Advances in Pulmonary Biopsy Techniques. IN THE PAST DECADE, refinements in transthoracic and transbronchial fine-needle aspiration (FNA) techniques, ...
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Miyagawa Y, Nagata N, Shigematsu N: Clinicopathological study of migratory lung infiltrates. Thorax 1991; 46:233-238 Muller NL, Staples CA, Miller RR: Bronchiolitis organizing pneumonia: CT features in 14 patients. AJR 1990; 154:983-987
Advances in Pulmonary Biopsy Techniques IN THE PAST DECADE, refinements in transthoracic and transbronchial fine-needle aspiration (FNA) techniques, the introduction of thoracoscopic biopsies, and the improvement in lesion imaging and specimen processing have led to a continued decline in the need for open lung biopsies. The main indications now for percutaneous transthoracic FNA are the biopsy of pulmonary nodules and aspiration of infectious lesions. The diagnostic yield of conventional transbronchial forceps biopsy diminishes with the size of the lesion, whether infectious or neoplastic, so that lesions less than 2 cm to 3 cm are best approached by FNA. In immunocompromised patients, in whom early diagnosis is paramount, small subsegmental and peripheral lesions should undergo FNA under computed tomographic or fluoroscopic guidance because a positive result provides both a diagnosis and confirmation of invasion for otherwise potentially saprophytic organisms like fungi. Transbronchial FNA by flexible bronchoscopy has the advantage of a lower risk of pneumothorax than percutaneous methods. Its 50% yield in peripheral lesions supplements conventional transbronchial forceps biopsy, washing, and brushing, so that using them together increases the overall yield to about 70%. Compared with transbronchial forceps biopsy, transbronchial FNA is a better technique for metastatic lesions because these tend not to be peribronchial in distribution and hence require deeper biopsies. In addition, about 50% to 60% of malignant mediastinal lymph nodes in paratracheal, subcranial, and aorticopulmonary sites can be sampled with transbronchial FNA guided by computed tomographic images. When successful in the evaluation of lung cancer, this method provides both a cytologic diagnosis and staging, without the need for mediastinoscopy. Because transbronchial FNA has only moderate sensitivity, a negative result does not rule out malignant adenopathy, and it should be noted that the method provides no information about whether disease has spread through the involved node's capsule, a known factor in prognostication. Other uses of transbronchial FNA include the biopsy of extrabronchial compressive lesions and superficially necrotic tumors that require deeper biopsies. Newer molecular biology and immunohistologic tools have partially eliminated the need for the larger biopsies obtainable only by thoracotomy. Immunohistologic methods using antibodies directed against cell surface antigens can usually separate, for example, reactive lymphocytosis from lymphoma. Gene rearrangement techniques are so sensitive that even cytologic specimens obtained by bronchoalveolar lavage may be adequate for diagnosing certain lymphomas. A polymerase chain reaction assay for Mycobacterium tuberculosis holds similar promise for very small or even expectorated specimens in tuberculosis. When large pleural or parenchymal specimens are required, diagnostic thoracoscopy is now an option. Under general anesthesia, a double-lumen tube is placed to permit collapse of the lung. A rigid thoracoscope is inserted by trocar for plain or video viewing. An operating probe or second thoracoscope, which can incorporate the use of ther-
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apeutic carbon dioxide or neodymium-yttrium-aluminumgarnet lasers, is positioned separately to permit wedge excisional biopsy or even segmentectomy. In pleural diseases, thoracoscopy has proved invaluable in diagnosis, and in appropriate cases, therapeutic pleural debridement and even ablation of pleural blebs can be accomplished using these techniques. NORMAN W. RIZK, MD Stanford, California REFERENCES Shure D: Transbronchial biopsy and needle aspiration. Chest 1989; 95:1130-1138 Wakabayashi A:-Expanded applications ofdiagnostic and therapeutic thoracoscopy. J Thorac Cardiovasc Surg 1991; 102:721-723 Wang KP, Kelly SJ, Britt JE: Percutaneous needle aspiration biopsy of chest lesions-New instrument and new technique. Chest 1988; 93:993-997
