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Open lung biopsy in the immunosuppressed patient
Open lung biopsy in the immunosuppressed patient Is it really beneficial? Considerable disparity of opinion exists concerning the risk: benefit ratio of open lung biopsy in immunosuppressed patients. Eighty-three consecutive patients who underwent open lung biopsy were analyzed. and 70 of the 83 (84 percent) patients were immunosuppressed. A specific etiologic diagnosis was obtained by open lung biopsy in 46 of 83 (55 percent) patients. and a nonspecific diagnosis in 37 of 83 (45 percent). Of 53 specific diagnoses in the 46 patients. /5 (28 percent) were infection and 35 (6/ percent) were neoplasm. Diagnostic errors occurred twice. for a diagnostic accuracy of 97.5 percent (8/ of 83). A change in treatment was dictated by biopsy results in 37 of 83 (45 percent) patients. No deaths were directly attributable to the operative procedure. but surgical complications occurred in eight of 83 (9.6 percent) cases. Hospital mortality rate was 25 percent (2/ of 83); late mortality rate was an additional 40 percent (25 of 62) with an average follow-up of 9.7 months. Of those patients whose lung biopsies dictated a change in treatment. eight of 37 (22 percent) died in the hospital; of those with no treatment change indicated. /3 of 46 (28 percent) died (p = N.S.). Patients whose biopsies yielded a specific diagnosis fared no better than those without diagnosis (hospital mortality 26 percent [J2 of 46] versus 24 percent [nine of 37]. p = N.S.). a finding at variance with previously published series. Total cumulative mortality rate for immunosuppressed patients was 63 percent (44 of 70). Only two of /3 nonimmunosuppressed patients died (cumulative mortality rate 15 percent). Financial analysis revealed that the cost of caring for these desperately ill patients is exceedingly high. Open lung biopsy is an accurate diagnostic tool with low surgical mortality and acceptable morbidity. Thoughtful individual consideration must be given to each case. with realistic assessment made of the benefits likely to result from a definitive diagnosis. given the patient's underlying disease and current state of health. Appropriate selection of patients for open lung biopsy is recommended. with aggressive early diagnosis and management of pulmonary infiltrates before multisystem failure has occurred.
Stephen J. Rossiter, M.D., D. Craig Miller, M.D., Andrew M. Churg, M.D., Charles B. Carrington, M.D., and James B. D. Mark, M.D., Stanford. Calif.
By
means of modern techniques, the majority of pulmonary infiltrates in general patient populations are diagnosed by indirect means, without pulmonary tissue actually being obtained for examination. However, these indirect methods fail to provide a specific diagnosis in 35 to 55 percent of patients with diffuse pulmonary disease. Even more challenging is that group of patients whose immunologic defenses are altered by underlying disease or by various types of therapy. Pulmonary infiltrates, often accompanied by fever, are From the Department of Surgery (Division of Thoracic Surgery) and Department of Pathology, Stanford University Medical Center, Stanford, Calif. 94305. Read at the Fourth Annual Meeting of The Samson Thoracic Surgical Society, Coronado, Calif., June 4-7, 1978.
338
common in this patient population; the differential diagnosis includes infection with pathogenic or opportunistic organisms, extension of basic disease (neoplasm, collagen-vascular disease), complication of therapy (radiation, chemotherapy), and a variety of other entities.":" For appropriate specific therapy to be administered for the pulmonary disease, aggressive diagnostic modalities are employed. If indirect methods are not quickly successful, some form of lung biopsy is generally recommended. 7 Open lung biopsy will provide a histologic diagnosis in the vast majority of cases. The resulting benefits, the risks, and the costs of open lung biopsy in the immunosuppressed population are less well defined and constitute the focus of this study.
0022-5223/79/030338+08$00.80/0 © 1979 The C. V. Mosby Co.
Volume 77 Number 3 March. 1979
Patients and methods A retrospective analysis was performed in which the substrate comprised all patients undergoing open lung biopsy for the diagnosis of pulmonary infiltrates on the Stanford University Thoracic Surgical Service between July, 1974, and December, 1977. Charts of all patients were reviewed and individual patients were contacted for further follow-up when possible. Living patients were followed for an average of 16.5 ± 13.3 months. A total of 83 cases were analyzed with a follow-up of 887 patient-months (range I to 42, mean 9.7 ± 11.4) (Table I). Data obtained included age, sex, primary diagnosis, presence or absence of immunosuppression, pulmonary symptoms, radiographic findings, prior diagnostic results, preoperative and postoperative respiratory status, site of biopsy, histologic and culture results of biopsy, effect of biopsy on treatment, outcome of treatment, status at follow-up, cause of death, autopsy findings, hospital stay, and cost of hospital care and biopsy. Open lung biopsies were performed in the operating room with the patient under general anesthesia. Sites for pulmonary biopsy were chosen by the surgeon during intrathoracic exploration. Small thoracotomy incisions were employed without rib resection. These were most often made anteriorly, but lateral or posterior incisions were employed when anatomic location of an infiltrate so dictated. A wedge of pulmonary tissue was excised, with hemostasis and pneumostasis secured with running catgut suture or stapling devices. Intercostal tube drainage was routinely employed, with tubes removed on the first or second postoperati ve day if no air leak was present. After samples were sent for aerobic and anaerobic bacterial, fungal, acid-fast bacilli (AFB), and viral cultures and smears, the lung biopsy was personally received by the pathologist. Touch preparations of a freshly cut surface were made and stained with Gomori's methenamine silver (GMS) stain to demonstrate fungi and Pneumocystis, and occasionally with AFB and Gram stains. Portions of the tissue were saved for electron microscopic and immunofluorescence studies, and the remainder were perfused with formalin. Sections were routinely stained with hematoxylin and eosin and with GMS, AFB, and Gram stains where indicated. In a number of instances, a frozen section was prepared at the time of biopsy with GMS and hematoxylin and eosin stains performed for a rapid diagnosis. Actuarial survi val curves were constructed by lifetable methods, and statistical significance of variables was assessed by the Gehan test (assigning a two-tailed
Open lung biopsy in immunosuppressed patient
339
Table I. Patients having open lung biopsy No. of patients Operative range Duration of follow-up Average follow-up (all patients) Average follow-up (living patients) Maximum follow-up (living patients) Minimum follow-up (living patients) Males Females Age (average, range)
83 July, 1974, to November, 1977 887 pt.vmo. 9.7 mo. ± IIA (S.D.) 16.5 mo. ± 13.3 (S.D.)
42 mo. I mo. 37 (45%) 46 (55%) 40 yr. (4 mo. to 77 yr.)
Table II. Immunosuppression in patients having open lung biopsy (n = 70) * No.
