LETTERS AND CORRECTIONS

Letters submitted for publication must be typed double-spaced. Text length must not exceed 500 words, and no more than five references may be used. Complete references must be furnished, as specified in "Information for Authors" (page 1-6). Specific permission to publish should be appended as a postscript. Publication depends on availability of space: We give preference to comment on recent content and to new information. Letters for this section should be concise—the Editor reserves the right to shorten them and make changes that accord with our style.

Doxorubicin Cardiomyopathy TO THE EDITOR: The recent article by Bristow and colleagues (Ann Intern Med 88:168-175, 1978) advocating the routine use of right endomyocardial biopsy in patients receiving doxorubicin raises several questions. In their study a scoring system based on the ultrastructural characteristics of myocytes was used to quantitate the severity of drug-induced damage to the heart. Myofibrillar loss, a major criterion of their scoring system, can involve either thick or thin myofilaments, or both (1). Buja and associates (2) have shown that doxorubicin-induced myofibrillar loss mainly involves thick filaments. Bristow and co-authors, however, do not give a precise definition of this change in their patients but merely state that "scanty cells showing early myofibrillar dropout" indicate a Grade-1 change, whereas "definite myofibrillar dropout" indicates more severe changes. Other ultrastructural characteristics described in this study, such as vacuolization and dilatation of sarcoplasmic reticulum, are nonspecific and have been associated with diverse forms of myocardial injury (1-3). These problems are compounded (4) because doxorubicin-induced myocardial changes are focal in distribution, do not occur synchronously in all cells, each affected myocyte does not necessarily undergo the entire spectrum of morphologic alterations, and adjacent cells may not show the same degree of change. Thus the validity of the scoring system in their study, particularly for quantitative evaluation, is questionable. The myocardial sampling procedure is vitally important in studies of this type. The authors indicate that four myocardial samples were taken serially from the right ventricular septum. However, the way in which they insured uniformity of sampling site and sampling sequence in each patient so that the biopsy material represented right interventricular septum and not other adjacent structures is unclear. Also unclear is whether the final score (0 to + 3) in each patient represented evaluation of a single sample, an average of all four samples, or the sample showing the most severe changes. In the absence of such details, statistical evaluation seems less meaningful. The purpose of endomyocardial biopsy, according to these authors, is to provide an alternative means of monitoring left ventricular function. Close inspection of the data in their Table 1, however, does not establish an unequivocal relation between biopsy changes in the right ventricle and the degree of left ventricular dysfunction. For instance, one patient who died from intractable left heart failure had minimal biopsy changes ( + 1 ) . Interestingly, the pre-ejection period to left ventricular ejection time (PEP/LVET) ratio in this patient (0.66) suggested severe left ventricular dysfunction. Two other patients had minimal biopsy changes with grossly abnormal P E P / L V E T ratio. A t the other end of the spectrum are two patients in whom biopsy samples indicated maximal degenerative changes ( + 3 ) but in whom no overt clinical evidence or significant hemodynamic evidence of gross left ventricular failure could be documented. The authors indicate that left heart catheterizations were done 136

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in six patients, yet no information is provided on the relation, if any, between the left ventricular end-diastolic pressure and right ventricular biopsy scores in these patients. Since doxorubicin predominantly affects the left ventricle, how accurately do morphologic alterations in biopsy material obtained from the right ventricle reflect the contractile status of the left ventricle? The invasive nature of endomyocardial biopsy severely limits its usefulness, especially in sequential studies. We believe that noninvasive techniques such as serial echocardiography (5) offer a safer and more practical, yet equally sensitive, means for evaluating left ventricular function in patients receiving doxorubicin therapy. S H Y A M A L K. S A N Y A L , F.A.A.P., F.A.C.C. W A R R E N W. JOHNSON, M . D .

St. Jude Children's Research Hospital; Memphis, T N 38101

REFERENCES 1. SANYAL SK, JOHNSON WW, THAPAR MK, PITNER S: An ultrastructural

basis for electrocardiographic alterations associated with Duchenne's progressive muscular dystrophy. Circulation, 57:1122-1129, 1978 2. BUJA LM, FERRANS VJ: Myocardial injury produced by antineoplastic drugs. Recent Adv Stud Cardiac Struct Metab 6:487-497, 1975 3. M A R O N BJ, FERRANS VJ, ROBERTS WC: Ultrastructural features of de-

generated cardiac muscle cells in patients with cardiac hypertrophy. Am JPathol79:3Sl-434, 1975 4. JAENKE RS, FAJARDO LF: Adriamycin-induced myocardial lesions. Am

J Surg Pathol 1:55, 1977 5. RAMOS A, M E Y E R RA, KORFHAGEN, J, W O N G KY, K A P L A N S: Echo-

cardiographic evaluation of adriamycin cardiotoxicity in children. Cancer Treat Rep 60:1281-1284, 1976

