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Lung Biopsy in Immunosuppressed Patients
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rill-blllill IIIIYIII il chili mldicill Lung Biopsy in Immunosuppressed Patients* Eugene D. Robin, M.D.; and Conor M. Burke, M.B.
The advent of new fOrms of treatment using immunosuppressive agents led to the emergence of a large population ofimmunocompromised patients well before the current epidemic of AIDS. Patients with primary hematologic, oncologic and miscellaneous For editorial comment see page 163 disorders were now at increased risk of infection by a whole host of ordinary and unusual infectious agents. It became obvious that a major site ofinfection was the lung and that death from pulmonary infection was relatively common. In response to this important clinical problem, the routine use of lung biopsy to determine the cause of infection and to treat it with specific agents became a widely accepted mode of management. The perceived benefit was based on the assumption that identification ofinfecting organisms led to more rational and presumably more effective treatment. I" Even in retrospect, this assumption was overly simplistic for a variety of reasons. Lung biopsy, however performed, does not reveal the cause of infection in a sizable percentage of patients. Following biopsy, one may still be confronted with a diagnosis of GOK (God only knows). Biopsies often reveal nontreatable forms of lung infection such as viral infections or some fungal or parasitic infections. 5 Lung biopsy faces the twin betes noire bedeviling tests, the hazards offalse positives and false negatives, inescapable characteristics of all diagnostic procedures. 6 The causes offever and pulmonary infiltrates in these patients are not always infectious in nature. In heart-lung transplant patients, for example, obliterative bronchiolitis is common. 7 In a series summarizing experience with immuDocompromised patients, 25 percent had noninfective causes of pulmonary complications including hemorrhage, pulmonary embolism, pulmonary edema or extension to the lung of the *From Stanford University School of Medicine, Stanford, CA. This is the first in a series of columns dealing with risk-benefit analysis. Contrary opinions either as letters or as articles are solicited. Reprint requests: Dr. Robin, Division of Respiratory Medicine, Stanford University School of Medicine, Stanford 94305 278
primary disease. 5 Most important, the outcome in patients is frequently more related to the primary disease than to secondary pulmonary infection. Even successful treatment of infection may not salvage the patient. Finally, these patients are often acutely ill, febrile, anemic, hypoxic and platelet-depleted, scarcely good candidates for invasive diagnostic approaches so that morbidity and mortality from biopsy is not uncommon. 8 None of these considerations seemed to impact heavily on the consciousness ofexpert consultants, and thousands of patients have been, and are being subjected to lung biopsy without a clinical trial which establishes a favorable risklbenefit ratio. More attention appears to have been devoted to the relative merits of open lung biopsy versus transbronchial biopsy versus lung aspiration versus cutting needle biopsy, than to the central issue: the outcome of patients subjected to any of these forms of biopsy. Despite extensive literature, no adequate prospective trial has been performed to determine the efficacy of lung biopsy in this group of patients. However, recent studies-all ofwhich have been retrospectivestrongly suggest lack of efficacy using the criterion of patient survival. Pennington and Feldman9 found lifesaving changes in treatment in two of 21 patients studied with lung biopsy. Tenholder and Hoopero found that biopsy procedures to document opportunistic infection were of little value before treatment. Rossiter et alll found no significant difference in mortality rates between patients with a specific diagnosis and those without or between those whose treatment was altered because of diagnosis and those with no treatment change. Webster and Clar)(12 concluded that there is no controlled study showing that the use of more invasive diagnostic procedures appreciably improved the long-term prognosis for any class of immunocompromised patients. Puksa et al13 found that making a specific diagnosis did not improve patient survival. Williams et all. found that making a specific diagnosis did not appear to greatly improve survival. Wardman and Cooke8 concluded that "it is difficult to find evidence ofbenefit from more invasive procedures." McCabe et allS found in a specific group of Lung Biopsy in Immunosuppressed PatIents (Robin, Burke)