Percent
43 12 14 2
61 17 20 3
1
1
48
69 81
Underlying disease Lymphoma Leukemia Carcinoma/sarcoma Collagen- vascular Renal transplant (plus lymphoma)
Treatment for underlying disease Radiation therapy Chemotherapy plus steroids
57
'Two patients had two diagnoses each.
significance level to the p value thus obtained), Fisher's exact test, Student's t test, and chi square analysis as appropriate. 8- t 1
Results Of the 83 patients undergoing open lung biopsy, 70 (84 percent) were immunocompromised hosts and 13 (16 percent) were not immunocompromised. Immunosuppression was considered to be present if the patient had a primary diagnosis of lymphoma, hematologic malignancy, collagen-vascular disease, organ transplant, or carcinoma/sarcoma for which he or she received radiation therapy, chemotherapy, or corticosteroids (Table II). One patient had received a renal transplant and later developed nodular sclerosing Hodgkin's disease, and another patient had both adenocarcinoma of the colon and lymphocytic lymphoma. All except one of the 13 nonimmunosuppressed patients had bilateral or diffuse radiographic changes and underwent biopsy so that the disease could be defined further. Three of these patients had pneumonitis, five had restrictive lung disease, one had fever of unknown
The Journal of
340 Rossiter et al.
Thoracic and Cardiovascular Surgery
Table III. Specific etiologic diagnoses in patients having open lung biopsy (n = 53) *
100 p (GEHAN) = .01
_ _ _ _ _ _ _ _ _ _ _ _'--N-O-.-'--P-e-rc-e-nr--
90
Neoplasm Previously diagnosed Previously undiagnosed Infection Other (infarct, sarcoid, etc.)
80
70 ...J
« ~
t
:::J
IZ
60
50
Hospital death
U
a::
w
40
Infection
No.
No.
Pneumocystis carinii Mycobacterium tuberculosis
9
30
6 0 2 I 0
.............•
Viral (adenovirus, cytomegalovirus) Fungal (Aspergillus) Bacteria
20
10
6
Table IV. Infections in patients having open lung biopsy, with treatment results (n = IS)
W
Q.
4
28
'Seven patientshad combined diagnoses of infection and neoplasm .
> a:: (I)
62
33 2 15 3
• IMMUNOSUPPRESSED (n=70) o NON-IMMUNOSUPPRESSED (n=13)
00
6 YEARS POST·BIOPSY
Fig. 1. Mortality rates for open lung biopsy. Immunosuppressed versus nonimmunosuppressed patients. origin, and two had other cryptogenic infiltrates. In the over-all group, 52 (63 percent) had generalized or bilateral infiltrates, 30 (36 percent) had localized infiltrates, and one patient (1.2 percent) had a normal chest roentgenogram. Eighteen (22 percent) of the 83 patients were asymptomatic, but symptoms were present in 78 percent, often multiple in the same patient (dyspnea 55 percent, fever 41 percent, cough 28 percent, and other II percent). Diagnostic yield. Seventy-seven invasive pulmonary diagnostic procedures were performed prior to open lung biopsy in the 83 patients. A specific etiologic diagnosis was made in two of the 39 transtracheal aspirates, two of 25 bronchoscopies, and one of 13 percutaneous needle lung aspirates. There were two complications as a result of these other procedures (two pneumothoraces after needle aspiration). Open lung biopsy provided a diagnostic accuracy of 97.5 percent (81 of 83) as confirmed by clinical course, later diagnostic procedure, or autopsy. Two infections
2 2
I
Total deaths
I
%
No.
%
66 0
7 0
100
2
77 0 100
100 0
1 0
100 0
(Nocardia and Aspergillus) were missed with this technique. However, a specific etiologic diagnosis was made in only 46 of 83 (55 percent) patients (Table III). Nonspecific diagnoses (e.g., interstitial fibrosis) were made in 37 of 83 (45 percent). Infections diagnosed are listed in Table IV. The single bacterial infection (Providentia) was being treated by appropriate antibiotics preoperati vely because of positive blood cultures for the same organism. All patients with Pneumocystis infections had diffuse radiographic infiltrates. Prebiopsy antibiotics were employed in 34 of 83 (41 percent) patients with 15 recei ving anti-Pneumocystis, eight receiving antifungal, two receiving antituberculous, and 27 receiving antibacterial agents. Anatomic sites of 86 biopsies in the 83 patients were as follows: right upper lobe, eight cases; right middle lobe, 30 cases; right lower lobe, 21 cases; left upper lobe, 10 cases; lingula, six cases; left lower lobe, II cases. There was no correlation between site of biopsy and diagnostic yield. Deaths and benefits. Fig. I demonstrates mortality rates for the over-all group (n = 83), for the immunosuppressed group (n = 70; follow-up = 608 patient-months; mean = 8.6 ± 10.2 months; range = I to 39), and for the nonimmunosuppressed group (n = 13; follow-up = 279 patient-months; mean = 15.8 ± 15.5 months; range = I to 42). Immunocompromised
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Open lung biopsy in immunosuppressed patient
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-
laO
34 I
CJ OVERALL GROUP
> I-
80
~
«
I-
a:
60
0
::!: I-
z
w
IMMUNOSUPPRESSED GROUP
rz?22 NON ·IMMUNOSUPPRESSED GROUP
p < .01
=. :01
p
55% 46
NS .
40
o a: w
e,
20
0
n=83
n=13
n=83
TOTAL MORTALITY
n=62
HOSPITA L MORT A LITY
n=50
n=12
LATE MORTA LI T Y
Fig. 2. Open lung biopsy . Actuarial survival.
Table V. Terminal events in patients having open lung biopsy
Table VI . Economic costs for immunosuppressed patients having open lung biopsy (n = 25)
Hospital deaths
Late deaths
Event
(n = 2/)
(n = 25)
Respiratory failure Sepsis Central nervous system event Cardi omyopathy Airway obstruction (tumor) Unknown
18
15 4
2 1
o o o
I I I 3
hosts fared significant ly worse with regard to total mortality and late morta lity rates. They also had a threefold greater hospital mortality rate, which was not stat istically significant. This disparity in survival is further emphasized in Fig. 2, which graphically displays actu arial survival of the immunocompromised versus the immunocompetent patients (p < 0.05) . No death was attributable directly to the biopsy procedure. Death was often due to multisystem failure and combinations of events, especially sepsis plus respiratory failure ; terminal events are summarized in Table V. Total mortality rates and hospital mortality rates did not significantly differ between patients with a specific diagnosis and those without (Fig. 3). Similar mortality rates also occurred whether or not open lung biopsy dictated a treatment change (Fig . 4) . Com plications. Eight complications occurred in 83 biopsies, for a rate of 9.6 percent. Each of the following complications occurred once : tension pneumothorax, pneumothorax, wound hematoma, empyema (Staphylococcus), persistent air leak, pneumonia, re-
_ __
_
_
_
_
_
_
Total hospitalization cost (average; range) Surgical costs (average; range) Months to follow-up or death (average; range) Cost/month (average)
1
Alive
' - -D-e-ad - --
$7,632 (3,946-19,608) $1,839 (1,626- 2,532) 6.2 (1-26) $1,231
$16,904 (2,040-50,877) $1,592 ( 1,151-2,005) 3.1 (0 .1-18) $5,425
currence of angiosarcoma in chest tube site, and persis tent incisional pain. Costs. Hospital bills of the last 25 patients were reviewed (Table VI). Only in-patient hospital costs were analyzed. Surgical costs include professional fees, operating room fees, anesthetic charges, and supplies . Although surgical costs were similar, total hospitalization costs for patients who died averaged twice the cost for those alive at the time of follow-up. Similarly, total hospitalization costs divided by time of survival (to death or date of follow-up) were four times greater among those who died . Discussion The technique of open lung biopsy by means of a limited thoracotomy is well established, generally safe, and provides the most satisfactory tissue samples for examination. I . 2 The mere existence of such a technique is not a suitable justification for its universal application to every patient with pulmonary infiltrate, however. Documentation of the diagnostic yields and risks must
The Journal of Thoracic and Cardiovascular Surgery
342 Rossiter et al.
p = NS
SPECIFIC DIAGNOSIS n = 46
p = NS
NO SPECIFIC DIAGNOSIS n = 37
TREATMENT ALTERED n = 37
TREATMENT NOT ALTERED n = 46
Fig. 3. Open lung biopsy. Specific diagnosis as determinant of survival.