In comment: Drs. Sanyal and Johnson raise important questions on the use of right ventricular endomyocardial biopsy to evaluate doxorubicin-induced cardiomyopathy. The use of myofibrillar "dropout" in scoring endomyocardial biopsies does not require subtle breakdown into thick and thin filaments since both are lost. Scoring is not based on the loss of a few thick or thin filaments but on a much more gross loss of myofibrils that can be appreciated by light microscopy. The paper by Buja and colleagues (1) was based on necropsy tissue, which does not provide reliable ultrastructural changes, as conceded by the same two authors in another paper (2). "Definite myofibrillar dropout" in Grade 2 refers to total loss of myofibrils; this change is easily seen on light microscopy. We have never claimed that the myocyte changes are specific for anthracycline damage but rather that they are characteristic: these lesions are similar to doxorubicin-induced lesions in animals (3), they increase with doxorubicin dose, and they are not seen in pretreatment biopsies. It is therefore reasonable to assume they are due to doxorubicin. Similar lesions seen in other types of cardiomyopathies have a different distribution, and mitochondrial changes are more predominant. The final pathologic score is the highest score of 10 Epon blocks (Fisher Scientific Co., Fairlawn, N e w Jersey) screened per biopsy per patient. A n analysis of multiple biopsy specimens from 10 patients gave identical scores for each sample from the same patient. Animal studies show that anthracycline lesions are readily found in the distal right ventricular septum ( B I L L INGHAM ME: Unpublished data), and fluoroscopic guidance of the bioptome assures that each biopsy is taken from a similar anatomic position in man. The patient mentioned by Sanyal and Johnson with a + 1 biopsy who died in heart failure had mitral regurgitation and was 78 years old. Thus factors other than doxorubicin may have contributed to his cardiac dysfunction. The two patients with

+ 3 biopsies who were not in overt heart failure had catheterization evidence of left ventricular dysfunction. The question of the relevance of right ventricular biopsy to left ventricular function is best answered by our recent analysis (4) of 67 patients evaluated with right ventricular biopsy, right heart catheterization, echocardiogram, and systolic time intervals. Biopsy score correlated extremely well with catheterization-proven left ventricular dysfunction, whereas assessment of left ventricular function by systolic time intervals or echocardiogram correlated poorly. If performed properly right ventricular biopsy has extremely low morbidity (our Stanford results: no deaths in more than 1500 biopsies, morbidity 0.5%). Sequential procedures are easily done; some cardiac transplant patients have had more than 30 biopsies. Since morphologic changes precede hemodynamic deterioration, the biopsy adds an element of prediction and in complicated cases allows for assessment of the contribution of anthracycline treatment to the degree of cardiac dysfunction. Consequently, we strongly disagree that other methods currently offer a "safer" way in which to exceed standard dose limitation guidelines or to risk trading undertreatment of neoplastic disease for prevention of cardiomyopathy. M . R. BRISTOW, M.D., PH. D. M . E . BlLLINGHAM, M.D. Stanford University Hospital; Stanford, C A 94305 REFERENCES

1. BUJA LM, FERRANS VJ: Myocardial injury produced by antineoplastic drugs. Recent Adv Stud Cardiac Struct Metab 6:487-497, 1975 2. BUJA LM, FERRANS VJ, M A Y E R RJ, ROBERTS WC, HENDERSON ES:

Cardiac ultrastructural changes induced by daunorubicin therapy. Cancer 32:771-787, 1973 3. JAENKE RS: An anthracycline antibiotic-induced cardiomyopathy in rabbits. Lab Invest 30:292-304, 1974

In contrast to systolic time intervals, the echocardiogram was helpful in detecting doxorubicin-induced cardiac dysfunction. Three of 11 patients who received more than 300 mg/m 2 body surface area had abnormally low fractional shortening. All 16 patients receiving less than that amount had normal values (p < 0.05). The single patient who developed clinical congestive heart failure had the lowest fractional shortening. The ejection fraction was of less value. Only one of 11 patients receiving more than 300 mg/m 2 body surface area of doxorubicin had an abnormality, compared to none of 16 receiving lower doses (p is not significant). These results are in contrast to the reports of Ewy and co-workers (2) and Jones, Ewy, and Goves (4), who found abnormal ejection fraction in 4 6 % of their patients who received larger doses of doxorubicin. We believe that the best noninvasive technique currently available for the early detection of doxorubicin cardiotoxicity is the echocardiographic assessment of fractional shortening. Because the pathologic process is diffuse, the fractional shortening should be representative of global left ventricular function. It is not surprising that the ejection fraction was of less value than fractional shortening since the error of a single measurement is cubed in its calculation. Systolic time intervals, previously reported to be helpful in detecting doxorubicin cardiotoxicity, were of little value in our hands. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. T E R R Y B. T R I , M . D . JAMES WILKINS, M.D.

Letterman Army Medical Center; Presidio of San Francisco, CA 94129 M I C H A E L P. C O R D E R , M . D .

