Short-course Chemotherapy for Pleural Tuberculosis

Short-course Chemotherapy for Pleural Tuberculosis· Nine Years' experience in Routine Treatment Service Asim K. Dutt, M.D., F.C.C.P.;t Dory Moers, R.N.; and WiUiam W Stead, M.D., F.C.C.P.

Short-course chemotherapy (See) for pulmonary tuberculosis for nine months with isoniazid (INH) and rifampin (RIF) is weD established. However, there is still no report on results of such therapy in pleural disease. From January 1976 through December 1984, we treated 201 patients (average age 61.6 years) for pleural tuberculolis, 143 with

see for nine months of mainly INH and RIF and 58 with conventional therapy (CT) for 18 to 24 months. FindinllS indicated that see with INH and RIF was as effective as in pulmonary tuberculosis. The results were equivalent or even better than CT given for prolonged periods.

Short-course chemotherapy (SCC) with isoniazid (INH) and rifampin (RIF) for nine months is now well established for newly diagnosed tuberculosis. 1-3 The therapy is recommended for pulmonary tuberculosis by the American Thoracic Society (ATS) and Centers for Disease Control (C~C), and the recent Concensus Statement of therapy for tuberculosis by the American College of Chest Physicians.P Both statements include use of SCC fur other forms of tuberculosis, albeit not based on large experiences. Even though SCC is very effective in treatment of pulmonary tuberculosis and may be effective in various forms of extrapulmonary tuberculosis.?" there is still no report of results of such therapy in pleural disease. We have, therefore, analyzed our experience with see in pleural disease for the past nine years (1976 through 1984). .

side effects and careful observations fur toxicity and compliance during therapy are described previously." Since mid-I918, this protocol of therapy has been used fur all forms of tubercqlosis including pleural disease.

PATIENTS AND METHODS

From January 1976 through December 1984, 201 patients with pleural disease were treated at the chest clinics of the Arkansas Department of Health. Their age, sex, and race are shown in 'Iable 1. The mean age was 61.!> years with a range of 18to 98 years excluding Bvechildren under 15 years of age. In contrast with earlier reports, 60 percent of the patients were over the age of 60. The mean age of the CT group was 59.3 years (range 18to 94)and 62.6 years (range 17 to 98) fur SCC group. .

Since January 1976, the standard regimen of the Tuberculosis Program of the Arkansas Department of Health fur patients with pulmonary tuberculosis has been SCC with INH and RIF fur nine months. The patients receive 'the greater part of treatment as outpatients. The details of the program have been given in an ear~er communication.! Protocol of Therapy

Since January 1976, a protocol of therapy fur pulmonary tuberculosis consisted onN H 300 mg and RIF 600 mg daily furone month followed by INH 900 mg and RIF 600 mg twice weekly fOr another eight months. Details of bacteriologic monitoring, baseline laboratory studies, and repetition only on development of symptoms of *From the Arkansas Department of Health and John L. McClellan Veterans Medical Center, Utile Rock, AR. tPresently Chief of Medicine, Alvin C. York VA Medical Center, Murfreesboro, TN; Professor and Vice Chairman, Department of Medicine, Meharry Medical College, Nashville. Manuscript received October 14; revision accepted January 2. Reprint requests: Mr: lloyd Adams, TB Program Administrator, 4815 West Markham, UttLe Rock 72201

112

'&eatment Regimens for Pleural Disease

From 1976 to 1984, 135 patients with pleural tuberculosis were treated with SCC. Eight patients al~ received initially four drugs (streptomycin (SM), INH, RIF, and pyrazinamide [PZAJ), t'oIlowed by INH and RIF fur a total of nine months as they were suspected of harboring INH-resistant organisms. Thus, 143 patients ~ived SCC. A total of nine months of therapy was given, which in ten patients required somewhat more calendar time to make fur time lost due to drug intolerance, and other problems. During this period, 58 patients were treated fur 18 to 24 months with conventional therapy <,cr). Therapy was self-administered except that in a few patients when noncompliance was suspected, the ingestion of drugs was directly supervised by a public health nurse or other responsible person. .