Fig. 4. Open lung biopsy. Treatment change as determinant of survival.
be combined with an analysis of the benefits likely to accrue to patients subjected to the procedure. The immunosuppressed host is both a diagnostic and therapeutic challenge; opportunistic infections, active neoplasm, complications of therapy, and vasculitis are among the possible causes of pulmonary infiltrate. Clearly, many of the diagnoses can be made by careful history and physical examination, systemic evaluation, and noninvasive laboratory examination (such as sputum cultures). Occasionally, extrathoracic procedures (lymph node biopsies, cutaneous biopsies) will be fruitful. Judicious therapeutic trials are at times indicated. There remains a core of patients, however, for whom diagnosis is impossible without obtaining pulmonary tissue. Various methods have been employed to procure these specimens. Needle aspirates have proved useful in the cytologic diagnosis of solid peripheral lesions and have been efficacious in diagnosing pulmonary infections in the immunocompromised host. Bandt, Blank, and Castellino'" specifically diagnosed 76 percent of 25 pulmonary infiltrates in altered hosts. Percutaneous needle aspirates or transtracheal aspirates have supplied sufficient microbiologic information for management of pulmonary infiltrates in all of the 140 Stanford heart transplant patients. Of course, neoplasm, fibrosis secondary to radiation or chemotherapy, and vasculitis were generally not serious considerations in these patients. Cutting needle biopsies have a greater risk of pneumothorax (3 to 31 percent) and provide a specific diagnostic yield of 34 to 81 percent for immunocompetent patients." Trephine air drill biopsy provided a diagnostic yield (specific etiology) of 65 percent in 17 immunocompromised patients reported by Cunningham and colleagues;" but pneumothorax occurred in 60 percent of cases and significant hemorrhage in 18 percent. The same author achieved a 42
percent specific diagnosis rate in 31 transbronchiallung biopsies via the fiberoptic bronchoscope, whereas Pennington and Feldman" reported a 64 percent rate using this method. The low diagnostic yield of nonthoracotomy procedures (five of 77) in our series is certainly a factor of selection. Patients whose diagnosis was made by methods other than open lung biopsy usually did not require thoracotomy and were not included in this series. No statement regarding the comparative efficacy of these various procedures can be made from our data. Open lung biopsy in the immunocompromised host is highly accurate (diagnostic accuracy of 97.5 percent in our series), but specific etiologic diagnosis was made in only 55 percent of our patients (compared to 87.5 percent in Wolff's!" series of 24 patients, 23 with infection). Infection accounted for only 28 percent of the specific diagnoses in our series, with neoplasm present in 71 percent. Results of treating these infections were dismal, with notable exceptions in the one bacterial and two tuberculous pneumonias. The 77 percent mortality rate in Pneumocystis carinii infections is high, albeit comparable to some other reports," and perhaps reflects a late stage of disease at the time of diagnosis. The formidable mortality rate (63 percent) for immunosuppressed patients compared to the 15 percent mortality for immunocompetent patients is not surprising. The underlying diseases and the required toxic drugs are associated with a substantial number of deaths even in the absence of pulmonary disease. A central issue which requires elucidation is the benefit likely to accrue to a patient if a specific diagnosis is made by open lung biopsy. In this series no significant difference in mortality rate was noted between patients with a specific diagnosis and those without, or between those whose treatment was altered because of diagnosis
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and those with no treatment change. These data do not indicate, however, that open lung biopsy is without value. It is possible that the patients with specific diagnoses constituted a higher risk group, and mortality rate in this group might have been much higher had no diagnoses been made. Patients often were referred late in the course of their disease, with multiple organ failure. Other authors- 4 have reported lower mortality rates for patients with a specific diagnosis than for those without; an over-all survival rate of 75 percent for immunosuppressed patients undergoing open lung biopsy has also appeared in the literature, 14 although the spectrum of disease was different (23 of 24 patients with infection). A definite statement regarding the value of diagnosis can be made only if a group of patients with specific diagnoses is prospectively randomized into treatment and no treatment groups; such a study is unlikely to occur. Pennington and Feldman" performed a retrospective analysis of the impact of transbronchial lung biopsy on the mortality rate of 47 immunosuppressed patients. Although the rate of specific diagnoses increased from 47 to 62.5 percent after the introduction of the biopsy technique, mortality rate remained static. The obvious limitations of such a study again preclude sweeping conclusions. The financial cost data are not particularly surprising. It is widely known that, with advanced technology and support, the cost of dying is high. Although the survival statistics for immunosuppressed patients with pulmonary infiltrates are depressing, it should be remembered that mortality rate due to the untreated underlying disease is very substantial. We certainly do not advocate diagnostic or therapeutic nihilism on the basis of this report. Rather, we recommend an individualized application of open lung biopsy, predicated on the total clinical situation. Aggressive early diagnosis is certainly indicated for a new pulmonary infiltrate in a 20-year-old patient with Hodgkin's disease in remission. Thoracotomy would probably be inappropriate for the same infiltrate in an 80-year-old patient with leukemia, granulocytopenia, sepsis, respiratory failure, renal failure, and myocardial failure in whom chemotherapy had failed. The gray zone between these hypothetical cases is the area where sound clinical judgment is required. Our approach to the immunosuppressed patient with pulmonary infiltrate consists of careful history, physical examination, and systemic evaluation followed by routine sputum studies (preferably transtracheal aspirate) and body fluid cultures as appropriate. Sputum studies are of less value in interstitial infiltrates. If in-
fection is highly suspected, percutaneous needle aspiration may be performed. (This procedure is not utilized if lymphoma is likely because of the difficulty in making a cytologic diagnosis.) Depending on the clinical situation, if no diagnosis is obtained by the previous methods, early open lung biopsy is advocated, prior to systemic decompensation and far-advanced infection. It is hoped that such an approach, combined with advances in treatment of the basic underlying diseases, will contribute to increased survival for these most challenging patients.