University of Iowa Hospitals; Iowa City, IA 52242

4. M A S O N JW, BRISTOW MR, BILLINGHAM ME, D A N I E L S JR: Invasive

and noninvasive methods of assessing adriamycin cardiotoxicity in man: superiority of histopathologic assessment using endomyocardial biopsy. Cancer Treat Rep, in press

REFERENCES 1. RINEHART JJ, LEWIS RP, BALCERZAK SP: Adriamycin cardiotoxicity in

man. Ann Intern Med 81:475-478, 1974 2. BRISTOW MR, M A S O N JW, BILLINGHAM ME, D A N I E L S JR: Endomyo-

T o T H E EDITOR: Rinehart, Lewis, and Balcerzak (1) have recommended the use of systolic time intervals for the early detection of doxorubicin cardiotoxicity. Eighty-nine percent of their patients who received greater than 300 mg/m 2 body surface area of doxorubicin had a significant increase in the ratio of the pre-ejection period/left ventricular ejection time (PEP/LVET). They suggest that this increase represents early cardiotoxicity of the drug, thus providing a guideline for dosage limitation. However, one of their nine patients who received lower dosages of doxorubicin and one of their nine control subjects who received no doxorubicin also had a significant increase in their systolic time intervals. Neither the absolute P E P / L V E T value nor the magnitude of change from baseline correlated well with the occurrence of clinical heart failure. Bristow and associates (2) have reported similar results. Nine of 12 patients receiving more than 250 mg/m 2 body surface area of doxorubicin had an increased PEP/LVET. Elevated values, however, were also found in one of three patients who received less than that amount, and the P E P / L V E T correlated poorly with the cumulative dose of doxorubicin. To find a more reliable indicator of doxorubicin cardiotoxicity, we used systolic time intervals and echocardiography in 27 patients with cancer who received 30 to 754 mg/m 2 body surface area of doxorubicin. The echocardiographic variables studied were fractional shortening of the left ventricular internal dimension during systole and ejection fraction. In our series, systolic time intervals were an apparently poor indicator of doxorubicin cardiotoxicity. Two of 11 patients who received more than 300 mg/m 2 body surface area had an abnormally elevated P E P / L V E T compared to two of 16 who received less than that amount (p is not significant). None of the 16 patients in whom serial studies were obtained had a significant increase in PEP/LVET. The P E P / L V E T was normal in the only patient who developed clinical congestive heart failure.

cardial biopsy and systolic time intervals in detection of adriamycin cardiotoxicity (abstract). Circulation 54(suppl 2):II-80, 1976 3. E W Y GA, JONES SE, GROVES BM, D U R I E BGM, WRIGHT I: Echocardi-

ographic diagnosis of adriamycin heart disease (abstract). Proc West Sect Oncol, 1975 4. JONES SE, E W Y GA, GROVES BM: Echocardiographic detection of

adriamycin heart disease (abstract). Proc Am Soc Clin Oncol, 1975

R-on-T Phenomenon T o T H E EDITOR: Drs. Engel, Meister, and Frankl have implied in their article "The 'R-on-T' Phenomenon'* (Ann Intern Med 88:221-225, 1978) that the R-on-T phenomenon may have little clinical significance in terms of mortality. Although this seems to be substantiated by their data, and is probably true, the interpretation depends on how one looks at the data. On page 223 under the subheading "Epidemiology of R-onT," the reported increment of death among the insured population is 33%, and the reported increment in patients with coronary heart disease is 50%. Although the numbers are themselves small, when looked at as an increased percentage the numbers are rather large. I do not dispute their interpretation but do wish to point out that the data may have an alternate interpretation. SEYMOUR HERSCHBERG, M.D.

Misericordia Hospital Medical Center; Bronx, N Y 10451 T o T H E EDITOR: The recent review by Engel and colleagues purports to reappraise the early cycle ectopic, but their approach to this topic is unsettling. The implication to the casual reader (the abstract "peruser") is that R-on-T is no longer a meaningful marker for a high-risk-for-sudden-death patient subset ("R-on-T . . . represents at worst only a small risk in terms of sudden death"). For the more careful reader, the artiLetters and Corrections

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cle isolates the early cycle ectopic from its usual concomitants—advanced grades (multiform, repetitive ectopics) of arrhythmia. The authors do note this association, but its placement in the text is such that many readers will misconstrue the authors* abstract and conclusions. Although it is true that a wide range of coupling intervals may initiate a paroxysm of sustained ventricular arrhythmia and primary ventricular fibrillation in the acute phase of myocardial infarction need not arise from R-on-T, this does not negate the persistent evidence that within certain populations an early cycle ectopic may well portend sudden death. Schulze, Strauss, and Pitt (1) and Ruberman and associates (2) have found an association between the early cycle ectopic and sudden death. Indeed Ruberman and co-workers noted that "the cumulative probability for sudden coronary death among men with early beats or runs was 21.0 percent as compared to 10.6 percent for the remaining men with complex beats." The obvious retort may be that risk relates only to the repetitive forms and not to early cycle ectopy. In our experience among patients with malignant ventricular arrhythmia (3), the concept of Grade 5 (R on T) remains valid. It may have particular import in exercise-induced ventricular fibrillation or tachycardia (4). Realistically, those patients who have R-on-T usually have a high frequency of ectopics and thus a high frequency of complex and repetitive ventricular premature beats (VPB) (2). Hence, the presence of an isolated early cycle VPB should alert the physician to the potential for other grades of potentially malignant arrhythmia for that particular patient. This is not true of VPB occurring in other phases of the cardiac cycle. Granted that mid cycle or late cycle ectopics initiate repetitive arrhythmia and are to be treated accordingly (as the authors suggest), yet the specificity of the early VPB in certain populations remains a valid predictor of enhanced risk whether as "guilt by association" with repetitive arrhythmia or simply as a low-energy discharge occurring during critical intermittent changes in cardiac vulnerability. A n additional concern is the methodologic problem of quantifying early VPB with presently available monitoring systems. In fact, we do not know the precise frequency of early cycle ectopy during a given 24-h period. A t present, monitoring "hardware" does not reliably quantitate these forms. When we integrated an early cycle VPB detector to our current semiautomated scanning systems (5), we noted a variability in VPB coupling intervals, a higher than anticipated early cycle frequency, and the consistent association of that grade to other repetitive forms ( G R A B O Y S TB, L E N S O N R, L O W N B: Unpublished obser-