Lung Transplantation HUMAN LUNG transplantation actually predated heart transplantation, beginning with a single-lung transplant done in 1963. Over the next 15 years, about 44 single-lung transplants were attempted worldwide. The results were uniformly dismal, however, and the procedure was abandoned. Studies of animals suggested that en bloc transplantation of the heart and both lungs provided better vasculature to the tracheobronchial tree, leading to the first successful human heart-lung transplant at Stanford University Medical Center in 1981. This procedure is successful for combined cardiopulmonary disease, particularly congenital heart disease and right ventricular failure associated with pulmonary hypertension. Combined heart-lung blocks are in limited supply, however, stimulating efforts to use lung-only grafts. Single-lung transplantation was successfully reintroduced in 1983. Major principles advocated were selecting recipients with fibrotic disease only; wrapping the bronchial anastomosis with omentum; not giving preoperative corticosteroids; and avoiding administering maintenance corticosteroids in the early postoperative period. Over the past five years the original principles have been progressively modified: Single-lung transplantation is appropriate for patients with fibrotic disease, emphysema, and perhaps pulmonary hypertension; omental wrapping of the bronchial anastomosis is not required; patients may be successfully transplanted while receiving low dosages of corticosteroids; and instituting corticosteroid therapy immediately following transplantation may be acceptable. Double-lung transplantation was introduced in 1986. The original procedure involved a low tracheal anastomosis and was technically flawed, with a high rate of tracheal dehiscence. It has now been replaced with bilateral bronchial anastomoses with improved results. The results of lung and heart-lung transplantation continue to improve with one- and five-year survival rates approaching 75% and 50%, respectively. Candidates for transplantation should have a life expectancy of less than 2 to 3 years without transplantation and be otherwise healthy. Most programs set age limits for transplantation, such as age 60 for single lung, age 50 for double lung, and age 45 for heart-lung transplantation. Rejection monitoring requires frequent assessment of pulmonary function along with bronchoscopy and transbronchial biopsy. The long-term immunosuppression regimen consists of cyclosporine, azathioprine, and prednisone. Long-term immunosuppression places transplant patients at risk for various unusual infections. In addition, oblitera-
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tive bronchiolitis, possibly a manifestation of chronic lung allograft rejection, develops in some recipients and is the major cause of late graft failure. Frequent monitoring of pulmonary function and transbronchial biopsy may allow early detection of this process, but obliterative bronchiolitis progresses inexorably once it is established, despite augmentation of the immunosuppressive regimen. The major limitation of lung or heart-lung transplantation continues to be an insufficient number of suitable donors, inequities in transplantation funding, and late graft failure from obliterative bronchiolitis. Nonetheless, lung and heartlung transplantation have become accepted therapeutic options for many patients with heretofore fatal pulmonary disorders. E. CLINTON LAWRENCE, MD JAMES THEODORE, MD VAUGHN A. STARNES, MD
Stanford, California REFERENCES Calhoon JH, Grover FL, Gibbons WJ, et al: Single lung transplantation: Alternative indications and technique. J Thorac Cardiovasc Surg 1991; 101:816-825 Lawrence EC: Diagnosis and management of lung allograft rejection. Clin Chest Med 1990; 11:269-278 Theodore J, Stames VA, Lewiston NJ: Obliterative bronchiolitis. Clin Chest Med 1990; 11:309-321
Monoclonal Therapy for Bacteremia and Sepsis GRAM-NEGATIVE BACITEREMIA occurs in 300,000 to 500,000 patients each year. The mortality ranges from 10% to 80% and is highly dependent on a patient's underlying condition and concurrent disease processes. Gram-negative bacteremia is associated with organ failure, which increases mortality, especially if more than one organ is affected. Studies have been done that predict in which septic patient organ failure will develop and, therefore, who will have the highest morbidity and mortality. These predictors have not yet been used clinically, however. Antiendotoxin antibodies have been used to treat bacteremic patients and patients who appear "septic" despite negative blood cultures. The infusion of endotoxin recapitulates a sepsis-like illness in animals; endotoxin levels are not always detectable in patients with sepsis or even in those with bacteremia, however. Nonetheless, the infusion of polyclonal antiserum to