2 3 4 5 6 7 8 9 10
II 12
13
14
REFERENCES Klassen KP, Andrews NC: Biopsy of diffuse pulmonary lesions. A 17 year experience. Ann Thorac Surg 4: 117124, 1967 Gaensler EA, Moister MVB, Hamm J: Open lung biopsy in diffuse pulmonary disease. N Engl J Med 270: 13191331, 1964 Greenman RL, Goodall PT, King 0: Lung biopsy in immunocompromised hosts. Am J Med 59:488-496, 1975 Pennington JE, Feldman NT: Pulmonary infiltrates in patients with hematologic malignancy: Assessment of transbronchial biopsy. Am J Med 62:581-587, 1977 Armstrong 0: Infectious complications in cancer patients treated with chemical immunosuppressive agents. Transplant Proc 5:1245-1248, 1973 Crowther 0: Infection associated with immunosuppressive therapy. Postgrad Med J 48:325-327, 1972 Glenn WL, Liebow AN, Lindskog GE: Thoracic and Cardiovascular Surgery With Related Pathology, ed. 3, New York, 1975, Appleton-Century-Crofts, pp 569-593 Anderson RP, Bonchek L, Grunkemeier GL, et al: The analysis and presentation of surgical results by actuarial methods. J Surg Res 16:224-230, 1974 Cutler SJ, Ederer F: Maximum utilization of life table method in analyzing survival. J Chron Dis 8:699-712, 1958 Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 Gehan EA: Generalized Wilcoxon test for arbitrary singly-censored samples. Biometrika 52:203-223, 1965 Bandt PO, Blank N, Castellino RA: Needle diagnosis of pneumonitis. Value in high risk patients. lAMA 220: 1578-1580, 1972 Cunningham JH, Zavala DC, Corry RJ, Keirn LW: Trephine air drill, bronchial brush, and fiberoptic transbronchial lung biopsies in immunosuppressed patients. Am Rev Respir Dis 115:213-220, 1977 WolffLJ, Bartlett MS, BaehnerRL, Grosfeld MD, Smith JW: The cause of interstitial pneumonitis in immunocompromised children. An aggressive systematic approach to diagnosis. Pediatrics 60:41-45, 1977
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Discussion DR. NOEL H. FISHMAN San Francisco, Calif
The authors of this interesting paper have demonstrated once again that despite formidable risk, open lung biopsy can be performed in extremely ill and hypoxic, immunosuppressed patients with low mortality and morbidity rates. Asked to comment on this excellent paper, I reviewed our own series of open lung biopsies at the University of California in San Francisco. The data from the two institutions are similar in many respects. This paper asks whether establishing a specific diagnosis by open lung biopsy increases patient survival and whether the procedure is cost effective. Unfortunately, these questions were not answered because variables such as the interval between discovery of pulmonary infiltrates and the performance of the biopsy cannot be controlled in a retrospective study such as this one. The authors were understandably disappointed to find no difference in survival between the patients in whom a specific diagnosis was made and those in whom a specific diagnosis could not be made. However, as they pointed out, the mortality rate might have been even higher in the patients with specific diagnosis had they not received specific treatment. There is no reason to assume a priori that the patients with specific diagnoses are comparable as a group to those in whom a specific diagnosis was not made. The authors were also discouraged by the low survival rate in patients with specific infections. In the UC series, however, a greater percentage of patients had specific infections and the survival rate was higher. The authors stated that the patients were usually referred for lung biopsy late in the course of their respiratory failure. Obviously, many were moribund and biopsy was performed too late to permit effective therapy. Dr. Rossiter is correct, therefore, in suggesting a controlled study to demonstrate whether earlier diagnosis could result in increased survival and cost effectiveness. An important question is whether nondirected polypharmacy might lead to better patient survival and cost effectiveness than diagnostic open lung biopsy. Using a number of drugs, most of the infectious agents commonly found in immunosuppressed patients could be treated. Without controlled data the use of nondirected polypharmacy can be neither justified nor dismissed, but I raise the topic for consideration in certain homogeneous immunosuppressed patient populations such as those who have had renal or cardiac transplantation and are receiving drugs that decrease host resistance to infection. A serious problem with "shotgun" antimicrobial therapy is that patients with undiagnosed neoplastic pulmonary infiltrates would not be treated. In our series, in two thirds of the patients with underlying malignancies, the same malignancy was responsible for the pulmonary infiltrates. The hospital mortality rate was only 8 percent, emphasizing the importance of directed radiation
Thoracic and Cardiovascular Surgery
or chemotherapy in these patients. In nearly one third of these patients, the pulmonary infiltrates were not neoplastic. It would appear, therefore, that a specific diagnosis is essential whenever there is a strong suspicion of disseminated malignancy. The authors of this excellent paper have tried to answer two important questions arising in modem clinical medical practice and raised additional questions. I commend them for their systematic analysis and thorough presentation. DR. G. HUGH LAWRENCE Portland, are.
Reading the abstract prompted me to review our experience in the Cardiopulmonary Division of the University of Oregon. We have treated a smaller number of patients (32) in whom the set was slightly different in that there was a subgroup which can be separated out. This subgroup comprised patients, usually in the 30 to 40 year age range, who came into the hospital with a totally unexplained and morbid pulmonary infiltrate, usually bilateral. This group, which was one third of the series, appeared to profit both therapeutically in the final result from the open biopsy. However, in the remainder of the group that were either immunosuppressed or immunodeficient, we found our experience to be even more dismal than that reported by the authors and by Dr. Fishman in discussion. These patients have high morbidity and mortality rates and tax the services of the hospital and the financial resources in the community. It is important to ask how often biopsy yields a specific diagnosis of a condition that can be treated and how often the patient responds and returns to some form of gainful existence. We found in 32 patients, with a subgroup of about 25 immunosuppressed or immunodeficient patients, that only two answered this final question positively. One was a patient with Aspergillosis and another with type III atypical tuberculosis. A typical example on the other side of the problem would be a patient in whom we were delighted to get a diagnosis of cryptococcosis, which was confirmed at autopsy 2 days later. We have to adopt a certain selectivity in the group of patients whom we subject to biopsy; therefore, Dr. Rossiter's paper is extremely timely. He asked whether we will get a better end result if we operate upon these patients earlier. I would ask whether we would be performing more biopsies needlessly by this approach. Dr. Fishman's concept of a therapeutic trial certainly would bear certain enthusiasm for those of us who have followed these patients and their resultant complications. I am reminded that in his recent biography, Sulton is quoted as saying that he did not rob banks because that is where the money was. He robbed banks because he liked to. I must say, when I get a consultation for an open lung biopsy, I admit, I don't like to do them. I think it is time for us to develop selection criteria instead of performing biopsies willy-nilly. The usual consultation is requested late in the
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March,1979
week when the other tests have failed. Then we perform the biopsy and treat the complications of the biopsy for the next several weeks. We have to exert more selectivity. I think the contribution of the authors is a very valuable one.
DR. ROSSITER(Closing) I would like to thank Dr. Fishman and Dr. Lawrence for their comments. It is gratifying to see that other centers have had remarkably similar experience with these very ill patients. I found it interesting that the survival rate with certain infections was somewhat better at UCSF. Perhaps it is due to earlier referral from your intemists-a pattern we are attempting to establish. Alternatively, perhaps the fog in San Francisco has therapeutic benefit. The question of therapeutic trial is a very good one. Again, I think that has to be individualized. Various drugs have significantly differing toxicities. Therapy for Pneumocystis can now be initiated with a relatively nontoxic trial of trimethoprim and sulfamethoxazole. However, a similar therapeutic trial for fungal disease would include a prolonged course of amphotericin and is considerably more toxic.