vations). Thus the "absence" of R-on-T in some studies may indeed relate to methodologic detection problems. T H O M A S B. G R A B O Y S , M . D .

Harvard University School of Public Health; Boston, M A 02115 REFERENCES 1. S C H U L Z E R A J R , STRAUSS H W , P I T T B: Sudden death in the year fol-

lowing myocardial infarction. Relation to ventricular premature contractions in the late hospital phase and left ventricular ejection fraction. Am J Med 62:192-199, 1977 2. R U B E R M A N W, W E I N B L A T T E, G O L D B E R G J D , F R A N K CW, S H A P I R O S:

Ventricular premature beats and mortality after myocardial infarction. N Engl J Med 297:750-757, 1977 3. L O W N B, GRABOYS TB: Management of patients with malignant ventricular arrhythmias. Am J Cardiol 39:910-918, 1977

there were 12 deaths, whereas actuarial tables predicted 8.68 deaths—thus a 3 3 % increment of death with early extrasystoles. The three unpredicted deaths, if significant, might be explained by the association of R-on-T with heart disease, other forms of ventricular ectopy, and repetitive beating. We do not deny that R-on-T can be an event inciting tachycardia when there is heart disease or a predisposition to tachycardia. But there were 47 long-term survivors of R-on-T in this study, which indicates that R-on-T is most often benign. Ruberman and colleagues (2) have reported a 50% greater age-adjusted death rate for patients with R-on-T than that for patients with ectopic beats appearing only later in diastole. We think this too represents the association of R-on-T with heart disease, other forms of ventricular ectopy, and repetitive beating. In the same study the increment of death rate seen with multiform ectopic beats was 9 2 % and the increment seen with runs of ectopic beats, 129%. There were 39 deaths in coronary heart disease patients with ventricular ectopic beats; only nine of these patients had R-on-T. There were 60 coronary patients with R-on-T who did not die. Dr. Graboys emphasizes several points that prompted us to review R-on-T. R-on-T is associated with other forms of ectopy, and it becomes difficult to decide whether R-on-T has independent clinical significance or is "guilty by association.*' In fact, many studies have combined data for R-on-T with that for repetitive beating. Ruberman and associates (3) in the paper referred to by Dr. Graboys point out, "If no effort had been expended in this study on the detection of early ventricular premature beats, the number of patients considered to be at high risk by virtue of exhibiting any complex form would have been hardly different—454 rather than 462 patients. Only eight of the 83 patients with early ventricular premature beats had this as their sole complex feature." In Dr. Graboys experience (4) six of seven treated patients who died suddenly had repetitive beating; R-on-T was not described. The main purpose of our discussion was to emphasize that R-on-T can occur in the absence of repetitive beating, in which case it may not be guilty of anything. We too have been concerned about the methodologic problems that have not allowed precise detection or quantification of R-on-T (except when programmed in the electrophysiology laboratory). Dr. Graboys correctly points out that R-on-T may have often been missed. But the difficulty in noticing R-on-T introduces another sort of bias: It is possible that R-on-T is more likely to be noticed in the setting of malignant arrhythmia; attention to R-on-T would be less when the clinical setting is benign. We wonder whether the increased importance of R-on-T in the setting of exercise observed by Dr. Graboys, D e Silva, and Lown (5) could reflect the fact that R-on-T is a more likely timing of ventricular ectopy during exercise, because as heart rate increases the proportion of the cardiac cycle devoted to the QT interval increases. We await data on the prevalence of R-onT during exercise and its association with tachycardia, which are not discussed in the abstract to which Dr. Graboys refers (5). Thus R-on-T is often seen in the setting of severe heart disease and malignant ventricular ectopy, as first emphasized by Smirk and Palmer (6). But we do not interpret these data to mean that R-on-T is an independent risk factor in terms of cardiac mortality. T O B Y R. E N G E L , M . D . , F . A . C . P .

