Michael Lippmann

Elastolytic Activity in Pulmonary Lavage Fluid from Patients with Adult Respiratory-Distress Syndrome

To test the hypothesis that adult respiratory-distress syndrome (ARDS) is related to increased activity of the proteolytic enzyme elastase released from neutrophils in the lung, we determined the differential white-cell count, the elastolytic activity, the source of elastase, and the concentration and activity of the endogenous protease inhibitor alpha-1-antiprotease (alpha-1-AP) in bronchoalveolar lavage fluid from 23 patients with ARDS and from 55 patients without this syndrome. Neutrophil predominance (> 80 per cent) was observed in 18 of 23 patients with ARDS. High elastolytic activity of neutrophil origin was found in 12 of 23 patients with ARDS (52 per cent), in none of 16 normal nonsmokers (P < 0.01), in two of 17 normal smokers, and in three of 22 patients with chronic obstructive pulmonary disease. Although there were no significant differences in alpha-1-AP concentrations, its activity was reduced in eight of nine patients with ARDS and high elastolytic activity. We conclude that in many patients with ARDS, high levels of neutrophil elastolytic activity in the lungs are associated with reduced alpha-1-AP function.

Angiotensin converting enzyme inhibitor induced angio-oedema: a review of the pathophysiology and risk factors

Angio‐oedema (AE) is a known adverse effect of angiotensin converting enzyme inhibitor (ACE‐I) therapy. Over the past several decades, evidence of failure to diagnose this important and potentially fatal reaction is commonly found in the literature. Because this reaction is often seen first in the primary care setting, a review was undertaken to analyse and document the keys to both diagnostic criteria as well as to investigate potential risk factors for ACE‐I AE occurrence. A general review of published literature was conducted through Medline, EMBASE, and the Cochrane Database, targeting ACE‐I‐related AE pathomechanism, diagnosis, epidemiology, risk factors, and clinical decision making and treatment. The incidence and severity of AE appears to be on the rise and there is evidence of considerable delay in diagnosis contributing to significant morbidity and mortality for patients. The mechanism of AE due to ACE‐I drugs is not fully understood, but some genomic and metabolomic information has been correlated. Additional epidemiologic data and clinical treatment outcome predictors have been evaluated, creating a basis for future work on the development of clinical prediction tools to aid in risk identification and diagnostic differentiation. Accurate recognition of AE by the primary care provider is essential to limit the rising morbidity associated with ACE‐I treatment‐related AE. Research findings on the phenotypic indicators relevant to this group of patients as well as basic research into the pathomechanism of AE are available, and should be used in the construction of better risk analysis and clinical diagnostic tools for ACE‐I AE.

Nonresolving pneumonia and mimics of pneumonia

Physicians caring for patients with community-acquired pneumonia are often faced with the dilemma of how to approach a patient with slowly resolving or even nonresolving pneumonia. When the radiograph has failed to resolve by 50% in 2 weeks or completely in 4 weeks, the pneumonia should be considered to be nonresolving or slowly resolving. The causes of a nonresolving pneumonia and an approach to the work-up are presented.

Amiodarone-induced pulmonary toxicity in the rat

A rat model of amiodarone-induced pulmonary toxicity is described. The rats were fed, by gavage, 175 mg/kg/day of amiodarone hydrochloride suspended in methyl cellulose. Controls received methyl cellulose alone. Groups of rats were examined after 1, 3, 6, 9, and 12 weeks of feeding. We found that drug-fed rats had significantly more macrophages, neutrophils, and lymphocytes in the bronchoalveolar lavage (BAL). The early increase in cellularity was due to an increase in macrophages, and the macrophage count peaked after 6 weeks of drug treatment. The number of neutrophils in the experimental animals remained high throughout the course of the experiment. An increasing number of lymphocytes was seen in the BAL between 6 and 12 weeks of drug treatment. Protein in the lavage fluid was significantly elevated after 12 weeks of amiodarone exposure. Histologic sections were abnormal after 3 weeks of drug treatment, characterized by interstitial thickening with accumulation of mononuclear cells and alveoli packed with large foamy macrophages. There was only minimal evidence of fibrosis. This model appears to be very similar to human amiodarone-induced pulmonary toxicity and should be useful for the study of the pathogenesis of amiodarone-induced toxicity.

Saddle pulmonary embolism: is it as bad as it looks? A community hospital experience.