In conclusion, we re-emphasize that open lung biopsy is technically feasible even in the most moribund patient and can provide a specific etiologic diagnosis in approximately half of the patients. In certain of these patients the establishment of a diagnosis is critical to survival, but in many others no currently available therapeutic modalities are likely to alter the inexorable progression of their disease state. It is incumbent on us to evaluate any such procedure, especially one that is solely diagnostic, in terms of risk: benefit ratios. In complicated situations an algorithm with a decision table can be constructed, but clinical judgment must remain the basis for individualized applications of these techniques. A low yield procedure in a critically ill patient is a long shot but is not necessarily inappropriate. This is especially true at a tertiary referral center where the extremes of feasibility in medical care are properly explored. It is proper, however, only if the physician, the patient, and the patient's family are fully aware of the likelihood of a favorable outcome.
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: "The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors." Authors will be consulted, when possible, regarding republication of their material.
Stephen J. Rossiter, M.D., D. Craig Miller, M.D., Andrew M. Churg, M.D., Charles B. Carrington, M.D., and James B. D. Mark, M.D., Stanford. Calif.
By
means of modern techniques, the majority of pulmonary infiltrates in general patient populations are diagnosed by indirect means, without pulmonary tissue actually being obtained for examination. However, these indirect methods fail to provide a specific diagnosis in 35 to 55 percent of patients with diffuse pulmonary disease. Even more challenging is that group of patients whose immunologic defenses are altered by underlying disease or by various types of therapy. Pulmonary infiltrates, often accompanied by fever, are From the Department of Surgery (Division of Thoracic Surgery) and Department of Pathology, Stanford University Medical Center, Stanford, Calif. 94305. Read at the Fourth Annual Meeting of The Samson Thoracic Surgical Society, Coronado, Calif., June 4-7, 1978.
338
common in this patient population; the differential diagnosis includes infection with pathogenic or opportunistic organisms, extension of basic disease (neoplasm, collagen-vascular disease), complication of therapy (radiation, chemotherapy), and a variety of other entities.":" For appropriate specific therapy to be administered for the pulmonary disease, aggressive diagnostic modalities are employed. If indirect methods are not quickly successful, some form of lung biopsy is generally recommended. 7 Open lung biopsy will provide a histologic diagnosis in the vast majority of cases. The resulting benefits, the risks, and the costs of open lung biopsy in the immunosuppressed population are less well defined and constitute the focus of this study.
0022-5223/79/030338+08$00.80/0 © 1979 The C. V. Mosby Co.
Volume 77 Number 3 March. 1979
Patients and methods A retrospective analysis was performed in which the substrate comprised all patients undergoing open lung biopsy for the diagnosis of pulmonary infiltrates on the Stanford University Thoracic Surgical Service between July, 1974, and December, 1977. Charts of all patients were reviewed and individual patients were contacted for further follow-up when possible. Living patients were followed for an average of 16.5 ± 13.3 months. A total of 83 cases were analyzed with a follow-up of 887 patient-months (range I to 42, mean 9.7 ± 11.4) (Table I). Data obtained included age, sex, primary diagnosis, presence or absence of immunosuppression, pulmonary symptoms, radiographic findings, prior diagnostic results, preoperative and postoperative respiratory status, site of biopsy, histologic and culture results of biopsy, effect of biopsy on treatment, outcome of treatment, status at follow-up, cause of death, autopsy findings, hospital stay, and cost of hospital care and biopsy. Open lung biopsies were performed in the operating room with the patient under general anesthesia. Sites for pulmonary biopsy were chosen by the surgeon during intrathoracic exploration. Small thoracotomy incisions were employed without rib resection. These were most often made anteriorly, but lateral or posterior incisions were employed when anatomic location of an infiltrate so dictated. A wedge of pulmonary tissue was excised, with hemostasis and pneumostasis secured with running catgut suture or stapling devices. Intercostal tube drainage was routinely employed, with tubes removed on the first or second postoperati ve day if no air leak was present. After samples were sent for aerobic and anaerobic bacterial, fungal, acid-fast bacilli (AFB), and viral cultures and smears, the lung biopsy was personally received by the pathologist. Touch preparations of a freshly cut surface were made and stained with Gomori's methenamine silver (GMS) stain to demonstrate fungi and Pneumocystis, and occasionally with AFB and Gram stains. Portions of the tissue were saved for electron microscopic and immunofluorescence studies, and the remainder were perfused with formalin. Sections were routinely stained with hematoxylin and eosin and with GMS, AFB, and Gram stains where indicated. In a number of instances, a frozen section was prepared at the time of biopsy with GMS and hematoxylin and eosin stains performed for a rapid diagnosis. Actuarial survi val curves were constructed by lifetable methods, and statistical significance of variables was assessed by the Gehan test (assigning a two-tailed
Open lung biopsy in immunosuppressed patient
339
Table I. Patients having open lung biopsy No. of patients Operative range Duration of follow-up Average follow-up (all patients) Average follow-up (living patients) Maximum follow-up (living patients) Minimum follow-up (living patients) Males Females Age (average, range)
83 July, 1974, to November, 1977 887 pt.vmo. 9.7 mo. ± IIA (S.D.) 16.5 mo. ± 13.3 (S.D.)
42 mo. I mo. 37 (45%) 46 (55%) 40 yr. (4 mo. to 77 yr.)
Table II. Immunosuppression in patients having open lung biopsy (n = 70) * No.
Percent
43 12 14 2
61 17 20 3
1
1
48
69 81
Underlying disease Lymphoma Leukemia Carcinoma/sarcoma Collagen- vascular Renal transplant (plus lymphoma)
Treatment for underlying disease Radiation therapy Chemotherapy plus steroids
57
'Two patients had two diagnoses each.
significance level to the p value thus obtained), Fisher's exact test, Student's t test, and chi square analysis as appropriate. 8- t 1
Results Of the 83 patients undergoing open lung biopsy, 70 (84 percent) were immunocompromised hosts and 13 (16 percent) were not immunocompromised. Immunosuppression was considered to be present if the patient had a primary diagnosis of lymphoma, hematologic malignancy, collagen-vascular disease, organ transplant, or carcinoma/sarcoma for which he or she received radiation therapy, chemotherapy, or corticosteroids (Table II). One patient had received a renal transplant and later developed nodular sclerosing Hodgkin's disease, and another patient had both adenocarcinoma of the colon and lymphocytic lymphoma. All except one of the 13 nonimmunosuppressed patients had bilateral or diffuse radiographic changes and underwent biopsy so that the disease could be defined further. Three of these patients had pneumonitis, five had restrictive lung disease, one had fever of unknown
The Journal of
340 Rossiter et al.
Thoracic and Cardiovascular Surgery
Table III. Specific etiologic diagnoses in patients having open lung biopsy (n = 53) *
100 p (GEHAN) = .01
_ _ _ _ _ _ _ _ _ _ _ _'--N-O-.-'--P-e-rc-e-nr--
90
Neoplasm Previously diagnosed Previously undiagnosed Infection Other (infarct, sarcoid, etc.)
80
70 ...J
« ~
t
:::J
IZ
60
50
Hospital death
U
a::
w
40
Infection
No.
No.