up

Patient Profile

RESULfS OF THERAPY

Extent of Disease

Ofl43 patients receiving SCC, the disease appeared to be confined to the pleura in 52 while the remaining 91 had pleuropulmonary involvement. Sputum cultures were positive for Mycobacterium tuberculosis in 66 (73 percent) of the latter patients. Among 58 CT patients, 34 patients had only pleural disease and 19 patients had pleuropulmonary involvement, of whom 15patients (79 percent) had positive bacteriology in the sputum. Short-iXlU188 Chemolherapy

lor Pleural Tuberculosis (Dult. Moers. Stead)

Table I-Age, Sex, and Race Distribution Among 201Patients with Pleural Thberculoai3 Other

Black

White Age Group

M

F

M

F

:SIS

2 6 19 34 13 74 (36.8%)

1 8 8 18 10 45 (22.4%)

2 12 13 21 9 57 (28.4%)

6 3 10 5 24 (11.9%)

1~9

40-59 60-79 80-99 Total

Other Associated Sites of Disease

Among the see group, the pleural involvement was associated with tuberculosis at other extrapulmonary sites in 16 instances as follows: pericardial, five; disseminated (miliary), three; lymphadenitis, two; genitourinary, two; vertebral, one; peritoneal, one; cecum, one; and laryngeal, one. The Cf group showed disease of the pericardium in three, peritoneum in two, lymph node in one, and disseminated (miliary) in one. Associated Medical Disorders

In 41 instances among see patients, pleural disease

was associated with medical disorders which are considered risk factors fur tuberculosis. Diabetes was

present in eight patients, four of whom were receiving insulin, three were treated with oral hypoglycemic agents, and one was controlled with diet only. Six patients were receiving long-term corticosteroid therapy for other medical indications. Two patients had undergone gastrectomy in the past. Malignancy was present in ten patients as follows. lung, three; colon, one; breast, one; thyroid, one; prostrate, two; biliary, Table 2-Mode cfDiagn0si8 in 201 Patients with Pleural Thberculosis* Therapy Group

Diagnosis Pos bacteriology and/or histology Pos culture Sputum Pleural fluid Pleural tissue Pos histology only Pleural tissue Lymph node Bone marrow Peritoneum Clinical: Pos PPD

Short Course Chemotherapy N: 143

Conventional Therapy M:58

114 (80%)

36 (62%)

89 (78%) 66 (74%)t 43 (48%)t 35 (39%)t

7 (78%)* 1 (11%)* 1 (10%)* 29 (20%)

*Pos, positive; Culture: M tuberculosis. tPercentage of positive cultures. *Percentage with positive histology.

one; and teratoma, one. The majority of these patients were receiving cytotoxic and/or corticosteroid therapy when pleural tuberculosis was diagnosed. Three patients had hematologic malignancy: leukemia, two and multiple myeloma, one. Thirteen patients were assessed to be excessive users of alcohol. These medical conditions were present in ten instances among CT group of patients as follows: diabetes, three; malignancy, three; gastrectomy, one; corticosteroid therapy, one; leukemia, one; and alcohol abuse, one. Mode of Diagnosis

Among 143 patients given see, the diagnosis was proven bacteriologically, histologically, or through both methods in 114 (80 percent) (Table2); culture was positive for M tuberculosis from pleura or sputum in 89 (78 percent) as shown in Table 2. The diagnosis was clinical in 29 (20 percent) based on positive tuberculin test, compatible pleural fluid studies, exclusion of other causes, and clinical response to antituberculosis treatment. Of 58 patients receiving cr, the diagnosis was confirmed bacteriologically, histologically, or both ways in 36 patients (62 percent), in 27 patients (75 percent) by culture as shown in Table 2. The diagnosis was clinical in 22 (38 percent) patients. Exclusion during Therapy

Twenty eight patients were excluded from the see Table 3-Tennination cf Therapy during 1mJtment in Number cfPatientI

Causes

9 (25%)

25 (22%)

23 (92%)* 1 (4%)* 1 (4%)*

22 (38%)

Total 5 (2.5%) 33 (16.4%) 43 (21.4%) 83 (41.3%) 37 (18.4%) 201 (100%)

1 (0.5%)

27 (75%) 15 (56%)t 20 (74%)t 12 (44%)t

F

M

Non TB death TB death Moved Refused therapy Drug side effects Therapy discontinued Treatment failure Total Completed therapy

Short Course Chemotherapy N: 143 11 5

2 1 8

Conventional Therapy N:58

5 2 1 2 2 2

1 28 115 (80.4%)

14 44 (75.9%)