patients, those with acute leukemia, that open lung biopsy was oflittle help in directing medical therapy or influencing clinical outcome. These reports are not a pre-selected litany used to make a point. This is the collective experience with the procedure. The few reports which suggest improved survival9•16 cannot withstand critical scrutiny. If the objective of patient management is to improve patient survival it is difficult to justify (previous and current) extensive use of lung biopsy in this group of patients. Given the failure to demonstrate clear bene6t, the risk-benefit ratio must be regarded as clearly unfavorable for most patients. A common decision analysis in this literature asks the physician to choose between empirical management (nonspecific use of antibiotics) and lung biopsy. Given the absence of data derived from an acceptable prospective clinical trial, the choice is really between noninvasive and invasive empirical management. Noninvasive management at least prevents direct physical harm to the patient. Several commentaries are in ordet: Does this mean that lung biopsy is never justified in the immunosuppressed? There are occasionally patients in whom a specific treatable infection seems a reasonable possibility and the hazards ofan empiric trial with specific antibiotics seems greater than the hazards of lung biopsy. This should prove to be the case only rarely. Pending a clinical trial, the more or less routine use of biopsy should be abandoned. H lung biopsy is undertaken, the patient or family should be informed that the measure is undertaken in desperation and not on the basis of clear-cut medical indications. When should appropriate clinical trials have been performed? Obviously before and not after the mass use of lung biopsies. This is no longer possible and large numbers of patients may have been harmed as a result. Has the wanton use of lung biopsy been solely the responsibility of the chest doctor or thoracic surgeon? Of course not. Not uncommonly, the chest doctor has acted as the surrogate of the infectious disease expert or the hematologist or the oncologist. The pulmonologist may even be responding to the demand of an overzealous housestaff who confuse the need to know to provide better care with the desire to knowl7 and who have been taught (erroneously, we believe) that the more data gathered, the more scientific and rigorous the practice of medicine. How about the malpractice problem? It is claimed by some that employing lung biopsy is a form of defensive medicine. If so, this communication may at least serve to provide a basis in law for more rational decision-making which emphasizes that no biopsy is an acceptable or even preferred alternative. How about the addition to new knowledge that routine lung biopsies have added? That does count for
something, but not to the individual patients who have been made involuntary participants in clinical investigation. How much more reliable such knowledge would be if obtained during the course of a well designed clinical trial. Do we need a well designed, clinical trial to deal with some of the problems discussed here? Indeed we do. Without such trials, any pro or con opinions (including our own) will remain just that; opinions. An acceptable clinical trial would settle the major issues, as well as possibly defining small subpopulations of patients who might benefit from lung biopsy. Such a trial should be prospective, include more or less homogenous groups of patients, for example, acute leukemics or patients with AIDS; the control group would undergo noninvasive empiric management, the experimental group would have lung biopsy added. The outcome would be defined in terms of survival rate, quality and length. In these patients there cannot be improved lifestyle without improved survival and the very act of biopsy produces some morbidity. What is such a trial likely to show? Again, as mere opinion, it will show that lung biopsy does not lead statistically to improved survival. What should be done until the results of such a trial become available? We must recognize that lung biopsy has been and is being done despite the best information available. That information strongly suggests that the risks of lung biopsy commonly exceed the benefits and therefore that the procedure should be offered only under exceptional circumstances. REFERENCES 1 Greenman RL, Goodall PI: King '[ Lung biopsy in immu-