4. G R A B O Y S TB, D E S I L V A R D , L O W N B: Ambulatory monitoring and ex-

ercise stress testing in the management of patients with malignant ventricular arrhythmia (abstract). Am J Cardiol 41:400, 1978

Medical College of Pennsylvania; Philadelphia, P A 19129

5. A R M I N G T O N R D , G R A B O Y S TB, L O W N B, L E N S O N R: Semiautomated

data reduction of ventricular ectopic activity: methodology and clinical application. Association for the Advancement of Medical Instrumentation Meetings, Washington, D.C., 1978

In comment: Dr. Herschberg is correct in his percentage analysis, but the numbers of patients reported were small. Rodstein, Wolloch, and Gubner (1) have reported that among 59 persons in an insured population with early ventricular extrasystoles 1 3 8

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REFERENCES 1. R O D S T E I N M, W O L L O C H L, G U B N E R RS: Mortality study of the signifi-

cance of extrasystoles in an insured population. Circulation 1971

44:617-625,

2. R U B E R M A N W, W E I N B L A T T E, F R A N K CW, G O L D B E R G J D , SHAPIRO S,

F E L D M A N CL: Ventricular premature beats and mortality of men with coronary heart disease. Circulation 52(suppl 3):III-199-III-201, 1975 3. R U B E R M A N W, W E I N B L A T T E, G O L D B E R G J D , F R A N K CW, S H A P I R O S:

Ventricular premature beats and mortality after myocardial infarction. N

Engl J Med 297:750-757, 1977 4. LOWN B, GRABOYS TB: Management of patients with malignant ventricular arrhythmias. Am J Cardiol 39:910-918, 1977 5. GRABOYS TB, D E S I L V A RD, L O W N B: Ambulatory monitoring and ex-

ercise stress testing in the management of patients with malignant ventricular arrhythmia (abstract). Am J Cardiol 41:400, 1978 6. SMIRK FH, PALMER DG: A myocardial syndrome: with particular reference to the occurrence of sudden death and of premature systoles interrupting antecedent T waves. Am J Cardiol 6:620-629, 1960

Small-Cell Carcinoma of the Lung

To THE EDITOR: The reports of Weiss (1), Livingston and coauthors (2), and Johnson, Brereton, and Kent (3) clearly indicate an improved prognosis and survival for patients with small-cell carcinoma of the lung. Our group at the University of Chicago has treated patients with small-cell carcinoma using a previously described combined modality program of radiation therapy and cyclophosphamide, doxorubicin and methotrexate with rescue (4). The results of this treatment program in 19 patients with clinically and pathologically staged "limited disease," stage IIIMO (disease confined to the lungs and mediastinum) and state IIISCN+ (disease confined to the ipsilateral hemithorax and supraclavicular lymph nodes), are shown in Figure 1. The 2-year survival for patients with stage IIIMO small-cell carcinoma is 43%; this contrasts with the median survival for patients with stage IIIscN+ small-cell carcinoma, which is only 14 months. Eight of 19 patients in our series have had relapses, four within the central nervous system (brain, three; spinal cord, one) and four within the chest. Our results indicate that the involvement of supraclavicular lymph nodes is a poor prognostic sign in patients with smallcell carcinoma. In contrast, a fraction of patients with stage IIIMO small-cell carcinoma may have prolonged disease control and survival. Although prophylactic CNS irradiation has decreased the prevalence and morbidity of CNS relapse, it has not improved the overall survival of patients with small-cell carcinoma (5). Clearly our results and those of Livingston and associates (2) show that more aggressive therapy needs to be employed to attain better local tumor control if a greater proportion of stage IIIMO cases are to be salvaged. JACOB D . B I T R A N , M.D., F.A.C.P. T H O M A S D E M E E S T E R , M.D., F.A.C.S. R I C H A R D K. D E S S E R , M . D . H A R V E Y M. G O L O M B , M . D .

Michael Reese Hospital and Medical Center; Chicago, IL 60616

Figure 1 . Survival curve f o r patients with small-cell carcinoma stages lll M 0 and MISCN+- There is a statistically significant difference in survival.

88:532-537, 1978) I wish to add these practical clinical points. 1. Although nitrogen mustard is probably the most effective of the antineoplastic agents used to sclerose the pleura, the systemic toxicity of this therapy is unpredictable. Studies using the agent intrapleurally have not reported systematic evaluations of marrow toxicity, but all agree that some of the drug is absorbed. Although myelotoxicity is less with intrapleural therapy than with intravenous use, it is a potential complication (1, 2). In patients with neutropenia or in patients receiving simultaneous myelotoxic chemotherapy, alternative intrapleural therapy is indicated. 2. The statement that resolution of malignant effusions rarely occurs with chemotherapy may no longer be true for patients with breast cancer treated with combinations that include doxorubicin (3). 3. Bleomycin should be added to the list of agents that are effective when administered intrapleurally for the control of malignant effusions (4). R I C H A R D S. S T E I N , M . D .