Pneumocystis carinii Mycobacterium tuberculosis
9
30
6 0 2 I 0
.............•
Viral (adenovirus, cytomegalovirus) Fungal (Aspergillus) Bacteria
20
10
6
Table IV. Infections in patients having open lung biopsy, with treatment results (n = IS)
W
Q.
4
28
'Seven patientshad combined diagnoses of infection and neoplasm .
> a:: (I)
62
33 2 15 3
• IMMUNOSUPPRESSED (n=70) o NON-IMMUNOSUPPRESSED (n=13)
00
6 YEARS POST·BIOPSY
Fig. 1. Mortality rates for open lung biopsy. Immunosuppressed versus nonimmunosuppressed patients. origin, and two had other cryptogenic infiltrates. In the over-all group, 52 (63 percent) had generalized or bilateral infiltrates, 30 (36 percent) had localized infiltrates, and one patient (1.2 percent) had a normal chest roentgenogram. Eighteen (22 percent) of the 83 patients were asymptomatic, but symptoms were present in 78 percent, often multiple in the same patient (dyspnea 55 percent, fever 41 percent, cough 28 percent, and other II percent). Diagnostic yield. Seventy-seven invasive pulmonary diagnostic procedures were performed prior to open lung biopsy in the 83 patients. A specific etiologic diagnosis was made in two of the 39 transtracheal aspirates, two of 25 bronchoscopies, and one of 13 percutaneous needle lung aspirates. There were two complications as a result of these other procedures (two pneumothoraces after needle aspiration). Open lung biopsy provided a diagnostic accuracy of 97.5 percent (81 of 83) as confirmed by clinical course, later diagnostic procedure, or autopsy. Two infections
2 2
I
Total deaths
I
%
No.
%
66 0
7 0
100
2
77 0 100
100 0
1 0
100 0
(Nocardia and Aspergillus) were missed with this technique. However, a specific etiologic diagnosis was made in only 46 of 83 (55 percent) patients (Table III). Nonspecific diagnoses (e.g., interstitial fibrosis) were made in 37 of 83 (45 percent). Infections diagnosed are listed in Table IV. The single bacterial infection (Providentia) was being treated by appropriate antibiotics preoperati vely because of positive blood cultures for the same organism. All patients with Pneumocystis infections had diffuse radiographic infiltrates. Prebiopsy antibiotics were employed in 34 of 83 (41 percent) patients with 15 recei ving anti-Pneumocystis, eight receiving antifungal, two receiving antituberculous, and 27 receiving antibacterial agents. Anatomic sites of 86 biopsies in the 83 patients were as follows: right upper lobe, eight cases; right middle lobe, 30 cases; right lower lobe, 21 cases; left upper lobe, 10 cases; lingula, six cases; left lower lobe, II cases. There was no correlation between site of biopsy and diagnostic yield. Deaths and benefits. Fig. I demonstrates mortality rates for the over-all group (n = 83), for the immunosuppressed group (n = 70; follow-up = 608 patient-months; mean = 8.6 ± 10.2 months; range = I to 39), and for the nonimmunosuppressed group (n = 13; follow-up = 279 patient-months; mean = 15.8 ± 15.5 months; range = I to 42). Immunocompromised
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Open lung biopsy in immunosuppressed patient
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March, 1979
-
laO
34 I
CJ OVERALL GROUP
> I-
80
~
«
I-
a:
60
0
::!: I-
z
w
IMMUNOSUPPRESSED GROUP
rz?22 NON ·IMMUNOSUPPRESSED GROUP
p < .01
=. :01
p
55% 46
NS .
40
o a: w
e,
20
0
n=83
n=13
n=83
TOTAL MORTALITY
n=62
HOSPITA L MORT A LITY
n=50
n=12
LATE MORTA LI T Y
Fig. 2. Open lung biopsy . Actuarial survival.
Table V. Terminal events in patients having open lung biopsy
Table VI . Economic costs for immunosuppressed patients having open lung biopsy (n = 25)
Hospital deaths
Late deaths
Event
(n = 2/)
(n = 25)
Respiratory failure Sepsis Central nervous system event Cardi omyopathy Airway obstruction (tumor) Unknown
18
15 4
2 1
o o o
I I I 3
hosts fared significant ly worse with regard to total mortality and late morta lity rates. They also had a threefold greater hospital mortality rate, which was not stat istically significant. This disparity in survival is further emphasized in Fig. 2, which graphically displays actu arial survival of the immunocompromised versus the immunocompetent patients (p < 0.05) . No death was attributable directly to the biopsy procedure. Death was often due to multisystem failure and combinations of events, especially sepsis plus respiratory failure ; terminal events are summarized in Table V. Total mortality rates and hospital mortality rates did not significantly differ between patients with a specific diagnosis and those without (Fig. 3). Similar mortality rates also occurred whether or not open lung biopsy dictated a treatment change (Fig . 4) . Com plications. Eight complications occurred in 83 biopsies, for a rate of 9.6 percent. Each of the following complications occurred once : tension pneumothorax, pneumothorax, wound hematoma, empyema (Staphylococcus), persistent air leak, pneumonia, re-
_ __
_
_
_
_
_
_
Total hospitalization cost (average; range) Surgical costs (average; range) Months to follow-up or death (average; range) Cost/month (average)
1
Alive
' - -D-e-ad - --
$7,632 (3,946-19,608) $1,839 (1,626- 2,532) 6.2 (1-26) $1,231
$16,904 (2,040-50,877) $1,592 ( 1,151-2,005) 3.1 (0 .1-18) $5,425
currence of angiosarcoma in chest tube site, and persis tent incisional pain. Costs. Hospital bills of the last 25 patients were reviewed (Table VI). Only in-patient hospital costs were analyzed. Surgical costs include professional fees, operating room fees, anesthetic charges, and supplies . Although surgical costs were similar, total hospitalization costs for patients who died averaged twice the cost for those alive at the time of follow-up. Similarly, total hospitalization costs divided by time of survival (to death or date of follow-up) were four times greater among those who died . Discussion The technique of open lung biopsy by means of a limited thoracotomy is well established, generally safe, and provides the most satisfactory tissue samples for examination. I . 2 The mere existence of such a technique is not a suitable justification for its universal application to every patient with pulmonary infiltrate, however. Documentation of the diagnostic yields and risks must
The Journal of Thoracic and Cardiovascular Surgery
342 Rossiter et al.
p = NS
SPECIFIC DIAGNOSIS n = 46
p = NS
NO SPECIFIC DIAGNOSIS n = 37
TREATMENT ALTERED n = 37
TREATMENT NOT ALTERED n = 46
Fig. 3. Open lung biopsy. Specific diagnosis as determinant of survival.