nocompromised hosts. Am J Med, 1975; 59:488-96 2 Leight GS, Michaelis LL. Open lung biopsy for the diagnosis of acute diffuse pulmonary infiltrates in the immunocompromised patient. Chest 1978; 73:477-82 3 Toledo-Pereyra LH, DeMeester TR, Kinea1ey A, MacMahon H, Churg A, Golomb H. The benefits ofopen lung biopsy in patients with previous nondiagnostic transbronchial biopsy; a guide to appropriate therapy. Chest 1980; 77:647-50 4 Matthay RA, Farmer WC, Ordero D. Diagnostic fiberoptic bronchoscopy in the immunocompromised host with pulmonary infiltrates. Thorax 1977; 32:539-45 5 Rosenow EC, Wilson WR, Cockerill, FR. Pulmonary disease in the immunocompromised host. Mayo Clin Proc 1985; 60:473-87 6 Robin ED. Matters oflife and death: Risks vs benefits of medical care. New York: WH Freeman, 1984 7 Burke CM, Theodore J, Dawkins lCD, Yousem SA, Blank N, Billingham ME, et al. Post transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest 1984; 86:824-29 8 Wardman AJ, Cooke NJ. Pulmonary infiltrates in adult acute leukemia: Empirical treatment or lung biopsy (editorial).Thorax 1984; 39:647-50 9 Pennington JE, Feldman NL Pulmonary infiltrates and fever in patients with hemotologic malignancy. Am J Med 1977; 62: 581-87 10 Tenholder MF, Hooper RG. Pulmonary infiltrates in leukemia. Chest 1980; 78:468-73 CHEST I 89 I 2 I FEBRUARY. 1988
277
11 Rossiter SJ, Miller DC, Churg AM, Carrington CB, Mark JBD. Open lung biopsy in the immunocompromised patient. Is it really beneficial? J Thorac Cardiovasc Surg 1979; 77:338-45 12 Webster J, Clarke J. A doctors dilemma-l980 (editorial) Chest 1980; 78:417-418 13 Puksa S, Hutcheon MA, Hyland RH. Usefulness of transbronchial biopsy in immunosuppressed patients with pulmonary infiltrates. Thorax 1983; 38:146-50 14 Williams B, Yungbluth M, Adams G, Glassroth J. The role of fiberoptic bronchoscopy in the evaluation of immunocompro-
mised hosts with diffuse pulmonary infiltrates. Am Rev Respir Dis 1985; 131:880-85 15 McCabe RE, Brooks RG, Mark JBD, Remington JS. Open lung biopsy in patients with acute leukemia. Am J Med 1985; 78: 609-16 16 Philips MJ, Knight RIC, Green M. Fibreoptic bronchoscopy and diagnosis of pulmonary lesions in lymphoma and leukemia. Thorax 1980; 35:19-25 17 Reuben DB. Learning diagnostic restraint. N Eng! J Med 1985; 310:591-93
ACCP Course: Antlthrombotlc Therapy Course Director: 'Thomas M. Hyers, M.D., FCCf Date: February 28, 1986. Sponsor: American College ofChest Physicians. Location: The Embassy Suite Hotel, San Antonio, Texas. Course Description: A culmination of a one year project with ACCP and NIH to develop recommendations for rational use ofantithrombotic therapy in specific situations. Rational use of heparin and warfarin anticoagulation will be emphasized. Special small group sessions in which participants are invited to bring cases and problems for discussion. Ample time will be allowed for questions and interaction with the speakers. For further infonnation contact: Division of Education, Acc~ 911 Busse Hwy, Park Ridge, IL 60068 (312:698-2200). A 18sk Force sponsored by the American College ofChest Physicians and the National Heart Lung and Blood Institute has been working for approximately one year on developing recommendations for the rational use of antithrombotic therapy in cerebrovascular, cardiovascular and venous thromboembolic diseases. In this one-day course, select members ofthe Task Force will summarize these recommendations. Presentations will assess the data on which the recommendations are based and will outline areas in which current knowledge is incomplete and further studies are needed. The rational use ofheparin and warfarin anticoagulation will be emphasized. Ample time will be allowed for questions and interaction with the speakers. The highlight ofthe program will be afternoon small group sessions in which participants are invited to bring their own cases and problems for discussion with the faculty.
