Tuberculosis in Heart Transplant Recipients

Tuberculosis in Heart Transplant

Recipients*

Michael M. Korner, MD; Nobuaki Hirata, MD; Gero Tenderich, MD; Kazutomo Minami, MD; Hermann Mannebach, MD; Knut Kleesiek, MD; and Reiner Korfer, MD

Study objectives: To clarify the prevalence and factors associated with tuberculosis, as well as patient survival in heart transplant recipients. Design: A retrospective review of case records of all heart transplant recipients from March 1989 to February 1996 during a 7-year period. Setting and patients: During the period reviewed, 727 orthotopic heart transplantations were in 716 patients at the Heart Center Northrhine-Westphalia, Germany. performed Results: Tuberculosis was proved in seven (1%) patients (four men/three women; age, 33 to 71 years; two miliary lesions, three pulmonary lesions, and two urogenital lesions). None of them had primary history of tuberculosis. Tuberculin skin tests were not performed before transplantation because there were no lesions indicating primary infection of tuberculosis. The immunosuppressive regimen was based on double-drug (cyclosporine + azathioprine) therapy. Immunosuppression had been intensified by methylprednisolone pulses at least three times in those seven patients, and prednisone had been used orally in six of seven patients. Tuberculosis developed from 2.5 to 41 months after transplantation. Tuberculosis was found by routine examinations in four of seven patients. Diagnoses were made with both direct microscopy and cultures in six patients, and by histologic study in one. Treatment consisted of isoniazid, rifampicin, ethambutol, and pyrazinamide. Two patients with miliary lesions were treated with four drugs, and the others were treated with three drugs. Isoniazid was used in all patients. Rifampicin, which decreases cyclosporine serum levels, was not used from the beginning in one patient and treatment with it was stopped halfway in another patient because low cyclosporine level had induced rejection. Six of the seven patients are doing well while receiving antituberculous therapy. One patient died with miliary tuberculosis as a cause of death. Conclusions: The prevalence of tuberculosis in heart transplant recipients was higher than that in the general population. We recommend that a high degree of clinical suspicion is maintained for tuberculosis in heart transplant recipients with meticulous follow-up, and that the treatment of tuberculosis has to be with meticulous care, especially during the use of rifampicin. (CHEST 1997; 111:365-69)

Key words: heart transplantation; immunosuppression; tuberculosis Abbreviations: HTx-heart transplantation; IST-immunosuppressive therapy

\M ycohacterium tuberculosis has been increased especially in the United States and in some European countries, not including Germany, over the last few years, predominantly in immunocompro¬ *.*.*-

mised patients with HIV infection or IV drug use.12 The risk of developing tuberculosis was reported at *From the Heart Center Northrhine-Westphalia, University Hos¬ pital of Ruhr, University of Bochum, Bad Oeynhausen, Ger¬ many. Supported by the German Association of Organ Recipients. 1. Manuscript receivedDr.March 11, 1996; revision accepted August Korner, Department of Thoracic and Reprint requests:

Surgery, Heart Center Northrhine-Westphalia, of Ruhr, University of Bochum, Georgst. 11, University Hospital D-32545 Bad Oeynhausen, Germany Cardiovascular

10.5/100,000 for the year 1992 in the general popu¬ lation in the United States and at 17.5/100,000 for the year 1993 in those in Germany.3 Patients under¬ going organ transplantation are also at increased risk of developing infections, including tuberculosis caused by immunosuppressive therapy (1ST). The prevalence of tuberculosis in transplant recipients reported around the world and that in developed countries was 0.45 to 2.0%, 480/100,000 in renal transplant recipients, and 0.9 to 1.2%, 320/100,000 in liver transplant recipients.45 However, the prevalence of tuberculosis in recip¬ ients of a heart transplantation (HTx) is not well known. Since the number of HTx is increasing with CHEST / 111 / 2 / FEBRUARY, 1997

365

30,297 HTx until 1994 and the need of lifelong immunosuppression, the risk of infections, including tuberculosis, is increased. We reviewed the records

of seven patients with HTx with proven tuberculosis to determine the preva¬ follow-up periods as well as its of tuberculosis lence and presentation with HTx at our influence on survival of patients

in their center.