Fig. 4. Open lung biopsy. Treatment change as determinant of survival.
be combined with an analysis of the benefits likely to accrue to patients subjected to the procedure. The immunosuppressed host is both a diagnostic and therapeutic challenge; opportunistic infections, active neoplasm, complications of therapy, and vasculitis are among the possible causes of pulmonary infiltrate. Clearly, many of the diagnoses can be made by careful history and physical examination, systemic evaluation, and noninvasive laboratory examination (such as sputum cultures). Occasionally, extrathoracic procedures (lymph node biopsies, cutaneous biopsies) will be fruitful. Judicious therapeutic trials are at times indicated. There remains a core of patients, however, for whom diagnosis is impossible without obtaining pulmonary tissue. Various methods have been employed to procure these specimens. Needle aspirates have proved useful in the cytologic diagnosis of solid peripheral lesions and have been efficacious in diagnosing pulmonary infections in the immunocompromised host. Bandt, Blank, and Castellino'" specifically diagnosed 76 percent of 25 pulmonary infiltrates in altered hosts. Percutaneous needle aspirates or transtracheal aspirates have supplied sufficient microbiologic information for management of pulmonary infiltrates in all of the 140 Stanford heart transplant patients. Of course, neoplasm, fibrosis secondary to radiation or chemotherapy, and vasculitis were generally not serious considerations in these patients. Cutting needle biopsies have a greater risk of pneumothorax (3 to 31 percent) and provide a specific diagnostic yield of 34 to 81 percent for immunocompetent patients." Trephine air drill biopsy provided a diagnostic yield (specific etiology) of 65 percent in 17 immunocompromised patients reported by Cunningham and colleagues;" but pneumothorax occurred in 60 percent of cases and significant hemorrhage in 18 percent. The same author achieved a 42
percent specific diagnosis rate in 31 transbronchiallung biopsies via the fiberoptic bronchoscope, whereas Pennington and Feldman" reported a 64 percent rate using this method. The low diagnostic yield of nonthoracotomy procedures (five of 77) in our series is certainly a factor of selection. Patients whose diagnosis was made by methods other than open lung biopsy usually did not require thoracotomy and were not included in this series. No statement regarding the comparative efficacy of these various procedures can be made from our data. Open lung biopsy in the immunocompromised host is highly accurate (diagnostic accuracy of 97.5 percent in our series), but specific etiologic diagnosis was made in only 55 percent of our patients (compared to 87.5 percent in Wolff's!" series of 24 patients, 23 with infection). Infection accounted for only 28 percent of the specific diagnoses in our series, with neoplasm present in 71 percent. Results of treating these infections were dismal, with notable exceptions in the one bacterial and two tuberculous pneumonias. The 77 percent mortality rate in Pneumocystis carinii infections is high, albeit comparable to some other reports," and perhaps reflects a late stage of disease at the time of diagnosis. The formidable mortality rate (63 percent) for immunosuppressed patients compared to the 15 percent mortality for immunocompetent patients is not surprising. The underlying diseases and the required toxic drugs are associated with a substantial number of deaths even in the absence of pulmonary disease. A central issue which requires elucidation is the benefit likely to accrue to a patient if a specific diagnosis is made by open lung biopsy. In this series no significant difference in mortality rate was noted between patients with a specific diagnosis and those without, or between those whose treatment was altered because of diagnosis
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March,1979
and those with no treatment change. These data do not indicate, however, that open lung biopsy is without value. It is possible that the patients with specific diagnoses constituted a higher risk group, and mortality rate in this group might have been much higher had no diagnoses been made. Patients often were referred late in the course of their disease, with multiple organ failure. Other authors- 4 have reported lower mortality rates for patients with a specific diagnosis than for those without; an over-all survival rate of 75 percent for immunosuppressed patients undergoing open lung biopsy has also appeared in the literature, 14 although the spectrum of disease was different (23 of 24 patients with infection). A definite statement regarding the value of diagnosis can be made only if a group of patients with specific diagnoses is prospectively randomized into treatment and no treatment groups; such a study is unlikely to occur. Pennington and Feldman" performed a retrospective analysis of the impact of transbronchial lung biopsy on the mortality rate of 47 immunosuppressed patients. Although the rate of specific diagnoses increased from 47 to 62.5 percent after the introduction of the biopsy technique, mortality rate remained static. The obvious limitations of such a study again preclude sweeping conclusions. The financial cost data are not particularly surprising. It is widely known that, with advanced technology and support, the cost of dying is high. Although the survival statistics for immunosuppressed patients with pulmonary infiltrates are depressing, it should be remembered that mortality rate due to the untreated underlying disease is very substantial. We certainly do not advocate diagnostic or therapeutic nihilism on the basis of this report. Rather, we recommend an individualized application of open lung biopsy, predicated on the total clinical situation. Aggressive early diagnosis is certainly indicated for a new pulmonary infiltrate in a 20-year-old patient with Hodgkin's disease in remission. Thoracotomy would probably be inappropriate for the same infiltrate in an 80-year-old patient with leukemia, granulocytopenia, sepsis, respiratory failure, renal failure, and myocardial failure in whom chemotherapy had failed. The gray zone between these hypothetical cases is the area where sound clinical judgment is required. Our approach to the immunosuppressed patient with pulmonary infiltrate consists of careful history, physical examination, and systemic evaluation followed by routine sputum studies (preferably transtracheal aspirate) and body fluid cultures as appropriate. Sputum studies are of less value in interstitial infiltrates. If in-
fection is highly suspected, percutaneous needle aspiration may be performed. (This procedure is not utilized if lymphoma is likely because of the difficulty in making a cytologic diagnosis.) Depending on the clinical situation, if no diagnosis is obtained by the previous methods, early open lung biopsy is advocated, prior to systemic decompensation and far-advanced infection. It is hoped that such an approach, combined with advances in treatment of the basic underlying diseases, will contribute to increased survival for these most challenging patients.
2 3 4 5 6 7 8 9 10
II 12
13
14
REFERENCES Klassen KP, Andrews NC: Biopsy of diffuse pulmonary lesions. A 17 year experience. Ann Thorac Surg 4: 117124, 1967 Gaensler EA, Moister MVB, Hamm J: Open lung biopsy in diffuse pulmonary disease. N Engl J Med 270: 13191331, 1964 Greenman RL, Goodall PT, King 0: Lung biopsy in immunocompromised hosts. Am J Med 59:488-496, 1975 Pennington JE, Feldman NT: Pulmonary infiltrates in patients with hematologic malignancy: Assessment of transbronchial biopsy. Am J Med 62:581-587, 1977 Armstrong 0: Infectious complications in cancer patients treated with chemical immunosuppressive agents. Transplant Proc 5:1245-1248, 1973 Crowther 0: Infection associated with immunosuppressive therapy. Postgrad Med J 48:325-327, 1972 Glenn WL, Liebow AN, Lindskog GE: Thoracic and Cardiovascular Surgery With Related Pathology, ed. 3, New York, 1975, Appleton-Century-Crofts, pp 569-593 Anderson RP, Bonchek L, Grunkemeier GL, et al: The analysis and presentation of surgical results by actuarial methods. J Surg Res 16:224-230, 1974 Cutler SJ, Ederer F: Maximum utilization of life table method in analyzing survival. J Chron Dis 8:699-712, 1958 Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 Gehan EA: Generalized Wilcoxon test for arbitrary singly-censored samples. Biometrika 52:203-223, 1965 Bandt PO, Blank N, Castellino RA: Needle diagnosis of pneumonitis. Value in high risk patients. lAMA 220: 1578-1580, 1972 Cunningham JH, Zavala DC, Corry RJ, Keirn LW: Trephine air drill, bronchial brush, and fiberoptic transbronchial lung biopsies in immunosuppressed patients. Am Rev Respir Dis 115:213-220, 1977 WolffLJ, Bartlett MS, BaehnerRL, Grosfeld MD, Smith JW: The cause of interstitial pneumonitis in immunocompromised children. An aggressive systematic approach to diagnosis. Pediatrics 60:41-45, 1977
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344 Rossiter et at.