278
Lung BIopsy In Immunosuppr8888d PatIents (Robin, Burke)
---1 •
rill-blllill IIIIYIII il chili mldicill Lung Biopsy in Immunosuppressed Patients* Eugene D. Robin, M.D.; and Conor M. Burke, M.B.
The advent of new fOrms of treatment using immunosuppressive agents led to the emergence of a large population ofimmunocompromised patients well before the current epidemic of AIDS. Patients with primary hematologic, oncologic and miscellaneous For editorial comment see page 163 disorders were now at increased risk of infection by a whole host of ordinary and unusual infectious agents. It became obvious that a major site ofinfection was the lung and that death from pulmonary infection was relatively common. In response to this important clinical problem, the routine use of lung biopsy to determine the cause of infection and to treat it with specific agents became a widely accepted mode of management. The perceived benefit was based on the assumption that identification ofinfecting organisms led to more rational and presumably more effective treatment. I" Even in retrospect, this assumption was overly simplistic for a variety of reasons. Lung biopsy, however performed, does not reveal the cause of infection in a sizable percentage of patients. Following biopsy, one may still be confronted with a diagnosis of GOK (God only knows). Biopsies often reveal nontreatable forms of lung infection such as viral infections or some fungal or parasitic infections. 5 Lung biopsy faces the twin betes noire bedeviling tests, the hazards offalse positives and false negatives, inescapable characteristics of all diagnostic procedures. 6 The causes offever and pulmonary infiltrates in these patients are not always infectious in nature. In heart-lung transplant patients, for example, obliterative bronchiolitis is common. 7 In a series summarizing experience with immuDocompromised patients, 25 percent had noninfective causes of pulmonary complications including hemorrhage, pulmonary embolism, pulmonary edema or extension to the lung of the *From Stanford University School of Medicine, Stanford, CA. This is the first in a series of columns dealing with risk-benefit analysis. Contrary opinions either as letters or as articles are solicited. Reprint requests: Dr. Robin, Division of Respiratory Medicine, Stanford University School of Medicine, Stanford 94305 278
primary disease. 5 Most important, the outcome in patients is frequently more related to the primary disease than to secondary pulmonary infection. Even successful treatment of infection may not salvage the patient. Finally, these patients are often acutely ill, febrile, anemic, hypoxic and platelet-depleted, scarcely good candidates for invasive diagnostic approaches so that morbidity and mortality from biopsy is not uncommon. 8 None of these considerations seemed to impact heavily on the consciousness ofexpert consultants, and thousands of patients have been, and are being subjected to lung biopsy without a clinical trial which establishes a favorable risklbenefit ratio. More attention appears to have been devoted to the relative merits of open lung biopsy versus transbronchial biopsy versus lung aspiration versus cutting needle biopsy, than to the central issue: the outcome of patients subjected to any of these forms of biopsy. Despite extensive literature, no adequate prospective trial has been performed to determine the efficacy of lung biopsy in this group of patients. However, recent studies-all ofwhich have been retrospectivestrongly suggest lack of efficacy using the criterion of patient survival. Pennington and Feldman9 found lifesaving changes in treatment in two of 21 patients studied with lung biopsy. Tenholder and Hoopero found that biopsy procedures to document opportunistic infection were of little value before treatment. Rossiter et alll found no significant difference in mortality rates between patients with a specific diagnosis and those without or between those whose treatment was altered because of diagnosis and those with no treatment change. Webster and Clar)(12 concluded that there is no controlled study showing that the use of more invasive diagnostic procedures appreciably improved the long-term prognosis for any class of immunocompromised patients. Puksa et al13 found that making a specific diagnosis did not improve patient survival. Williams et all. found that making a specific diagnosis did not appear to greatly improve survival. Wardman and Cooke8 concluded that "it is difficult to find evidence ofbenefit from more invasive procedures." McCabe et allS found in a specific group of Lung Biopsy in Immunosuppressed PatIents (Robin, Burke)