CHEST I 90 I 1 I JULY. 1986

113

Table 4-Follow-up cf 115 CtJ1Je8 after Complmon cf scc Months Follow up

No. of Patients

Non TB Deaths

1-12 13-24 25-36 37-48 49-00 61-72

20 20 19 18 16 10

8 4 2 1 1

73-84 85-96

6 3

97-104 Total

Moved

Relapse

2 6

Remaining

10 10 17 17 15 10 6 3

3 115

1 9

16

2 90

group because of deviation from the prescribed protocol. Fourteen patients were excluded from the cr group as shown in Table 3. The therapy failed in one patient from the see group when the sputum failed to convert to negative bacteriology after seven months of therapy. Tuberculosis deaths occurred in five patients. In three, the death occurred within fuur weeks of initiation of therapy due to leukemia, cerebrovascular accident, and acute myocardial infarction. Another two patients died at two and three months with active disease. Hence, they were considered treatment failures. Thus, li5 patients of see group and 44 cr group completed full course of therapy. Follow-up of Patients

One hundred fifteen patients were followed-up fur a median period of 30 months (range 1 to 104 months) after completion of see (Thble4). During this period of observation, there has been no relapse. Among 44 patients who had completed full course cr, two have relapsed during follow-up fur a median period of7B months (range 4 to 103 months), one at six months, and another at 17 months when their sputum culture reverted to positive (Table 5).

Side Effects of Drugs

Among the see group, side effects of the drugs occurred in eight (5.6 percent) patients. However, the major toxicity of hepatitis occurred in only one patient attributed to RIF. The remaining seven side effects Table 5-Follow-up cf 44 CtJ1Je8 after Complmon cfConventional TMrtJp"

Months Follow up

No. of Patients

NonTB Deaths

Moved

Relapse

1-12 13-24 25-36 37-48 49-00 61-72

4

2

1

1 2

1 (6 mo) 1 (17 mo)

1

73-84 85-96

97-108 Total 114

2 5 16 11 3 44

1

2 1

1 6

Remaining

2

2 (4.5%)

4 15 11 3 34

were minor, such as rash and gastrointestinal intolerance. Among 58 C'I' patients, major side effects occurred in three patients: hepatitis due to INH in one, in another, the causative drug could not be ascertained, and visual disturbance due to ethambutol occurred in one. The therapy was discontinued in one patient due to recurrent rash and fever. OvERALL RESULTS

Thus, while treating 143 patients with pleural disease with see, 25 did not complete full course therapy due to various reasons. Among liB who completed therapy, there were three treatment failures during nine years of observation: bacteriologic failure in one and tuberculosis death in two. There was no late relapse. At the same time, among 58 patients treated with conventional therapy, 44 completed full course of treatment but relapse occurred in two of them after discontinuation of therapy. Tuberculosis death occurred in two. DISCUSSION

During the past nine years in the routine treatment service, see with INH and RIF has produced excellent results in the treatment of pleural tuberculosis. There have been only three failures during therapy among liB patients and no relapse after stopping treatment in our prospective observations. As in other furms of tuberculosis, the results of see in pleural tuberculosis is as effective as or even better than the results obtained with conventional long term therapy.10.ll Even though see is now the recommended therapy fur pulmonary tuberculosis, the duration of therapy is not widely accepted or applied in extrapulmonary tuberculosis. 1Physicians remain reluctant to use see in any furm of extrapulmonary disease due to lack of information on its effectiveness in these situations. However, recently, the therapy has been endorsed by the consensus statement of the American College of Chest Physicians based on the findings of very limited reports on this furm of therapy in extrapulmonary tuberculosis." Most of these were retrospective observations on limited numbers of patients and often with short follow-up.v" We have recently reported results of treatment of patients with extrapulmonary tuberculosis." There is no other available report on results of see fur pleural tuberculosis to our best knowledge, and hence, we are unable to compare our results. However, it is difficult to imagine that results can be much superior with any regimen than what has been achieved in the present observation. It is not clear why observations on see in pleural tuberculosis have not been reported in the literature, even though the incidence of pleural tuberculosis is relatively high Short-course Chemolherapy for Pleural Tuberculoels (Duff. Moers.StNd)

