368
CORRESPONDENCE
In summary, by the end of 1966 we knew that (without rifampin) one year of therapy with any two drug regimens was inadequate, and secondly, that an intensification of the early phase of chemotherapy would probably enhance any regimen. However, the study of intermittent ethambutol and INH by the Madras Center referred to by Dr. Eidus also limited the period of total therapy to only one year and initial three-drug therapy to only two weeks. As expected, only 88 per cent of the patients were bacteriologically negative at one year, with 16 per cent relapsing during the subsequent year, an over-all failure rate of 38 per cent. Moreover, the regimen utilized 45 mg per kg rather than 50 mg per kg (a possibly significant difference, since the effect of EMB seems strongly related to the time of exposurean observation also supported by the Center's finding that EMB, 90 mg per kg once a week was more effective than 45 mg twice a week). In essence, once again, a nonsterilizing regimen given for an inadequate period of time and therefore expected to fail, did fail. The degree of failure did suggest that EMB was not as effective as streptomycin at the one-year mark, but data are now available confirming its effectiveness if used as recommended. The ATS Committee was aware of these significant limitations of intermittent treatment (both INH and streptomycin and INH and EMB) and felt strongly that only regimens proved over time to be equally effective as proved daily regimens (initial success rate of close to 100 per cent with subsequent relapses over two years of less than I per cent)4 should be recommended for general use. While it is possible that purely intermittent regimens extended to 18 or 24 months could meet the desired standards of success, the Committee felt it should base its recommendations on reported data and not supposition. Finally, the Committee did not consider the intermittent use of these drugs to be "merely completing and for maintaining" the therapeutic achievement of initial daily treatment since previous studies had demonstrated that discontinuance of daily therapy of less than six months' duration could lead to relapse rates as high as 62 per cent.l Rather, the intermittent use of these drugs is a rational and necessary continuation of a two-phase therapeutic approach, in which the partially sterilizing impact of three drugs (a Ia Cannetti and co-workers) was combined with the proved therapeutic effectiveness of an 18- to 24-month total treatment period. While Dr. Eidus is perhaps technically correct in his suggested modification of the title of the Statement, in reality, it is not necessary, since the Statement reflects what we considered to be the only acceptable use of intermittent chemotherapy at this point in time. 4 Johnston, R. F., and Wildrick, K. H.: Am Rev Respir Dis, 1974, 109, 636.
Fortunately, this entire issue may become moot if the exciting developments in short-term therapy using the sterilizing potential of rifa npin become confirmed by other centers. JOHN A. SBARBARO, M.D. Chairman, Scientific Assembly on Tuberculosis
TUBERCULIN SKIN TEST
To the Editor: The American Thoracic Society, Committee on Diagnostic Testing in its statement on the Tuberculin Skin Test (Am Rev Respir Dis, 104, 769-775) interprets a reaction of 5 mm through 9 mm of induration to a 5 TU of tuberculin, PPD administered by the intracutaneous Mantoux procedure as a "doubtful reaction." Reactions of induration in this size range are believed to be due to infection with either Mycobacterium tuberculosis or to infection with nontuberculous mycobacteria and for this reason are classed as "doubtful." This word has been perpetuated for many years in a number of publications. Reactions of 5 mm through 9 mm are not really doubtful, but ambiguous or inconclusive reactions. The term "inconclusive" appears to be more satisfactory and suggests that further testing is required to reach a conclusion. I would propose the word "doubtful" be dropped and the word "inconclusive" be substituted in referring to the interpretation of reaction sizes of induration from 5 mm through 9 mm. Perhaps even better words may be suggested by the readers of the Review. SoTIROS D. CHAPARAS, PH.D.
Director, Mycobacterial and Fungal Antigens Branch Bureau of Biologics, FDA Dr. Chaparas has made an interesting suggestion. Shall the REVIEW begin using "inconclusive" instead of "doubtful"? What do the readers think? EDITOR's COMMENT:
BILATERAL RECURRENT PNEUMOTHORACES
To the Editor: The article by Peiken, Lamberta, and Seriff in the October 1974 issue of the REVIEW has aroused my interest. Bilateral recurrent pneumothoraces is described as a rare complication of miliary tuberculosis, and I agree entirely, never having come across such a case. However, further on it is stated that pneumothorax is extremely rare in acute miliary tuberculosis of the lungs, only seven cases being found in a review of world literature. This surprised me as this has not been my experience.
