Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone.

We have studied the interaction between virulent Legionella pneumophila and human alveolar macrophages, the resident phagocytes at the site of infection in Legionnaires' disease. L. pneumophila multiplied 2.5-5 logs within 3 d, as measured by colony forming units, when incubated with freshly explanted alveolar macrophages in monolayer culture. At the peak of bacterial multiplication, the alveolar macrophage monolayers were destroyed. L. pneumophila multiplied more rapidly in 4-d-old than in freshly explanted alveolar macrophages. Inside alveolar macrophages, L. pneumophila were located within membrane-bound vacuoles whose cytoplasmic sides were studded with ribosomes. Alveolar macrophages that were incubated with concanavalin A (Con A) stimulated human mononuclear cell supernatants (cytokines), inhibited L. pneumophila multiplication, and the degree of inhibition was proportional to the concentration of Con A supernatant added. Anti-L. pneumophila antibody in conjunction with complement promoted phagocytosis of L. pneumophila by alveolar macrophages. By electron microscopy, most (75%) of the phagocytized L. pneumophila were intracellular. However, freshly explanted alveolar macrophages were able to kill only 0-10% of an innoculum of L. pneumophila even in the presence of antibody and complement. At the same time, alveolar macrophages also killed opsonized Escherichia coli poorly. Increasing the ratio of macrophages to bacteria, adhering the macrophages to microcarrier beads, or preincubating the macrophages for 24 or 48 h with Con A supernatants failed to augment alveolar macrophage killing of opsonized E. coli. Corticosteroids appear to increase patient susceptibility to Legionnaires' disease. However, pretreatment of alveolar macrophages and monocytes with hydrocortisone had no influence on intracellular multiplication of L. pneumophila or on the inhibition of that multiplication by activated alveolar macrophages or monocytes. Hydrocortisone did impair cytokine-induced aggregation of alveolar macrophages. These findings demonstrate that L. pneumophila multiplies in human alveolar macrophages and that they do so within a ribosome-lined phagosome; that freshly explanted alveolar macrophages kill few L. pneumophila even in the presence of antibody and complement; that activated alveolar macrophages inhibit L. pneumophila multiplication; and that steroids do not exert a direct suppressive effect on the anti-L. pneumophila activity of activated or nonactivated alveolar macrophages. Our findings indicate that alveolar macrophages may play a central role in both the pathogenesis of Legionnaires' disease and in host defense against it. This paper shows that human resident macrophage can be activated to a higher state of antimicrobial capacity and that the human alveolar macrophage can serve as an effector call in call-mediated immunity.

Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer.

PURPOSE: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

The solitary pulmonary nodule: update 1995.

PURPOSE: This study analyzed the clinical characteristics, diagnostic evaluation, prevalence of malignancy, and outcome of patients with a solitary pulmonary nodule (SPN) encountered in the outpatient practice of a pulmonologist in an urban university hospital from 1990 to 1993. PATIENTS AND METHODS: SPN was defined as a round or ovoid density < or = 3 cm in diameter within the lung parenchyma. Patients with and without lung cancer in SPNs were compared. RESULTS: Forty patients had a mean age of 65 years, an almost equal sex distribution, high prevalences of cardiovascular disease (53%) and chronic obstructive pulmonary disease (COPD) (33%), but a low incidence of tuberculosis. The mean size of SPNs was 1.8 cm. The prevalence of malignancy was 53%. In SPNs < or = 2 cm in diameter, the prevalence of malignancy was 43%. Nonsurgical biopsy techniques made a diagnosis in 78% of patients. In 94% of patients with lung cancer in SPNs, the tumor was resectable (stage 1, 2, or 3A), emphasizing the need for early detection. Despite the small size of the SPNs, the prevalence of malignancy was high. CONCLUSION: Despite the advanced age and high prevalence of cardiovascular disease and COPD in patients with SPNs, lung cancer that occurs in these lesions appears to have a favorable prognosis if detected promptly.

Syphilitic aortic aneurysm presenting with the superior vena cava syndrome.

In a 65 year old man with hemoptysis, chest pain, weight loss, clubbing of the digits and a large mediastinal mass, the superior vena cava syndrome developed. He was treated for malignancy with radiation therapy and corticosteroids, but he died shortly after his admission to the hospital. Autopsy revealed syphilitic aortitis with an aneurysm of the ascending aorta compressing the superior vena cava and right mainstem bronchus. The postmortem serology corroborated the morphologic findings of tertiary syphilis. In this report we emphasize the important, although now uncommon, association between the superior vena cava syndrome and aneurysm of the aorta.