among all forms of extrapulmonary tuberculosis. Farer et al" reported an incidence of 0.54 per 100,000 population in the United States from 1969to 1973. The incidence, however, varies in various reports. Enarson et al13 reported an incidence of 4.3 percent in British Columbia. Farer et al" in the United States reported 3:6 percent, but Snider" reported an incidence of 17 percent in Oklahoma. One of the reasons may be that pleural tuberculosis is included with pulmonary disease fur sec and is not separated in the reports. It is also possible that clinicians exclude pleural disease from sec considering this an extrapulmonary form of disease. For this reason, the present observations are Informative in showing that sec is very effective in the treatment of pleural tuberculosis. In this study it is more so when the results were achieved under routine treatment conditions where the drugs were mostly self administered. The highly successful result of sec in pleural disease is not surprising when it is realized that the bacterial population in the tuberculous lesions of pleura is much smaller than the population in smear positive pulmonary disease where sec for nine months is highly effective." Tuberculous pleural effusion is thought to occur from rupture of a subpleural caseous focus in the lung into the pleural space. IS It is of particular interest that 60 percent of our patients were above age 60 with an average age of 61.6 years. In the past, tuberculous pleuritis occurred mostly in young persons as a manifestation of early postprimary tuberculosis. Now in the United States, the age of patients with tuberculous pleuritis has shifted considerably to elderly persons along with all other forms of tuberculosis.P" In 65 percent of the present series, pleural disease was accompanied by involvement of other extrapulmonary sites. The results further confirm that sec is effective in pleural disease irrespective of age and involvement of other sites. Also, the therapy is effective even in the presence of associated medical disorders which are usually considered risk factors for tuberculosis. Diagnosis of pleural disease was not confirmed in 20 percent of the patients among the sec group. However, it is well known that in spite of extensive investigations in a substantial number of patients, the diagnosis may not be confirmed." The unconfirmed tuberculous pleural lesions may vary, eg, 14percent in Berger and Mejias 20 series and 58 percent in Farers study," In this situation, most authors recommend antituberculosis therapy fur patients with positive tuberculin test result after reasonable exclusion of other diagnosis and then carefully follow the response of treatment. l2.18,17,19,2O In the present series, these unconfirmed cases with favorable response to antituberculosis chemotherapy did not reveal any other etiology fur the effusion during follow-up, The diag-

nosis was confirmed bacteriologically and/or histologically in 80 percent of the patients which is considered higher than reported in Farers survey.12 Cultures of the pleural fluid and pleural biopsy specimen are expected to yield positive results in 50 to 70 percent of patients. 21 Therapy failed in one patient with pleuropulmonary disease when the sputum bacteriology did not convert to negative after seven months of treatment. The patient was an alcohol abuser and a very noncompliant patient. He eventually developed INH resistance and later was treated successfully with four-drug bactericidal therapy. Tuberculosis deaths occurred in five patients. Death occurred from nontuberculous causes in three patients within one month of initiation of therapy and were not considered failures of drug therapy. However, in the other two patients, death occurred two and three months after initiation of therapy due to active tuberculosis. Tuberculosis may have contributed to the deaths, and we have considered them failures of drug therapy. We have not observed any late relapse among sec patients during follow-upat 30 months (median) (range one to 104 months). Ninety five (83 percent) patients have been followed beyond 12months after completion of therapy. Since most late relapses occur within 12 months of stopping therapy" fur pulmonary tuberculosis, chances of further relapses are low. Two relapses have occurred among cr therapy patients at 6 and 17 months of follow-up with conversion of positive sputum bacteriology of M tuberculosis. The side effects of the drugs were of no major consequence, which is similar to our experience in a large number of patients2.113 and in other observations. 24 The drugs were well tolerated considering 60 percent of patients were above age 60 years. The minor side effects could be resolved by reintroducing the drugs one at a time and in increasing doses. As per our practice, monitoring of side effects ofdrugs was carried out by clinical monitoring and performing laboratory studies on development of symptoms only.2 Thus, an overall success of 97.5 percent was achieved in liS completed sec patients, with one bacteriologic failure during therapy and two tuberculosis deaths at two and three months during therapy. This compares favorably with 91.3 percent overall success among 46 conventional therapy patients with two tuberculosis deaths and two late relapses. In conclusion, sec with INH and RIF is as effective fur pleural tuberculosis as fur pulmonary tuberculosis. The results of therapy are equivalent or even better than conventional therapy fur prolonged periods. The sec has advantages of excellent patient acceptance, short duration, fewer number of doses, and acceptable side effects of drugs. Also, our regimen has the additional advantage of reduced cost and ease of CHEST I 90 I 1 I JULY, 1986