CORRESPONDENCE
I have always warned that a silent spontaneous pneumothorax (sometimes becoming a tension pneumothorax) is something to keep in mind as a complication of miliary tuberculosis of the lungs. There have been two such cases in this hospital during the current year, both in small children, and the diagnosis of miliary tuberculosis was beyond doubt. It never occurred to me to report them. If this complication occurs within the first six weeks of starting treatment I advise active measures to re-expand the lung. When this has not been done, an empyema has ensued that is otherwise avoided. After the first six weeks of treatment the risk of
369
empyema recedes, and the lung usually comes up on its own, but with its progress under frequent radiographic observation with an eye on the costophrenic angle. Even so, I prefer to re-expand the lung as quickly as possible in all cases at any time during treatment. D.J.M. JENKIN
Medical Superintendent Dr. A.]. Stals Hospital P. 0. Sta-lsana Westlake .... Cape South Africa 7945
CORRESPONDENCE
In summary, by the end of 1966 we knew that (without rifampin) one year of therapy with any two drug regimens was inadequate, and secondly, that an intensification of the early phase of chemotherapy would probably enhance any regimen. However, the study of intermittent ethambutol and INH by the Madras Center referred to by Dr. Eidus also limited the period of total therapy to only one year and initial three-drug therapy to only two weeks. As expected, only 88 per cent of the patients were bacteriologically negative at one year, with 16 per cent relapsing during the subsequent year, an over-all failure rate of 38 per cent. Moreover, the regimen utilized 45 mg per kg rather than 50 mg per kg (a possibly significant difference, since the effect of EMB seems strongly related to the time of exposurean observation also supported by the Center's finding that EMB, 90 mg per kg once a week was more effective than 45 mg twice a week). In essence, once again, a nonsterilizing regimen given for an inadequate period of time and therefore expected to fail, did fail. The degree of failure did suggest that EMB was not as effective as streptomycin at the one-year mark, but data are now available confirming its effectiveness if used as recommended. The ATS Committee was aware of these significant limitations of intermittent treatment (both INH and streptomycin and INH and EMB) and felt strongly that only regimens proved over time to be equally effective as proved daily regimens (initial success rate of close to 100 per cent with subsequent relapses over two years of less than I per cent)4 should be recommended for general use. While it is possible that purely intermittent regimens extended to 18 or 24 months could meet the desired standards of success, the Committee felt it should base its recommendations on reported data and not supposition. Finally, the Committee did not consider the intermittent use of these drugs to be "merely completing and for maintaining" the therapeutic achievement of initial daily treatment since previous studies had demonstrated that discontinuance of daily therapy of less than six months' duration could lead to relapse rates as high as 62 per cent.l Rather, the intermittent use of these drugs is a rational and necessary continuation of a two-phase therapeutic approach, in which the partially sterilizing impact of three drugs (a Ia Cannetti and co-workers) was combined with the proved therapeutic effectiveness of an 18- to 24-month total treatment period. While Dr. Eidus is perhaps technically correct in his suggested modification of the title of the Statement, in reality, it is not necessary, since the Statement reflects what we considered to be the only acceptable use of intermittent chemotherapy at this point in time. 4 Johnston, R. F., and Wildrick, K. H.: Am Rev Respir Dis, 1974, 109, 636.
Fortunately, this entire issue may become moot if the exciting developments in short-term therapy using the sterilizing potential of rifa npin become confirmed by other centers. JOHN A. SBARBARO, M.D. Chairman, Scientific Assembly on Tuberculosis
TUBERCULIN SKIN TEST
To the Editor: The American Thoracic Society, Committee on Diagnostic Testing in its statement on the Tuberculin Skin Test (Am Rev Respir Dis, 104, 769-775) interprets a reaction of 5 mm through 9 mm of induration to a 5 TU of tuberculin, PPD administered by the intracutaneous Mantoux procedure as a "doubtful reaction." Reactions of induration in this size range are believed to be due to infection with either Mycobacterium tuberculosis or to infection with nontuberculous mycobacteria and for this reason are classed as "doubtful." This word has been perpetuated for many years in a number of publications. Reactions of 5 mm through 9 mm are not really doubtful, but ambiguous or inconclusive reactions. The term "inconclusive" appears to be more satisfactory and suggests that further testing is required to reach a conclusion. I would propose the word "doubtful" be dropped and the word "inconclusive" be substituted in referring to the interpretation of reaction sizes of induration from 5 mm through 9 mm. Perhaps even better words may be suggested by the readers of the Review. SoTIROS D. CHAPARAS, PH.D.
Director, Mycobacterial and Fungal Antigens Branch Bureau of Biologics, FDA Dr. Chaparas has made an interesting suggestion. Shall the REVIEW begin using "inconclusive" instead of "doubtful"? What do the readers think? EDITOR's COMMENT:
BILATERAL RECURRENT PNEUMOTHORACES
To the Editor: The article by Peiken, Lamberta, and Seriff in the October 1974 issue of the REVIEW has aroused my interest. Bilateral recurrent pneumothoraces is described as a rare complication of miliary tuberculosis, and I agree entirely, never having come across such a case. However, further on it is stated that pneumothorax is extremely rare in acute miliary tuberculosis of the lungs, only seven cases being found in a review of world literature. This surprised me as this has not been my experience.
CORRESPONDENCE
I have always warned that a silent spontaneous pneumothorax (sometimes becoming a tension pneumothorax) is something to keep in mind as a complication of miliary tuberculosis of the lungs. There have been two such cases in this hospital during the current year, both in small children, and the diagnosis of miliary tuberculosis was beyond doubt. It never occurred to me to report them. If this complication occurs within the first six weeks of starting treatment I advise active measures to re-expand the lung. When this has not been done, an empyema has ensued that is otherwise avoided. After the first six weeks of treatment the risk of
369
empyema recedes, and the lung usually comes up on its own, but with its progress under frequent radiographic observation with an eye on the costophrenic angle. Even so, I prefer to re-expand the lung as quickly as possible in all cases at any time during treatment. D.J.M. JENKIN
Medical Superintendent Dr. A.]. Stals Hospital P. 0. Sta-lsana Westlake .... Cape South Africa 7945