Vanderbilt University; Nashville, TN 37232 REFERENCES 1. WEISBERGER AS, L E V I N E B, STORAASLI JP: Use of nitrogen mustard in

REFERENCES

1. WEISS RB: Small-cell carcinoma of the lung: therapeutic management. Ann Intern Med 88:522-531, 1978 2. LIVINGSTON RB, MOORE TN, HEILBRUN L, BOTTOMLEY R, L E H A N E

D, RIVKIN SE, THIGPEN T: Small-cell carcinoma of the lung: combined chemotherapy and radiation. A Southwest Oncology Group study. Ann Intern Med 88:194-199, 1978 3. JOHNSON RE, BRERETON H D , K E N T CH: Small-cell carcinoma of the

lung: attempt to remedy causes of past therapeutic failure. Lancet 2:289291, 1976 4. COOKSEY J, BITRAN JD, DESSER RK, D E M E E S T E R T, COLMAN M,

the treatment of serous effusions of neoplastic origin. JAMA 159:17041707, 1955 2. FRACCHIA AA, K N A P P E R WH, C A R E Y JT, F A R R O W JH: Intrapleural

chemotherapy for effusion from metastatic breast carcinoma. Cancer 26:626-629, 1970 3. JONES SE, D U R I E BG, SALMON SE: Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36:90-97, 1975 4. PALADINE W, C U N N I N G H A M TJ, SPONZO R, D O N A VAN

M, OLSON K,

HORTON J: Intracavitary bleomycin in the management of malignant effusions. Cancer 38:1903-1908, 1976

GRIEM M, GOLOMB HM: Response of small cell carcinoma of the lung to radiotherapy and cyclophosphamide, adriamycin, and methotrexate with rescue. Proc Am Assoc Cancer Res 17:5, 1977 5. TULLOH ME, M A U R E R LH, FORCIER RJ: For cancer and leukemia

group B. A randomized trail of prophylactic whole brain irradiation in small cell carcinoma of the lung. Proc Am Soc Clin Oncol 18:268, 1977

Malignant Pleural Effusion

To THE EDITOR: To the excellent review of malignant pleural effusion by Leff, Hopewell, and Costello (Ann Intern Med

Empyema and Rheumatoid Pleuropulmonary Disease

To THE EDITOR: In 1971 we reported our observations on the unusual and not previously emphasized association of empyema and rheumatoid pleuropulmonary disease (Ann Intern Med 74:665-671, 1971). In that article we noted that of 10 persons with rheumatoid pleural effusions seen during a 5-year period, five had developed empyema and one had died of this complication. In contrast, no patient with neoplastic effusion or hydrothorax seen during this period had empyema. We speculated Letters and Corrections

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that causative factors which may have acted singly or in combination in the development of empyema included steroid therapy, decreased resistance to infection, chronic bronchopulmonary infections, the pre-existence of rheumatoid pleural effusion, altered biochemical characteristics of the fluid, and, in particular, the formation of bronchopleural fistulas through necrotic subpleural rheumatoid nodules. We have followed up the nine survivors of that series for another 8 years. Since the original report was submitted in 1970, three fresh episodes of empyema have occurred in two of these nine patients. One of the original group of five who had empyema (Case 3) spontaneously developed an acute empyema on the opposite side 7 years later and died a short time thereafter of sepsis and purulent pericarditis. He had had small pleural effusions and multiple pulmonary nodules bilaterally for several years and had not received corticosteroids. The other two episodes occurred spontaneously and sequentially on opposite sides, 2 years apart, in a man who had had rheumatoid pleural effusions for at least 15 years; the second empyema was fatal. He had no radiologically visible pulmonary nodules but had received prednisone therapy, 7.5 mg daily, for several years. The other seven patients have remained free of empyema since 1970, although two have had persistent pleural effusions. The association of empyema and rheumatoid pleuropulmonary disease appeared striking when we wrote our report in 1970; the subsequent course of our patients has only reinforced that impression. Eight separate episodes of empyema in six of 10 patients with rheumatoid pleural effusions, with three deaths directly attributable to empyema, is impressive beyond coincidence. Our subsequent experience has reinforced our original conclusions: "Empyema . . . should be recognized as a fairly frequent complication of rheumatoid [pleuropulmonary] disease that occurs for reasons inherent in the disease process and its therapy. The diagnosis should be particularly suspected in patients with rheumatoid arthritis who are debilitated, hypoproteinemic, and anemic; who are receiving steroid therapy; and who develop fever and pleural effusion. . . . " F R E D E R I C K L. J O N E S , J R . , M . D . , F . A . C . P . R A N D O L P H C. B L O D G E T T , J R . , M . D . ,

F.A.C.P.