Materials

and

Methods

The records of 716 patients who underwent an orthotopic HTx 1996 at the during a 7-year period from March 1989 to February Heart Center Northrhine-Westphalia, Germany were reviewed and analyzed (Fig 1). The diagnosis of tuberculosis was made if one of the following criteria was present: (1) acid-fast bacilli on direct microscopy; (2) culture of M tuberculosis; and (3) biopsy specimen showing caseating granuloma with or without acid-fast bacilli or noncaseating granuloma with response to treatment. Data collected from patient records included the following: age, sex, diagnosis of underlying end-stage heart disease, and other underlying diseases; a history of tuberculosis, chest radiograph before and after HTx; and associated factors, including infection, rejection 1ST, antituberculous therapy, time from HTx to the diagnosis of tuberculosis, time from symptoms to antituberculous diagnostic procedures, complica¬ therapy, clinical presentation,outcome. tion of therapy, and clinical

Results

During the period under review, 727 orthotopic HTx were performed in 716 recipients. The duration of follow-up ranged from 1 month to 7 years.

Tuberculosis developed in seven patients (1%) (Ta¬ bles 1 and 2). The standardized annualized rate of the risk of developing tuberculosis was about 1,300/ 100,000 in HTx patients. These patients included four men and three women, ranging in age from 33 to 71 years with a mean (±SD) of 58.4±12.1 years.

(HTx) n=727 Orthotopic Heart Transplantation 1989 (March

February 1996)

Myopathy n=360 49.5%

poronary n=284 39.1%

Myocarditis *=3

0.4% n t> ut Re~HTxn=13 1.8%

Figure 1. 366

Valvular n-43

uf0/\A n=24 Congenital & n

a

10/.

Underlying end-stage heart disease in HTx recipients

Their HTx were performed due to dilatative cardio¬ myopathy in five patients and due to coronary artery disease in two patients. None of them had primary history of tuberculosis. Tuberculin skin tests are not routine at our center and were not performed before HTx. None of them had any previous tuberculous evidence by chest radiographs and urine cultures at the time of HTx. The basic 1ST is based on double-drug therapy (cyclosporine + azathioprine without the use of monoclonal or polyclonal antibodies for the induc¬ tion of 1ST). In case of moderate rejection according to Billingham,6 pulsed steroids with four 250-mg doses of methylprednisolone each 24 h were given over 3 days. If there were more than three episodes of ongoing rejection, prednisone (1 mg/kg/d) was given orally, and then tapered slowly to at least 0.05 mg/kg/d. In those seven patients at 1 month prior to the diagnosis of tuberculosis, 1ST consisted of cyclosporine+ azathioprine+prednisone in four patients, cyclosporine+prednisone in two patients (in whom azathioprine therapy had been stopped), and cyclosporine+azathioprine in one patient. The me¬ dian doses of those drugs were as follows: cyclospor¬

mg/d (n=7); azathioprine=35 ±14 and (n=5); prednisone=4.6±1.0 mg/d (n=6). mg/d

ine =275 ±63

1ST had been intensified with pulsed IV methylpred¬ nisolone more than three times for rejection epi¬ sodes in all of the patients. Major associated illness after HTx was renal dysfunction, hypertension, and viral infections. The creatinine level at the time of the diagnosis of tuberculosis was 1.77±0.64 mg/dL. Repeated bacterial and/or viral infections were found in three patients. Three patients had pulmonary tuberculosis and two patients had urogenital tuberculosis. The other two patients had miliary tuberculosis, one of whom had tuberculous abscess in the left thigh and tuber¬ culous meningitis and encephalitis (he died in the late course), and another had tuberculosis affecting both lungs and urogenital lesions. The time from HTx to diagnosis varied from 2.5 to 41 months (mean, 14.7± 14.8 months). Tuberculosis developed in the early posttransplant period, in the unstable states of 1ST, in four patients (2.5, 3.5, 4, and 9 months), and developed late, in the stable stage of 1ST, after HTx (14, 29, and 41 months). A of tuberculosis was made on sputum and diagnosis urine examination and/or invasive investigation. In six patients, acid-fast bacilli were found by direct microscopy and the cultures of M tuberculosis were positive. In one patient, diagnosis was made by

study. histologic The clinical findings at the time of diagnosis were and were un37.5°C in two subfever till

patients

Clinical

Investigations

Table 1.Clinical Factors in HTx Recipients Patient 2

Patient 1

(61)/M

Patient 6

Patient

'

