. A third died of complications of heart failure shortly after hospital discharge. One patient progressed to end-stage lung disease and required lung transplantation. Two patients experienced persistent pulmonary symptoms, accompanied in 1 by progressive lung fibrosis. One patient had nearly complete recovery of lung function 2 years following AIP. (Follow-up information was unavailable for 2 survivors.) In our literature review, 5 of 7 patients reported experienced some recovery of lung function. One case of progressive interstitial lung disease requiring lung transplantation was reported. The reported mortality was much higher than in our experience (74% versus 33%). The mean time from symptom onset to death was 26 days, compared with 34 days in our experience. The use of corticosteroids did not appear to influence survival, although this has not been tested in a rigorous manner. The better survival in our series may be related in part to a survivor selection bias. In contrast to previous reports, we found that survivors of AIP may experience recurrences and chronic, progressive interstitial lung disease. We did not identify any clinical or pathologic features that predict mortality in these patients. Likewise, there were no features that predicted the longitudinal course in survivors. Further study to identify causal factors is required in the hope of preventing morbidity and mortality related to this disease.

Diffuse alveolar hemorrhage and pulmonary capillaritis due to propylthiouracil.

Propylthiouracil (PTU) has recently been observed to be associated with antineutrophil cytoplasmic antibody (ANCA)-positive small vessel vasculitis, resulting in crescentic glomerulonephritis and, infrequently, diffuse alveolar hemorrhage (DAH). We describe a case of a 23-year-old pregnant woman who developed a perinuclear ANCA and antimyeloperoxidase-positive small vessel vasculitis manifesting as DAH and crescentic glomerulonephritis after she began taking PTU. An open lung biopsy was consistent with pulmonary capillaritis. She responded to corticosteroid therapy and discontinuation of PTU. DAH can be caused by pulmonary capillaritis, bland hemorrhage, or diffuse alveolar damage. To our knowledge, this represents the first documentation of an underlying pulmonary capillaritis in a case of PTU-induced DAH.

Mycoplasma pneumoniae-associated bronchiolitis causing severe restrictive lung disease in adults: report of three cases and literature review.

STUDY OBJECTIVES: To characterize adult Mycoplasma pneumoniae-induced bronchiolitis requiring hospitalization. DESIGN: We encountered an adult patient with severe bronchiolitis in the absence of pneumonia due to M. pneumoniae. To determine the relative frequency of such a condition, we retrospectively reviewed the medical records of adults over a 4-year period with a hospital discharge diagnosis of "bronchiolitis" from a university hospital. SETTING: University Hospital of the University of Colorado Health Sciences Center, Denver, CO. STUDY SUBJECTS: From 1994 to 1998, 10 adult inpatients were identified with a diagnosis of bronchiolitis. There were two with respiratory bronchiolitis, one with panbronchiolitis, one patient with bronchiolitis obliterans organizing pneumonia (BOOP), and six with acute inflammatory bronchiolitis. Including the initial patient, three had a definitive clinical diagnosis of Mycoplasma-associated bronchiolitis. RESULTS: The three adult patients with bronchiolitis due to M. pneumoniae are unusual because they occurred in the absence of radiographic features of a lobar or patchy alveolar pneumonia. Hospital admission was occasioned by the severity of symptoms and gas exchange abnormalities. One patient had bronchiolitis as well as organizing pneumonia (BOOP) that responded favorably to corticosteroid treatment. The other two had high-resolution CT findings diagnostic of an acute inflammatory bronchiolitis. One of the patients with inflammatory bronchiolitis had an unusual pattern of marked ventilation and perfusion defects localized predominantly to the left lung. All three had restrictive ventilatory impairment on physiologic testing. CONCLUSIONS: In adults, Mycoplasma-associated bronchiolitis without pneumonia is rarely reported, but in hospitalized patients, it may be more common than expected and may be associated with severe physiologic disturbances.

Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome.