Acute respiratory failure in scoliosis or kyphosis: prolonged survival and treatment.

Acute respiratory failure (ARF) in adults with severe thoracic spinal deformity is said to be a preterminal event with a median survival of one year. Twenty patients with ARF (mean +/- S.D., arterial oxygen tension [PaO2] 35 +/- 7 mm Hg, arterial carbon dioxide tension [PaCO2] 63 +/- 9 mm Hg, pH 7.34 +/- 0.08) due to severe scoliosis or kyphosis (spinal curve 113 +/- 28 degrees ) were seen between 1965 and 1980. All 20 survived the initial episode of ARF and during the follow-up period (median, six years) experienced 2.4 additional episodes of ARF. The age at presentation was 52 years (mean, range 13 to 78), and the cause of spinal deformity was idiopathic (seven patients), poliomyelitis (seven), tuberculosis (five), and arthrogryposis multiplex congenita (one). ARF was treated with controlled low dose oxygen by Venturi mask and intensive general measures in 13 patients and by mechanical ventilation in seven. Of the latter seven patients, ventilatory failure was treated in two with a tank respirator and a cuirass, avoiding endotracheal intubation. Outpatient management was similar to conventional therapy for chronic obstructive pulmonary disease (COPD). Severe restrictive ventilatory impairment characterized the group after recovery from the first episode of ARF: vital capacity (VC) 906 +/- 362 ml (31 percent predicted) and FEV1 589 +/- 197 ml (23 percent). During follow-up, the VC decreased by 1.5 ml/year and the FEV1 by 13.9 ml/year. The PaO2 increased by 2.6 mm Hg/year and the PaCO2 increased by 1.7 mm Hg/year. Successful management of ARF due to severe scoliosis or kyphosis is possible in the great majority of patients, and long-term survival may be expected. Unlike COPD, pulmonary function following ARF in kyphosis or scoliosis deteriorates at a slower than expected rate and, in fact, may improve with treatment over many years.

Cricoarytenoid arthritis in ankylosing spondylitis. A cause of acute respiratory failure and cor pulmonale.

A man with ankylosing spondylitis developed cor pulmonale and acute respiratory failure due to cricoarytenoid arthritis. He was successfully treated by endoscopic arytenoidectomy, and the surgical specimen showed ossified cartilage. Flow-volume curves documented extra-thoracic airway obstruction produced by ankylosis of the cricoarytenoid joints.

Simultaneous pulmonary and renal malignancy.

Simultaneous primary malignancy of the lung and kidney has been rarely recognized during life. Three patients with synchronous primary pulmonary and renal cancer are described. The pulmonary tumors were asymptomatic and were discovered on plain chest roentgenography. The renal tumors, also asymptomatic, were incidentally discovered on CT, performed for staging. Although one patient was treated with interleukin-2 for a presumed solitary pulmonary metastasis from renal carcinoma, in all three patients, both the kidney and lung tumors were eventually removed either concurrently or sequentially. Prior autopsy case series are reviewed. In the elderly, synchronous asymptomatic pulmonary and renal malignancy is not surprising, and it should be approached as a distinct clinical problem. With the use of chest roentgenography for screening high risk populations and CT for staging, simultaneous primary pulmonary and renal malignancy will probably be recognized increasingly.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer--a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high-risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT-based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Clinical utility of computed tomography in the diagnosis of pulmonary embolism.

This prospective clinical pilot study describes the clinical utility and cost effectiveness of computed tomography (CT) with contrast in the diagnosis and management of pulmonary embolism. The setting is a university teaching hospital, and the 20 patients, 26 to 81 years old, were found to have CT findings consistent with pulmonary embolism. Intraluminal pulmonary artery clots were observed on CT and contributed to clinical management, often obviating pulmonary arteriography. CT, particularly spiral CT, may demonstrate pulmonary embolism and offers advantages over ventilation-perfusion lung scanning and pulmonary arteriography in making the diagnosis of pulmonary embolism in high-risk patients or patients with preexisting parenchymal lung disease.

Radiographic screening for cancer. Proposed paradigm for requisite research.