lipid A in patients with gram-negative bacteremia can reduce mortality from 39% to 22%. Patients in septic shock also have had a reduction in mortality, but patients with septic neutropenia do not appear to benefit. The antiserum has never been marketed because of lot-to-lot variation and concern regarding blood products. Two monoclonal antibodies against endotoxin have recently been developed: HA-IA is a "humanized" immunoglobulin M (IgM) antibody, and E5 is a murine IgM antibody. In clinical studies, the HA-lA was found not to reduce morbidity and mortality in patients with bacteremia or sepsis. In a subset of 200 patients with gram-negative bacteremia with or without shock, mortality was reduced, and there was a trend for a decrease in organ failure in patients with bacteremia treated with the antibody. More patients in the placebo group had renal failure and hepatic failure and had Pseudomonas aeruginosa infections, however, leaving some question as to whether the treatment and placebo groups were comparable. In a study of patients treated with ES, mortality was not reduced, but in a subset of patients who had gram-negative bacteremia but who were not hypotensive, mortality was
reduced and there was a trend for less organ failure. A second trial used E5 to treat normotensive septic patients who, conversely, did not show a reduction in mortality. There did seem to be a benefit to the patients who received ES in terms of a resolution of organ failure, however. These therapies are expensive. Independent investigators estimated a cost of $24,100 per year of life saved with optimal drug use. They suggested a worst-case scenario, however, of a cost of $1,227,600 per year of life saved. A prudent suggestion would be to await further studies of these agents in selected bacteremic patients, including neutropenic and other immunosuppressed patients, to see if these agents are efficacious in all patients with bacteremia. Also, a comparison study of the two antibodies would clarify some of these issues. Other costly agents will be available shortly, such as antitumor necrosis factor and interleukin receptor antagonists; physicians must be critical of the cost-benefit of these drugs for a condition that has an extremely variable prognosis. JOE GUGLIELMO, PharmD JEANINE P. WIENER-KRONISH, MD San Francisco, California
REFERENCES Greenman RL, Schein RMH, Martin MA, et al: A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. JAMA 1991; 266:1097-1102 Schulman KA, Glick HA, Rubin H, Eisenberg JM: Cost-effectiveness of HA-IA monoclonal antibody for gram-negative sepsis-Economic assessment of a new therapeutic agent. JAMA 1991; 266:3466-3471 Ziegler EJ, Fisher CJ Jr, Sprung CL, et al: Treatment of gram-negative bacteremia and septic shock with HA- I A human monoclonal antibody against endotoxin. N Engl J Med 1991; 324:429-436
Conventional Treatment of Cystic Fibrosis TWENTY YEARS AGO cystic fibrosis meant death by age 7; today the median survival age is 28. This remarkable progress has been accomplished through nutritional support, tracheobronchial care, and multidisciplinary therapy. Nutritional support is focused on oral ingestion of pancreatic enzymes, high food intake, and vitamin and mineral supplements, particularly the lipid-soluble vitamins A, E, K, and sometimes D. The need for lipid-soluble vitamins is assessed directly by the measurement of vitamin A and vitamin E levels and indirectly by the measurement of prothrombin time and serum calcium levels for vitamins K and D. Acid-resistant pancreatic enzymes have contributed substantially to improved survival rates. The acid resistance allows the enzymes to pass undigested through the stomach into the duodenum. Food requirements for patients with cystic fibrosis can be 20% to 50% higher than normal for at least two recognizable reasons: Patients with cystic fibrosis have some malabsorption despite enzyme replacement, and their metabolic rate is high, probably because of bronchial inflammation and the increased work of breathing. Patients with advanced lung disease may have poor appetites. The use of a gastrostomy tube is gaining acceptance because nutrition status and longevity are correlated. Tracheobronchial care is less well defined but generally consists of the use of inhaled and oral bronchodilators, antibiotics, and clearing mucus by postural drainage and percussion, sometimes augmented with mucolytics. An active exercise program is also useful. These elements are based on clinical experience and common sense but lack vigorous scientific validation, except that patients are living longer. Antibiotics are used liberally in these patients. Increased