115

supervision when indicated, ACKNOWLEDGMENT: The authors wish to express appreciation to the physicians, communicable disease nurse specialists, and public health nurses affiliated with the Thberculosis Program who have been invaluable in the success of this program. Our thanks are due to Mr. Will Henderson for his careful laboratory work, Mrs. Nancy Brannon and her staff for maintenance of records in the central registry, Miss Connie Thomas for assistance with data recording, and Ms. Hazel O'Dell and Mr. RoyReeves for preparation of the manuscript. REFERENCES 1 American Thoracic Society. Guidelines for short course chemotherapy. Am Rev Respir Dis 1983; 127:790-96 2 Dutt AK, Moers D, Stead WW. Short course chemotherapy for tuberculosis with mainly twice weekly isoniazid and rifampin, community physicians seven years experience with mainly outpatients. Am J Med 1984; 77:233-42 3 Snider DE Jr, Cohn DL, Davidson PT, et al. Standard therapy for tuberculosis 1985. Chest 1985; 2(suppl):117-24 4 Sunakorn P, Pangparit S, Wangrum S. Short course chemotherapy in tuberculous meningitis: a pilot trial. J Med J\$socThailand 1980; 63:340-45 5 Summers GD, McNicol MW Tuberculosis of superficial lymph nodes. Br J Dis Chest 1980; 74:369-73 6 Moni DH, Hunter AM, RocchiccioliKMS, et al. Management of extrapulmonary tuberculosis (excluding miliary and meningeal) in South and West Wales(1976-1978). Br Med J 1982;285:415-18 7 Gow JG. Genitourinary tuberculosis: a seven year review. Br J Uro11979; 51:239-44 8 Skutel S, VargaJ, Obsitnik M, Moro 1.Sixmonths chemotherapy of urogenital tuberculosis (abstract). Bull Int Union Tuberc 1982; 57:46 9 Hannachi MR, Martini M, Boulaha LF, et al. Comparison of three daily short course regimens in osteoarticular tuberculosis in Algiers (abstract). Bull Int Union Tuberc 1982;57:46-47

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10 Dutt AK, Moers D, Stead WW Short course chemotherapy for extrapulmonary tuberculosis: nine years' experience. Ann Intern Med 1986; 104:7-12 11 Falk A. Tuberculous pleurisy with effusion:diagnosis and results of chemotherapy. Postgrad Med 1965; 38:631-35 12 Farer LS, Lowell AM, Meador MP. Extrapulmonary tuberculosis in the United States. Am J Epidemiol1979; 109:205-17 13 Enarson DA, Dorken E, Grzybowski S. Thberculous pleurisy. CMAJ 1982; 126:493-95 14 Snider DE Jr. Extrapulmonary tuberculosis ill Oklahoma 1965to 1973. Am Rev Respir Dis 1975; 111:641-46 15 Stead WW, Eichenholz A, Stauss HK. Operative and pathologic findings in twenty four patients with syndrome of idiopathic pleurisy with effusion, presumably tuberculous. Am Rev Respir Dis 1955; 71:473-502 16 Roper WH, Waring]]. Primary serofibrinous pleural effusion in military personnel. Am Rev 'Iuberc 1955; 71:616-34 17 Falk A. The prognostic significanceofidiopathic pleural effusion. Dis Chest 1950; 18:542-61 18 Stead WW, Lofgren JP, Warren E, Constance T. Tuberculosis as an endemic and nosocomial infection among the elderly' in nursing homes. N Eng! J Med 1985; ~12:1483-87 19 Light RW Pleural diseases. Philadelphia: Lea lX Febiger, 1983; 119-25 20 Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973; 63:88-92 21 Black LF. Pleural effusions (editorial). Mayo Clin Proc 1981; 56:201-02

22 Fox W The chemotherapy of pulmonary tuberculosis: a review. Chest 1979; 76(suppl):785-96 23 Dutt AK, Moers D, Stead WW. Undesirable side effects of isoniazid and rifampin in largely twice weekly short course chemotherapy for tuberculosis. Am Rev Respir Dis 1983; 128:419-24 24 Girling DJ. The hepatic toxicity of antituberculous regimens containing isoniazid, rifampin, and pyrazinamide. 'Iubercle 1978; 59:12-32

Short-oourse Chemotherapy lor Pleural Tuberculosis (Outt, Moers, Stead)