All-trans-retinoic acid (ATRA) can induce a clinical remission in patients with acute promyelocytic leukemia. An adverse condition called "retinoic acid syndrome" limits this therapy. It is characterized by fever and respiratory distress, along with weight gain, pleural or pericardial effusions, peripheral edema, thromboembolic events, and intermittent hypotension. The lung disease has been previously ascribed to an infiltration of leukemic or maturing myeloid cells into lung parenchyma, which is sometimes associated with pleural effusions and diffuse alveolar hemorrhage. We report a case of retinoic acid syndrome in an 18-yr-old woman who developed diffuse alveolar hemorrhage while being treated with ATRA for acute promyelocytic leukemia. An open lung biopsy revealed pulmonary capillaritis.

Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease.

STUDY OBJECTIVES: To demonstrate that pulmonary capillaritis and diffuse alveolar hemorrhage (DAH) occur and are isolated to the lung and therefore not part of systemic vasculitis at the time of the DAH episode in rheumatoid arthritis (RA) and mixed connective tissue disease (MCTD). DESIGN: Lung biopsy specimens from patients with DAH were reviewed and those with the histologic features of pulmonary capillaritis were identified. SETTING: The patients were selected from seven Denver-area general hospitals. PATIENTS: Fifty-eight patients with biopsy specimen proved pulmonary capillaritis (1991 to 1997) were identified and classified according to disease. Three patients met the American Rheumatism Association criteria for RA and one patient fulfilled clinical and serologic criteria for MCTD. INTERVENTIONS: All clinical, laboratory, and radiographic data on initial presentation and at follow-up periods were extracted from the charts of the four study patients. Histologic slides were reviewed and immunofluorescent studies of lung tissue were performed. MEASUREMENTS AND RESULTS: All four patients had a connective tissue disease diagnosis prior to the DAH episode. Symptoms referable to pulmonary capillaritis were of short duration (2 to 14 days) and there was no clinical or serologic evidence for an accompanying systemic vasculitis, in particular glomeronephritis. Three patients, two with RA and one with MCTD, demonstrated pulmonary immune complex deposition. Three resolved their illness following IV methylprednisilone and cyclophosphamide therapy. One RA patient died following a myocardial infarction. In the three survivors, no further episodes of DAH have occurred after a mean of 24 months (range, 10 to 48 months). CONCLUSIONS: To our knowledge, these are the first cases of DAH due to pulmonary capillaritis documented to complicate RA and MCTD. The capillaritis was not part of a systemic vasculitis at the time of the DAH episode, but rather represented an isolated small-vessel vasculitis of the lungs in this group of patients. Immune complex deposition may be involved in the pathogenesis.

Pulmonary capillaritis: a possible histologic form of acute pulmonary allograft rejection.

Acute rejection after lung transplantation occurs commonly and is usually characterized histologically by a perivascular mononuclear infiltrate. We report five cases of pulmonary capillaritis with a histologic appearance distinct from typical rejection, occurring in patients ranging in age from 18 to 45 years, with a variety of underlying diseases including alpha1 antitrypsin deficiency, pulmonary hypertension, cystic fibrosis, and rheumatoid arthritis. Four of the five patients had alveolar hemorrhage histologically, and two had frank hemoptysis. Time of onset ranged from 3 weeks to many months after transplantation. Three cases were fulminant, and there were two deaths. In only one case, with methicillin-resistant Staphylococcus aureus bronchitis, could infection be established. All were treated with intensification of immunosuppressive therapy. Plasmapheresis was carried out in two cases and coincided with temporary improvement, but its efficacy was questionable because of concurrent immunosuppressive therapy. Two had recurrent biopsy-proven acute rejection within 6 weeks of treatment, and one had recurrent severe pulmonary hemorrhage that abated with total lymphoid irradiation. Our experience suggests that pulmonary capillaritis in lung transplant recipients can be an acute, fatal illness with the potential for recurrence in the survivors. We speculate that it represents a form of acute vascular rejection. Early pathologic diagnosis and aggressive immunosuppressive therapy are recommended. Although a humoral component was not documented, the possible response to plasmapheresis requires continued evaluation.