61

Underlying disease Complications after HTx

DCM

DCM

IHD, NIDDM

DCM

DCM, NIDDM

IHD, ASD, PC, IDDM

DCM, NIDDM

Renal

Renal

Renal dysfunction; A-V block

Renal

Transient ischemic attack; IDDM

Repeated respiratory

Renal dysfunction

71

dysfunction

(66)/F

Patient 5

Patient 4

Age, yr (time of HTx)/Sex

(57)/M

Patient 3

(No, 1)*

65

dysfunction

Cyclosporine, mg/d (-»-» rifampicin) Azathioprine, mg/d Prednisone, mg/d Rejection therapy with pulsed steroids

325

(-

(pacesetter); repeated infections

50

-

975) 225 (-

50

7.5 Yes 4 times

Yes 4 times

?(iv))

(31)/M

CMV

200

(-

?

56

(52)/F

performed after HTx)

350) 250

225

25

25

25

5

2.5

5

Yes 5 times

Yes 5 times

Yes 3 times

(-

(58)/M

61

infections; mitral repeated regurgitation then valve replacement (was

infections

sepsis, IDDM

975) 375 (-

33

dysfunction;

(virus, bacterial);

Immunosuppression prior to 1 month of TB

(58)/F

62

Laparoscopic

cholecystectomy (2 yr after HTx)

3 yr

600)

?

275

Yes 4 times

(-

700)

Yes 3 times

*TB=tuberculosis; DCM=dilated cardiomyopathy; IHD=ischemic heart disease; NIDDM=noninsulin-dependent diabetes mellitus; IDDM.insulin-dependent diabetes mellitus; ASD atrial septal defect; PC=state after pericardectomy 10 yr before HTx; CMV= cytomega¬ lovirus; A-V=atrioventricular; .>.>=dosage increase. =

of the treatment of tuberculosis were from beginning 4,100 to 7,700/mm3 (mean, 6,600±l,600/mm3). All isolates tested were sensitive to isoniazid, rifampicin, ethambutol, and pyrazinamide. Two pa¬ tients with miliary tuberculosis were treated with those four drugs. The other five patients were

known in one patient, who had had other viral and bacterial infections for a long time, even at the time of onset of tuberculosis. The other four patients were entirely asymptomatic and the diagnosis was made by routine chest radiographs and/or urine cul¬ only tures. WBC counts before 2 to 4 weeks at the

Table 2.Clinical Factors in HTx Recipients (No. 2)* Patient 1

History of TB

Location of TB

Negative Lung

Patient 3

Patient 2

Negative

Miliary TB (lung, urogenital)

Negative

Miliary TB

(L thigh,

Patient 5

Patient 4

Negative Lung

Patient 7

Patient 6

Negative

Negative Lung

Urogenital

Negative

Urogenital

meningitis,

encepha¬

Chest radiographic Consolidation (R appearances upper zone)

Miliary pattern (bi upper-mid zone)

Time HTx to TB

2.5

diagnosis Time symptoms to therapy

Clinical TB

symptoms

3

mo

mo

litis) 9

mo

3 wk

Asymptomatic

Subfever

14

zone) mo

therapy

Duration of

therapy, mo

Outcome

(mo)

Isoniazid,

rifampicin, ethambutol

9

(rifampicin therapy was stopped halfway)

Doing well (51.3)

Isoniazid,

rifampicin, ethambutol, pyrazinamide

16

Doing well (62.9)

*TB=tuberculosis; R=right; L=left; bi=bilateral.

upper zone)

4

41

mo

mo

29

mo

2 wk

High fever

Subfever

Diagnosis methods Microscopy culture Microscopy culture Microscopy Microscopy ofTB

TB

Consolidation (bi

Consolidation (L lower

culture

Isoniazid,

rifampicin,

culture

Isoniazid,

rifampicin, ethambutol, pyrazinamide

pyrazina¬ mide

Died (10.2)

2

due (stopped to liver dysfunction)

Doing well (62.8)

Asymptomatic

Asymptomatic

Asymptomatic

Microscopy

Histology

Microscopy culture

Isoniazid, ethambutol,

Isoniazid, rifampicin, Isoniazid, rifampicin,

culture

pyrazinamide

ethambutol

12 8

(receiving therapy)

Doing well (32.8) Doing well (64.9)

ethambutol

8

(receiving therapy)

Doing well (41.8)