Discussion DR. NOEL H. FISHMAN San Francisco, Calif
The authors of this interesting paper have demonstrated once again that despite formidable risk, open lung biopsy can be performed in extremely ill and hypoxic, immunosuppressed patients with low mortality and morbidity rates. Asked to comment on this excellent paper, I reviewed our own series of open lung biopsies at the University of California in San Francisco. The data from the two institutions are similar in many respects. This paper asks whether establishing a specific diagnosis by open lung biopsy increases patient survival and whether the procedure is cost effective. Unfortunately, these questions were not answered because variables such as the interval between discovery of pulmonary infiltrates and the performance of the biopsy cannot be controlled in a retrospective study such as this one. The authors were understandably disappointed to find no difference in survival between the patients in whom a specific diagnosis was made and those in whom a specific diagnosis could not be made. However, as they pointed out, the mortality rate might have been even higher in the patients with specific diagnosis had they not received specific treatment. There is no reason to assume a priori that the patients with specific diagnoses are comparable as a group to those in whom a specific diagnosis was not made. The authors were also discouraged by the low survival rate in patients with specific infections. In the UC series, however, a greater percentage of patients had specific infections and the survival rate was higher. The authors stated that the patients were usually referred for lung biopsy late in the course of their respiratory failure. Obviously, many were moribund and biopsy was performed too late to permit effective therapy. Dr. Rossiter is correct, therefore, in suggesting a controlled study to demonstrate whether earlier diagnosis could result in increased survival and cost effectiveness. An important question is whether nondirected polypharmacy might lead to better patient survival and cost effectiveness than diagnostic open lung biopsy. Using a number of drugs, most of the infectious agents commonly found in immunosuppressed patients could be treated. Without controlled data the use of nondirected polypharmacy can be neither justified nor dismissed, but I raise the topic for consideration in certain homogeneous immunosuppressed patient populations such as those who have had renal or cardiac transplantation and are receiving drugs that decrease host resistance to infection. A serious problem with "shotgun" antimicrobial therapy is that patients with undiagnosed neoplastic pulmonary infiltrates would not be treated. In our series, in two thirds of the patients with underlying malignancies, the same malignancy was responsible for the pulmonary infiltrates. The hospital mortality rate was only 8 percent, emphasizing the importance of directed radiation
Thoracic and Cardiovascular Surgery
or chemotherapy in these patients. In nearly one third of these patients, the pulmonary infiltrates were not neoplastic. It would appear, therefore, that a specific diagnosis is essential whenever there is a strong suspicion of disseminated malignancy. The authors of this excellent paper have tried to answer two important questions arising in modem clinical medical practice and raised additional questions. I commend them for their systematic analysis and thorough presentation. DR. G. HUGH LAWRENCE Portland, are.
Reading the abstract prompted me to review our experience in the Cardiopulmonary Division of the University of Oregon. We have treated a smaller number of patients (32) in whom the set was slightly different in that there was a subgroup which can be separated out. This subgroup comprised patients, usually in the 30 to 40 year age range, who came into the hospital with a totally unexplained and morbid pulmonary infiltrate, usually bilateral. This group, which was one third of the series, appeared to profit both therapeutically in the final result from the open biopsy. However, in the remainder of the group that were either immunosuppressed or immunodeficient, we found our experience to be even more dismal than that reported by the authors and by Dr. Fishman in discussion. These patients have high morbidity and mortality rates and tax the services of the hospital and the financial resources in the community. It is important to ask how often biopsy yields a specific diagnosis of a condition that can be treated and how often the patient responds and returns to some form of gainful existence. We found in 32 patients, with a subgroup of about 25 immunosuppressed or immunodeficient patients, that only two answered this final question positively. One was a patient with Aspergillosis and another with type III atypical tuberculosis. A typical example on the other side of the problem would be a patient in whom we were delighted to get a diagnosis of cryptococcosis, which was confirmed at autopsy 2 days later. We have to adopt a certain selectivity in the group of patients whom we subject to biopsy; therefore, Dr. Rossiter's paper is extremely timely. He asked whether we will get a better end result if we operate upon these patients earlier. I would ask whether we would be performing more biopsies needlessly by this approach. Dr. Fishman's concept of a therapeutic trial certainly would bear certain enthusiasm for those of us who have followed these patients and their resultant complications. I am reminded that in his recent biography, Sulton is quoted as saying that he did not rob banks because that is where the money was. He robbed banks because he liked to. I must say, when I get a consultation for an open lung biopsy, I admit, I don't like to do them. I think it is time for us to develop selection criteria instead of performing biopsies willy-nilly. The usual consultation is requested late in the
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Open lung biopsy in immunosuppressed patient
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week when the other tests have failed. Then we perform the biopsy and treat the complications of the biopsy for the next several weeks. We have to exert more selectivity. I think the contribution of the authors is a very valuable one.
DR. ROSSITER(Closing) I would like to thank Dr. Fishman and Dr. Lawrence for their comments. It is gratifying to see that other centers have had remarkably similar experience with these very ill patients. I found it interesting that the survival rate with certain infections was somewhat better at UCSF. Perhaps it is due to earlier referral from your intemists-a pattern we are attempting to establish. Alternatively, perhaps the fog in San Francisco has therapeutic benefit. The question of therapeutic trial is a very good one. Again, I think that has to be individualized. Various drugs have significantly differing toxicities. Therapy for Pneumocystis can now be initiated with a relatively nontoxic trial of trimethoprim and sulfamethoxazole. However, a similar therapeutic trial for fungal disease would include a prolonged course of amphotericin and is considerably more toxic.
In conclusion, we re-emphasize that open lung biopsy is technically feasible even in the most moribund patient and can provide a specific etiologic diagnosis in approximately half of the patients. In certain of these patients the establishment of a diagnosis is critical to survival, but in many others no currently available therapeutic modalities are likely to alter the inexorable progression of their disease state. It is incumbent on us to evaluate any such procedure, especially one that is solely diagnostic, in terms of risk: benefit ratios. In complicated situations an algorithm with a decision table can be constructed, but clinical judgment must remain the basis for individualized applications of these techniques. A low yield procedure in a critically ill patient is a long shot but is not necessarily inappropriate. This is especially true at a tertiary referral center where the extremes of feasibility in medical care are properly explored. It is proper, however, only if the physician, the patient, and the patient's family are fully aware of the likelihood of a favorable outcome.
Information for authors Most of the provisions of the Copyright Act of 1976 became effective on January I, 1978. Therefore, all manuscripts must be accompanied by the following written statement, signed by one author: "The undersigned author transfers all copyright ownership of the manuscript (title of article) to The C. V. Mosby Company in the event the work is published. The undersigned author warrants that the article is original, is not under consideration by another journal, and has not been previously published. I sign for and accept responsibility for releasing this material on behalf of any and all co-authors." Authors will be consulted, when possible, regarding republication of their material.