Background:Saddle pulmonary embolism represents a large clot and a risk for sudden hemodynamic collapse. However, the clinical presentation and outcomes vary widely. On the basis of the findings of right heart dysfunction on echocardiograms, computed tomography angiography, or cardiac enzyme elevation, some argue for the use of thrombolytics or catheter thrombectomy even for hemodynamically stable patients. Objective:To investigate the outcomes and management of patients with saddle pulmonary embolism, including radiographic appearance (estimate of clot burden) and echocardiographic features. Interventions:None. Measurements and Main Results:This study is a retrospective evaluation of all patients with computed tomography angiography positive for pulmonary embolism from June 1, 2004, to February 28, 2009. Two radiologists selected those with saddle pulmonary embolism and evaluated the clot burden score. The clinical information, echocardiography, treatments, and outcomes of these patients were extracted via chart review. Saddle pulmonary embolism was found in 37 of 680 patients (5.4%, 95% confidence interval 4% to 7%) with documented pulmonary embolism on computed tomography angiography. For patients with saddle pulmonary embolism, the median age was 60 yrs and 41% were males. Major comorbidities were neurologic (24%), recent surgery (24%), and malignancy (22%). Transient hypotension occurred in 14% and persistent shock in 8%. One patient required mechanical ventilation. Echocardiography was performed in 27 patients (73%). Right ventricle enlargement and dysfunction were found in 78% and elevated pulmonary artery systolic pressure in 67%. Computed tomography angiography demonstrated a high median pulmonary artery clot burden score of 31 points. The median right ventricle to left ventricle diameter ratio was 1.39. Inferior vena cava filters were placed in 46%. Unfractionated heparin was administered in 33 (87%) and thrombolytics in four (11%). The median hospital length of stay was 9 days. Two of 37 saddle pulmonary embolism patients (5.4%) died in the hospital (95% confidence interval 0.7% to 18%). Conclusions:Most patients with saddle pulmonary embolism found on computed tomography angiography responded to the standard management for pulmonary embolism with unfractionated heparin. Although ominous in appearance, most patients with saddle pulmonary embolism are hemodynamically stable and do not require thrombolytic therapy or other interventions.

Amiodarone causes decreased cell-mediated immune responses and inhibits the phospholipase C signaling pathway

Amiodarone can cause pulmonary toxicity along with an increase in phospholipid in macrophages, lymphocytes, and other cell types. Phospholipid accumulates because amiodarone inhibits the lysosomal phospholipases A1 and A2. Since a wide array of cells are affected by amiodarone and because amiodarone might inhibit other phospholipases, we postulated that cellular functions might be affected. Therefore, the major focus of this study was to determine whether amiodarone inhibited cellular functions. We found that alveolar macrophages isolated from drug-fed rats were significantly less phagocytic, and that the rats had significantly depressed delayed-type hypersensitivity responses. Spleen cells isolated from the drug-fed rats also had severely depressed mitogen responses. Since the spleen cell proliferative response could be partially restored by stimulating the cells with ionomycin and phorbol myristate acetate, we postulated that amiodarone was inhibiting phospholipase C. To substantiate this hypothesis, we found that amiodarone could directly inhibit phospholipase C in vitro. We conclude that amiodarone affects both phagocytic responses and the development of cell-mediated immunity and that the lack of these normal responses could exacerbate amiodarone toxicity. One possible mechanism for decreased cellular functions may be the inhibition of phospholipase C. However, further studies are necessary to confirm this finding.

Clinical diagnosis of massive hemoptysis using the fiberoptic bronchoscope

Pulmonary resection, when possible, is the conventional treatment of massive hemoptysis. Alternatives include bronchial artery embolization, Fogarty catheter balloon tamponade, and pharmacologic approaches. We used endotracheal intubation and flexible bronchoscopy to locate the bleeding site in three of four patients with massive hemoptysis. These cases are used to review the etiology of massive hemoptysis and the usefulness of flexible bronchoscopy to localize the source of hemorrhage.

Hypercapnia complicating massive pulmonary embolism.

An elevated PaCO2 is distinctly unusual in pulmonary embolic disease. We report 2 patients with massive pulmonary emboli complicated by hypercapnia in the absence of underlying chronic obstructive lung disease. Profound alterations in ventilation/perfusion matching and reduced cardiac output are probable mechanisms of this gas-exchange problem.

Resolution of adult respiratory distress syndrome after recovery from fulminant hepatic failure.

Adult respiratory distress syndrome (ARDS) complicating the course of fulminant hepatic failure is nearly always fatal without orthotopic liver transplantation. We report the case of a 50-year-old woman with fulminant hepatic failure and ARDS that resolved after her recovery from the acute liver failure without liver transplantation. The pathogenesis is discussed, particularly with regard to liver-lung interactions.

Sarcoidosis Presenting as Unilateral Alveolar Consol idation

Sarcoidosis is a multisystem granulomatous disorder that has variable clinical and radiologic manifestations. We describe a rare case of a 35-year-old black woman who had a nonresolving focal alveolar infiltrate. Her symptoms did not improve with the administration of antibiotics, and a more extensive workup, including fiberoptic bronchoscopy with transbronchial biopsy and a conjunctival biopsy showed noncaseating granulomata. We conclude that sarcoidosis should be included in the differential diagnosis of nonresolving alveolar opacity in populations that have increased incidence.