CHEST/111 /2/FEBRUARY, 1997

367

treated with three drugs (isoniazid+rifampicin+ ethambutol in three patients; isoniazid+rifampicin+ in one patient; isoniazid+etham¬ pyrazinamide butol + pyrazinamide in one patient). Isoniazid was used in all patients. Rifampicin, which decreases levels, was not used from the cyclosporinein serum one patient and treatment with it was beginning stopped halfway because a low cyclosporine level had induced moderate rejection diagnosed by myocardial

biopsy ofspecimen. the

seven patients are doing well while antituberculous receiving therapy. One patient died with miliary tuberculosis (tuberculous meningitis and encephalitis) as a cause of death. This patient had suffered from repeated bacterial and viral infec¬ tions for a long time, even with the diagnosis of tuberculosis, and had sepsis and agranulocytosis as well.

Six

Discussion HTx recipients were exposed to increased risk of tuberculosis. Our data, with seven of 716 (1%) patients developing tuberculosis during a 7-year and the standardized annualizing rate of period, about 1,300/100,000/yr, is greater than 17.5/ 100,000/yr in the general population of Germany.3 Tuberculosis was associated with the degree of severe 1ST, especially in renal transplant recipi¬ ents.78 We think that the tendency also exists in our series. As a policy of our 1ST, steroid maintenance was avoided whenever possible. However, therapy steroids had to be used in six of seven patients with tuberculosis. In addition, more than three times intensification of 1ST was performed in all the patients. Three of seven patients had repeated viral and/or bacterial infections due to immunosuppression (one of whom with miliary tuberculosis died), which might demonstrate that those tuberculous patients were in severe delay of immunocompetence.

Tuberculin skin

tests

were

not

performed

rou¬

because there were no findings suggesting previous tuberculous infection by the preoperative examination. In the 17 preoperative positive skin tests of 2,380 liver transplant recipients, one (6%) In the 18 of 403 developed clinical tuberculosis.5 renal transplant recipients with positive skin tests, two (11%) developed tuberculosis compared with three of 70 (4.3%) with negative skin tests (p not We think that the prophylactic signifi¬ significant).9 cance is unknown because the patients with positive skin tests did not always develop tuberculosis signif¬ icantly. Furthermore, the sources of infection, whether exogenous infection or secondary reactiva¬

tinely

tion, were unknown, because we did not perform tuberculin skin tests. However, potential transplant recipients should be screened with an intermediated tuberculin skin test. Control skin tests should be performed to exclude anergy. Also, we suggest that prophylactic therapy with isoniazid should be given to the patients who had close contact with untreated patients or who were recent tuberculin converters, a donor with a positive skin test result.7 including We could detect the patients with tuberculosis without symptoms early on by our routine examina¬ tions, and the prognosis in our series was good. In

our outpatient clinic, we examine a patient every week until 2 months after HTx, every 2 or 3 weeks until 4 months after HTx, every 4 or 6 weeks until 6 months after HTx, every 8 weeks until 12 months after HTx, and thereafter every half year with rou¬ tine chest radiography and urine culture. These schedules will be continued. The treatment of tuberculosis was difficult. Rifam¬ picin is known to increase the P-450 cytochrome activity and decrease cyclosporine levels.10 There is a report that cyclosporine and rifampicin were used successfully in renal transplant recipients with tuber¬ culosis.11 However, we did not use rifampicin in one patient, and we stopped using rifampicin in one patient in whom the control of his serum levels was difficult and the levels remained low, which induced intensified 1ST. In the other four patients, excluding one dead patient, the daily cyclosporine dose had to be increased 2.5±0.5-fold and we had to measure the serum levels more frequently. In conclusion, the prevalence of tuberculosis in HTx recipients was higher than that in the general population. We recommend that a high degree of clinical suspicion be maintained for tuberculosis in HTx recipients with meticulous follow-up, and that the treatment of tuberculosis has to be done with meticulous care, especially during the use of rifam¬

picin.

ACKNOWLEDGMENT: The authors are thankful to Professor U. Raute Kreisen and Professor W. Lange, both pathologists, and Professor G. Goeckenjan, pneumonologist, for diagnostic and/or therapeutic support; to Mr. D.Kraus and Mr. J. Kraus for statistical evaluation; and to Mr. S. Wlost and Mr. H. Gromzic for thank the Eurotransplant graphs. The authors also preparing the Foundation International (Leiden, The Netherlands), all of the involved European Transplant Centers for their cooperation, and

the organ donors, together with their relatives, for the gift of life.

=

368

1 Tuberculosis

42:696-704

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