patients, those with acute leukemia, that open lung biopsy was oflittle help in directing medical therapy or influencing clinical outcome. These reports are not a pre-selected litany used to make a point. This is the collective experience with the procedure. The few reports which suggest improved survival9•16 cannot withstand critical scrutiny. If the objective of patient management is to improve patient survival it is difficult to justify (previous and current) extensive use of lung biopsy in this group of patients. Given the failure to demonstrate clear bene6t, the risk-benefit ratio must be regarded as clearly unfavorable for most patients. A common decision analysis in this literature asks the physician to choose between empirical management (nonspecific use of antibiotics) and lung biopsy. Given the absence of data derived from an acceptable prospective clinical trial, the choice is really between noninvasive and invasive empirical management. Noninvasive management at least prevents direct physical harm to the patient. Several commentaries are in ordet: Does this mean that lung biopsy is never justified in the immunosuppressed? There are occasionally patients in whom a specific treatable infection seems a reasonable possibility and the hazards ofan empiric trial with specific antibiotics seems greater than the hazards of lung biopsy. This should prove to be the case only rarely. Pending a clinical trial, the more or less routine use of biopsy should be abandoned. H lung biopsy is undertaken, the patient or family should be informed that the measure is undertaken in desperation and not on the basis of clear-cut medical indications. When should appropriate clinical trials have been performed? Obviously before and not after the mass use of lung biopsies. This is no longer possible and large numbers of patients may have been harmed as a result. Has the wanton use of lung biopsy been solely the responsibility of the chest doctor or thoracic surgeon? Of course not. Not uncommonly, the chest doctor has acted as the surrogate of the infectious disease expert or the hematologist or the oncologist. The pulmonologist may even be responding to the demand of an overzealous housestaff who confuse the need to know to provide better care with the desire to knowl7 and who have been taught (erroneously, we believe) that the more data gathered, the more scientific and rigorous the practice of medicine. How about the malpractice problem? It is claimed by some that employing lung biopsy is a form of defensive medicine. If so, this communication may at least serve to provide a basis in law for more rational decision-making which emphasizes that no biopsy is an acceptable or even preferred alternative. How about the addition to new knowledge that routine lung biopsies have added? That does count for
something, but not to the individual patients who have been made involuntary participants in clinical investigation. How much more reliable such knowledge would be if obtained during the course of a well designed clinical trial. Do we need a well designed, clinical trial to deal with some of the problems discussed here? Indeed we do. Without such trials, any pro or con opinions (including our own) will remain just that; opinions. An acceptable clinical trial would settle the major issues, as well as possibly defining small subpopulations of patients who might benefit from lung biopsy. Such a trial should be prospective, include more or less homogenous groups of patients, for example, acute leukemics or patients with AIDS; the control group would undergo noninvasive empiric management, the experimental group would have lung biopsy added. The outcome would be defined in terms of survival rate, quality and length. In these patients there cannot be improved lifestyle without improved survival and the very act of biopsy produces some morbidity. What is such a trial likely to show? Again, as mere opinion, it will show that lung biopsy does not lead statistically to improved survival. What should be done until the results of such a trial become available? We must recognize that lung biopsy has been and is being done despite the best information available. That information strongly suggests that the risks of lung biopsy commonly exceed the benefits and therefore that the procedure should be offered only under exceptional circumstances. REFERENCES 1 Greenman RL, Goodall PI: King '[ Lung biopsy in immu-