Computed tomography (CT) imaging as an excellent approach to the detection and characterization of small solitary pulmonary nodules (SSPN) raises three questions: (1) How often does CT imaging lead to detection of SSPN? (2) How often is such an SSPN malignant? (3) If malignant, how curable is it? The first question pertains to decisions about screening use of CT (clinical or mass screening), the second to decisions about screening for SSPN and diagnosis of malignancy given SSPN, and the third--in the context of known curability at ordinary clinical diagnosis--to decisions about screening for SSPN, diagnosis given SSPN and intervention given malignant SSPN. We present a three component study design that addresses these questions. The first is directed primarily to the first question. Some 1000 persons at high risk for lung cancer will be screened for SSPN using screening-type CT. The primary aim is to determine the prevalence of CT-detectable SSPN as a joint function of risk-relevant aspects of the person. The second component addresses the prevalence of malignancy among the detected cases of SSPN. To develop the prevalence function, a larger series of CT-detected SSPN will be obtained by developing a multi-center SSPN "registry." A subsequent, third component will focus on the registered cases of malignant SSPN screening incidentally detected and address their curability on the basis of long-term follow-up. This design, in lieu of a randomized trial, may represent a new paradigm for applied research on radiologic technologies in cancer screening, given its advantages in terms of research efficiency and implications to decisions about diagnostic workup and therapeutic intervention.

CT-guided transthoracic needle biopsy following indeterminate fiberoptic bronchoscopy in solitary pulmonary nodules.

We evaluated the role of computed tomography (CT)-guided transthoracic needle biopsy (TNB) in patients with solitary pulmonary nodule and indeterminate flexible fiberoptic bronchoscopy (FOB). A review of 112 patients with solitary nodules under 3 cm in size who underwent TNB was carried out. A total of 48 patients had prior FOB with negative or indeterminate results. We reviewed the results of CT-guided TNB of these 48 patients with respect to the cytology results, nodule size and location, and complications of the procedure. Among the 48 patients who had FOB with indeterminate cytology, 32 were found to have malignant cytology on subsequent TNB. Among the remaining 16 patients, eight had diagnostic thoracotomy, which showed that six of the nodules were benign and two were malignant. The remaining eight patients who did not undergo surgery have been followed for more than 2 years, without evidence of growth. Results were not influenced by size or location. TNB offers a high yield for diagnosis in this patient population.

Sarcoidosis, pulmonary hypertension, and acquired peripheral pulmonary artery stenosis.

An unusual case of a young woman with sarcoidosis and pulmonary hypertension who developed new bilateral continuous murmurs and was found to have peripheral pulmonary artery stenoses is reported. The patient has improved symptomatically, radiographically, and hemodynamically on steroid therapy.

Relief of hypoxia-related bronchoconstriction by breathing 30 per cent oxygen.

Airway resistance decreases when hypoxemic subjects with chronic obstructive pulmonary disease (COPD) breathe 30% O2. To verify this finding and to localize the site of action of O2, flow-volume curves on air and helium-O2 mixtures were obtained before and after subjects breathed 30% O2. Patients with COPD and hypoxemia showed an increase in flow rates and a decrease in the density dependence of flow while breathing 30% O2. Atropine produced a similar change in flow rates and density dependence, but then no further change occurred with 30% O2. Five control subjects with COPD, who performed the same sequence of tests without breathing 30% O2, showed no change in flow rates or density dependence. Normal control subjects also showed no change in flow rates or density dependence while breathing 30% O2. Breathing 30% O2, relieves hypoxia-induced bronchoconstriction and appears to act on large airways.

IFN-gamma-activated human alveolar macrophages inhibit the intracellular multiplication of Legionella pneumophila.

Human alveolar macrophages activated by human rIFN-gamma inhibit the intracellular multiplication of Legionella pneumophila, an intracellular bacterial pathogen and the agent of Legionnaires' disease. Activation of alveolar macrophages with IFN-gamma is dose dependent; significant inhibition of L. pneumophila multiplication (mean 1.60 +/- 0.20 logs) is achieved consistently with concentrations of IFN-gamma of greater than or equal to 2 x 10(-2) micrograms/ml (220 U/ml). Activation of alveolar macrophages is also time dependent. In macrophages treated continuously after explantation, macrophages infected at 48 to 96 h after explantation are more inhibitory than macrophages infected at 24 h after explantation. In macrophages not treated continuously after explantation but treated for various lengths of time before infection, the longer their exposure to IFN-gamma before infection, the greater the inhibition of L. pneumophila multiplication (96 greater than 72 greater than 48 greater than 24 h). IFN-gamma-activated alveolar macrophages exhibit morphologic signs of activation, including increased size, spreading, and aggregation. This paper demonstrates that a human resident macrophage can be activated with IFN-gamma such that it exhibits enhanced antimicrobial activity against a relevant pathogen.