Geisinger Medical Center; Danville, P A 17821

Diagnosis of Pulmonary Embolism T o T H E EDITOR: As the developer of radioalbumin macroaggregates for lung perfusion scanning and radioaerosol inhalation procedures for the assessment of airway patency and regional ventilatory function, plus having had extensive experience with these procedures and with radioactive gases in patients suspected of having pulmonary embolism, I must disagree with the main thrust of Dr. Eugene Robin's paper in the December 1977 issue (Ann Intern Med 87:775-781, 1977). His analysis is commendable for recognizing the high incidence of misdiagnoses of pulmonary embolism in the past, especially in previously healthy persons, many of whom may well have received prolonged and unnecessary anticoagulation therapy. Dr. Robin is also correct in stating that blood Po 2 values are useless in the diagnosis of pulmonary embolism. Likewise, experts in nuclear medicine agree that a normal multiple-view perfusion examination rules out pulmonary embolism for all practical purposes. However, they disagree with him completely regarding the lack of value of ventilation procedures and the indications for pulmonary angiography (1-3). At present, when there is a definite clinical suspicion of pulmonary embolism, perfusion imaging is done with a gamma camera. With normal findings the diagnosis is excluded. If ischemic regions are found, ventilation studies with radioaerosols or gases are done to distinguish arterial from airway obstruction. In the 5% to 10% of patients in whom the diagnosis still remains in doubt (those with infarction or pneumonia), an angiogram is taken using the perfusion data to ascertain the type of angiography needed. 140

July 1978 • Annals of Internal Medicine • Volume 89 • Number 1

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In contrast, Dr. Robin's evaluation of nuclear and angiographic procedures is biased and incomplete because it is based on the literature of the mid-1960s and late 1960s when perfusion examinations were done with rectilinear scanners and in only one or two projections and no ventilation procedures were being done. His belief that pulmonary embolism is nearly always associated with acute and persisting bronchospasm is almost completely wrong, because pulmonary-embolism-induced bronchospasm is a transitory phenomenon lasting for a few hours at the most (4). Therefore, by the time patients suspected of having pulmonary embolism are referred for a perfusion-ventilation examination, bronchospasm has already disappeared. Further, ventilation examinations are highly reliable in previously healthy patients suspected of having pulmonary embolism because these patients are usually free of complicating cardiopulmonary disease. Hence, in such persons, ventilation procedures with either technetium-99m-labeled aerosols or xenon133 or krypton-81m gases, or both, can distinguish airway from arterial obstruction with a high degree of efficiency (greater than 90%) (5). Dr. Robin's opinion that most patients suspected of having pulmonary embolism should be diagnosed angiographically is contrary to that of our country's leading radiologists and nuclear physicians (1, 2), who believe that angiography is needed in less than 10% of these patients. Further, the poor correlation between scan and angiographic findings reported by Dr. Robin from his own institution is unbelievable, in view of the high quality of nuclear medicine and radiology at Stanford, particularly the recent krypton ventilation imaging studies done during the past 2 years. The medical profession has been misinformed by Dr. Robin's article and needs to be re-educated regarding the true value, optimal applications, and indications for modern lung-imaging procedures and pulmonary angiography in patients suspected of having pulmonary embolism. G E O R G E V. T A P L I N , M . D .

UCLA School of Medicine; Los Angeles, CA 90024 REFERENCES

1. D E NARDO GL, DE NARDO SH: The lung, in Clinical Scintillation Imaging, 2nd ed., edited by FREEMAN LM, JOHNSON PM. New York, Grune and Stratton, 1975, pp. 461-536 2. MOSER KM: Pulmonary embolism. Am Rev Respir Dis 115:829-852, 1977 3. TAPLIN GV, CHOPRA SK: Inhalation lung imaging with radioactive aerosols and gases, in Progress in Nuclear Medicine, edited by GUTER M. Basel, S. Karger, in press, 1978 4. ISAWA T, TAPLIN GV, BEAZELL J, CRILEY JM: Experimental pulmo-

nary artery occlusion—acute and chronic effects on relative ventilation and perfusion. Radiology 102:101-109, 1972 5. TAPLIN GV, TASHKIN DP, CHOPRA SK, ANSELMI OE, ELAM D, CALVARESE B, COULSON A, DETELS R, ROKAW SN: Early detection of

chronic obstructive pulmonary disease using radionuclide lung-imaging procedures. Chest 71:567-575, 1977

Miliary Tuberculosis and Respiratory Distress Syndrome T o T H E EDITOR: In the reported cases of miliary tuberculosis associated with adult respiratory distress syndrome, histologic findings have not been discussed (1). We report here an additional case with the emphasis on the histopathologic features. Its possible pathogenesis is discussed in relation to the experimental work of one of the authors. A 64-year-old nonsmoking, alcoholic, black woman with chemical diabetes was admitted with a 2-month history of malaise followed by 1 week of fever and cough that produced a small amount of white sputum. She was febrile, tachycardic, and tachypneic. Diffuse pulmonary rales and a 25-cm liver were noted. Arterial blood gas on room air was pH 7.46, Pco2 24.5 mmHg, Po2 62.9 mmHg. Oxygen saturation was 93.8%. Chest roentgenogram showed bilateral diffuse miliary nodules. Isoniazid, ethambutal, and rifampin were instituted for suspected miliary tuberculosis. Progressive ventilatory insufficiency that required intubation and mechanical ventilation ensued. Classic clinical and radiologic features of adult respiratory distress