nocompromised hosts. Am J Med, 1975; 59:488-96 2 Leight GS, Michaelis LL. Open lung biopsy for the diagnosis of acute diffuse pulmonary infiltrates in the immunocompromised patient. Chest 1978; 73:477-82 3 Toledo-Pereyra LH, DeMeester TR, Kinea1ey A, MacMahon H, Churg A, Golomb H. The benefits ofopen lung biopsy in patients with previous nondiagnostic transbronchial biopsy; a guide to appropriate therapy. Chest 1980; 77:647-50 4 Matthay RA, Farmer WC, Ordero D. Diagnostic fiberoptic bronchoscopy in the immunocompromised host with pulmonary infiltrates. Thorax 1977; 32:539-45 5 Rosenow EC, Wilson WR, Cockerill, FR. Pulmonary disease in the immunocompromised host. Mayo Clin Proc 1985; 60:473-87 6 Robin ED. Matters oflife and death: Risks vs benefits of medical care. New York: WH Freeman, 1984 7 Burke CM, Theodore J, Dawkins lCD, Yousem SA, Blank N, Billingham ME, et al. Post transplant obliterative bronchiolitis and other late lung sequelae in human heart-lung transplantation. Chest 1984; 86:824-29 8 Wardman AJ, Cooke NJ. Pulmonary infiltrates in adult acute leukemia: Empirical treatment or lung biopsy (editorial).Thorax 1984; 39:647-50 9 Pennington JE, Feldman NL Pulmonary infiltrates and fever in patients with hemotologic malignancy. Am J Med 1977; 62: 581-87 10 Tenholder MF, Hooper RG. Pulmonary infiltrates in leukemia. Chest 1980; 78:468-73 CHEST I 89 I 2 I FEBRUARY. 1988
277
11 Rossiter SJ, Miller DC, Churg AM, Carrington CB, Mark JBD. Open lung biopsy in the immunocompromised patient. Is it really beneficial? J Thorac Cardiovasc Surg 1979; 77:338-45 12 Webster J, Clarke J. A doctors dilemma-l980 (editorial) Chest 1980; 78:417-418 13 Puksa S, Hutcheon MA, Hyland RH. Usefulness of transbronchial biopsy in immunosuppressed patients with pulmonary infiltrates. Thorax 1983; 38:146-50 14 Williams B, Yungbluth M, Adams G, Glassroth J. The role of fiberoptic bronchoscopy in the evaluation of immunocompro-
mised hosts with diffuse pulmonary infiltrates. Am Rev Respir Dis 1985; 131:880-85 15 McCabe RE, Brooks RG, Mark JBD, Remington JS. Open lung biopsy in patients with acute leukemia. Am J Med 1985; 78: 609-16 16 Philips MJ, Knight RIC, Green M. Fibreoptic bronchoscopy and diagnosis of pulmonary lesions in lymphoma and leukemia. Thorax 1980; 35:19-25 17 Reuben DB. Learning diagnostic restraint. N Eng! J Med 1985; 310:591-93
ACCP Course: Antlthrombotlc Therapy Course Director: 'Thomas M. Hyers, M.D., FCCf Date: February 28, 1986. Sponsor: American College ofChest Physicians. Location: The Embassy Suite Hotel, San Antonio, Texas. Course Description: A culmination of a one year project with ACCP and NIH to develop recommendations for rational use ofantithrombotic therapy in specific situations. Rational use of heparin and warfarin anticoagulation will be emphasized. Special small group sessions in which participants are invited to bring cases and problems for discussion. Ample time will be allowed for questions and interaction with the speakers. For further infonnation contact: Division of Education, Acc~ 911 Busse Hwy, Park Ridge, IL 60068 (312:698-2200). A 18sk Force sponsored by the American College ofChest Physicians and the National Heart Lung and Blood Institute has been working for approximately one year on developing recommendations for the rational use of antithrombotic therapy in cerebrovascular, cardiovascular and venous thromboembolic diseases. In this one-day course, select members ofthe Task Force will summarize these recommendations. Presentations will assess the data on which the recommendations are based and will outline areas in which current knowledge is incomplete and further studies are needed. The rational use ofheparin and warfarin anticoagulation will be emphasized. Ample time will be allowed for questions and interaction with the speakers. The highlight ofthe program will be afternoon small group sessions in which participants are invited to bring their own cases and problems for discussion with the faculty.
278
Lung BIopsy In Immunosuppr8888d PatIents (Robin, Burke)