Chronic eosinophilic pneumonia: an unusual cause of acute respiratory failure.

A 75-year-old man developed dyspnea, cough, peripheral radiographic infiltrates, eosinophilia, and severe hypoxemia requiring mechanical ventilation. An open lung biopsy revealed chronic eosinophilic pneumonia, and the patient recovered with corticosteroid therapy. Chronic eosinophilic pneumonia is a disease that should be included in the different diagnosis of treatable causes of acute respiratory failure.

Elevated carcinoembryonic antigen levels correlating with disease recurrence in a patient with adenoid cystic carcinoma.

BACKGROUND: Carcinoembryonic antigen (CEA) is an oncofetal glycoprotein involved in cell recognition and adhesion. Serum CEA has been extensively studied as a potential chemical marker for malignancy, most notably in patients with colon carcinoma. Serum CEA measurements have not been reported for patients with salivary gland carcinomas. METHODS: Serum CEA was measured in a case study using enzyme immunoassay with monoclonal antibody specific for CEA. Tissue was examined with standard histologic and immunohistologic methods. RESULTS: A patient was initially seen with adenoid cystic carcinoma (ACC) of the trachea and had a markedly elevated serum CEA level which declined after surgical resection. The serum CEA level became elevated again when the patient developed abdominal metastases and then declined after debulking of the tumor. Immunohistochemical study of the tumor was positive for CEA. CONCLUSIONS: The measurement of serum CEA levels may play a role in the management of patients with ACC. Clinical investigation utilizing monoclonal antibodies against CEA, for imaging and for the delivery of chemotherapy and radiotherapy may be worthwhile.

Oxygen concentration from room air. A new source for oxygen therapy in the home.

Most oxygen concentrators use molecular sieves that selectively adsorb molecules according to their size and polarity. Their present rental cost is about half that of the traditional oxygen tanks or liquid-oxygen systems. Two concentrators have been tested. They are able to produce both high oxygen concentrations (95% oxygen at 2 L/min) and high flow rates (10 L/min with 40% oxygen), which remained stable for one week. After 24 hours of continuous use, neither machine concentrated toxic gases from room air in a city. Both were suitable for use with 24% and 28% Venturi masks.

Coexisting lymphangioleiomyomatosis and bilateral angiomyolipomas in a patient with tuberous sclerosis.

A patient with tuberous sclerosis and known bilateral angiomyolipomas presented with a complete pneumothorax prior to scheduled renal surgery. Evaluation revealed the presence of pulmonary lymphangioleiomyoma, an unusual entity known to coexist with tuberous sclerosis. Pulmonary decortication and conservative renal surgery resulted in a satisfactory long-term result.

Immunogenetic and clinical findings in idiopathic pulmonary fibrosis. Association with the B-cell alloantigen HLA-DR2.

In order to assess the role of immunogenetic factors in the pathogenesis of idiopathic pulmonary fibrosis (IPF), HLA-A, B, C, and DR typing was performed on 20 Caucasian patients with IPF seen from 1978 to 1980 and in 200 healthy blood donors. An increase in the frequency of the B-cell alloantigen, HLA-DR2, was observed; HLA-DR2 was found in 65% of patients with IPF compared with 26% of the control subjects (corrected p value = 0.005, chi-square = 11.476, relative risk = 5.286). Although not significant, increases were observed in HLA-B7 and HLA-A3, antigens known to be in linkage disequilibrium with HLA-DR2. The HLA-DR2 was observed in 12 of 14 patients with "ground glass linear" and "cystic honeycombing" radiographic patterns, whereas it was observed in only 1 of 6 patients with "ascinar nodular" radiographic patterns (p = 0.01). No other correlation was observed between HLA type and clinical, laboratory, or pathologic parameters. We conclude that immunogenetic factors, perhaps genes within the major histocompatibility complex, are relevant to the pathogenesis of IPF.