syndrome evolved (widened alveolar-arterial gradient, decreased total static compliance, low pulmonary wedge pressure, bronchoscopically patent central airways, fluffy bilateral pulmonary-edema radiographically with decreased lung volume). Treatment included 10-cm positive end-expiratory pressure with FIo2 0.65. Shock with Klebsiella sepsis was documented while she was in the intensive care unit. After 10 days of therapy her pulmonary status improved dramatically, but she died during a massive gastrointestinal hemorrhage. At autopsy, the apices of both lungs contained stellate 2-cm scars and were diffusely dark red and firm with scattered 1- to 2-mm yellow nodules throughout all lobes. All sections of lung showed severe interstitial and perivascular edema with dilated lymphatics and an interstitial infiltrate of neurocytes, lymphocytes, and plasma cells. In some areas, alveolar edema was also present. Thick, brightly acidophilic hyaline membranes lined many alveoli and alveolar ducts, and some clusters of alveoli were lined by large cuboidal epithelial cells with large nuclei, prominent nucleoli, andfinelyvacuolated acidophilic cytoplasm. In the right middle lobe were ill-defined patches of interstitial thickening, and in these areas the alveoli were lined by columnar, sometimes ciliated epithelium. A careful search of many sections revealed no small-vessel thrombi. Granulomas, some with central necrosis and positive acid-fast stain, were present in the lungs, myocardium, liver, spleen, and bone marrow. With the electron microscope most alveoli were lined by large cuboidal cells with very irregular surface microvilli (Figure 1). The nuclei were very large and the nucleoli prominent. The hyaloplasm contained abundant neutral lipid, and, in some, lammelar bodies typical of granular pneumocytes were found. Capillary thrombi were not seen. The clinical features of miliary tuberculosis are nonspecific. The importance of the chest roentgenogram in the early diagnosis of miliary tuberculosis has been strongly emphasized by Berger and Samortin (2). Acute respiratory distress syndrome is a distinct syndrome with characteristic clinical, radiologic, and pathologic findings that have been discussed extensively in the medical literature. The early histologic picture is discussed above. The later phase is often characterized by interstitial fibrosis (3). The precise cellular base of this type of lung injury is unclear. Damage to vascular endothelium is currently thought to be the most likely site of injury, but the few electron microscopic studies that have been reported have revealed injury or regeneration of alveolar epithelium without structural injury to capillary endothelium (4). Our patient's lungs showed epithelial regeneration at various stages of evolution, which suggests a series of individual insults to epithelium. The sequence of epithelial injury and repair with consequent alterations in lung compliance has been reproduced experimentally in dogs by the use of N-nitroso-N-methyl-urethane (5). These findings in experimental injury as well as our observation in this patient with miliary tuberculosis and our experience with patients in various clinical settings suggest that epithelial injury

Figure 1 . An injured alveolar epithelial cell. The cell is elongated and contains many surface microvilli. The cystoplasm is vacuolated and contains four lamellar inclusions, suggesting that it is a granular pneumocyte. (Electronmicrograph, original magnification, x 8500.)

is a cornerstone of the acute respiratory distress syndrome. The cause for epithelial injury in our patient with miliary tuberculosis remains to be defined. A direct toxic effect of mycobacteria is a possibility. J O H N T. H S U , M . D . JOSEPH P. P A D U L A , M . D . S T E P H E N F. R Y A N , M . D .

St. Luke's Hospital Center; New York, N Y 10025 REFERENCES

1. HUSEBY JS, HUDSON LD: Miliary tuberculosis and adult respiratory distress syndrome. Ann Intern Med 85:609-611, 1976 2. BERGER HW, SAMORTIN TG: Miliary tuberculosis: diagnostic methods with emphasis on the chest roentgenogram. Chest 58:586-589, 1970 3. KATZENSTEIN AA, BLOOR CM, LIEBOW AA: Diffuse alveolar dam-

age—the role of oxygen, shock and related factors. Am J Pathol 85:210228, 1976 4. NASH G, FOLEY FD, LANCLINAIS PC: Pulmonary interstitial edema and

hyaline membrane in adult burn patients: electron microscopic observations. Hum Pathol 5:149-160, 1974 5. RYAN SF: Experimentalfibrosingalveolitis. Am RevRespirDis 105:776791, 1972

G a m m a Globulin and Non-A Type Hepatitis

T o T H E EDITOR: In the March issue the V A Cooperative Study Group elegantly showed that hepatitis B immune globulin (HBIG) is superior to immune serum globulin (ISG) in preventing hepatitis type B among persons exposed by needle stick to HBsAG (1). However, they incorrectly stated that it was impossible to determine whether ISG has any efficacy in the prevention of hepatitis type B because a non-gamma globulin placebo has not been used in any clinical trial. The first gamma globulin trial in which HBsAg testing was available was a randomized, double-blind study of 107 803 subjects in which the efficacy of commercial ISG with a modest anti-HBs titer was compared to an albumin placebo (2). That study suggested that ISG had a protective effect against endemic hepatitis type B (p=0.02), and the data became more convincing when serum specimens were subsequently tested by serum radioimmune assay (p

False-positive serologic tests for echinococcal infection.

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