Tuberculous Pleurisy Is More Common in AIDS Than in Non-AIDS Patients With Tuberculosis

Tuberculous Pleurisy Is More Common in AIDS Than in Non-AIDS Patients With Tuberculosis* Michael D. Steven A.

Frye, MD, FCCP; Carol J. Pozsik, RN; and

Sahn, MD, FCCP

Objective: To investigate the incidence, clinical features, and treatment of tuberculous pleurisy patients. Methods: We reviewed all cases of pleural tuberculosis in AIDS patients in South Carolina from 1988 through 1994. Clinical findings, test results, treatment, and outcome were analyzed. Main results: Twenty-two (11%) of the 202 AIDS patients with tuberculosis had pleural involvement compared to 6% (169/2,817) pleural involvement in non-AIDS patients (p=0.01). Associated features of AIDS tuberculous pleurisy included substantial weight loss (7.65 ±1.35 kg) and lower lobe infiltrates (12/22; 55%). No difference in pleural fluid characteristics was found when comparing AIDS patients with a serum CD4 count ^200/p,L to patients with CD4 count <200/|xL. Two (9%) of the 22 patients died of tuberculosis. Chest radiograph follow-up of 20 patients showed complete resolution in 7, improvement in 10, and no improvement in 3. Conclusions: In South Carolina, pleural involvement is more common in AIDS patients than in non-AIDS patients with tuberculosis. Tuberculous pleurisy has several atypical features in AIDS patients such as substantial weight loss and lower lobe infiltrates. The outcome of treatment is 1997; 112:393-97) good for most patients. (CHEST in AIDS

Key words: AIDS; pleurisy; tuberculosis

Abbreviations: AFB=acid-fast bacilli;

PPD.purified protein derivative

HP uberculosis is the most common cause of pleural -¦- effusions in HIV-positive patients in Africa1 but accounts for only 8 to 20% in Western series.2-4 It is well established that extrapulmonary tuberculosis is more common among persons with HIV infection;57 those with lower CD4 cell counts have more ex¬

trapulmonary

manifestations.8 However, the inci¬ dence of tuberculous pleurisy in HIV-positive pa¬ tients has been reported as higher,9 lower,10 and the same711-13 as in HIV-negative patients. The inci¬ dence varies considerably in different parts of the world. Jones et al8 reported that HIV-positive pa¬ tients with tuberculosis and lower CD4 cell counts have fewer pleural effusions. Other aspects of this disease are equally controversial. Our observations, *From the Division of

Pulmonary and Critical Care

Medicine

(Drs. Frye and Sahn), Department of Medicine, Medical Uni¬ Carolina, Charleston, and the South Carolina versity of South DepartmentSC.of Health and Environmental Control (Ms. Pozsik), Columbia, Presented in part at the Annual Scientific Session of the American College of Chest Physicians, New York, October 30, 1995.

received September 3, 1996; revision accepted Feb¬ Manuscript1997.

ruary 13,

along with those of others, begin to provide a profile of tuberculous pleurisy in HIV-positive patients. Materials

and

Methods

We identified all cases of pleural tuberculosis in South Carolina from 1988 through 1994 by reviewing the state tuberculosis registry. From this group, we identified those patients who were also HIV positive. All patients with tuberculosis are routinely offered HIV testing. Case information was obtained from the treating physicians and by review of the records. Patient confi¬ dentiality was maintained. These cases were reviewed retrospec¬ tively for clinical findings, test results, treatment, and outcome. HIV antibody by enzyme immunoassay was confirmed by Western blot technique. Definite cases of tuberculous pleuritis included (1) positive culture of the pleural fluid or pleural biopsy specimen for Mycobacterium tuberculosis, and (2) positive spu¬ tum culture for M tuberculosis and a lymphocyte-predominant exudative pleural effusion, positive acid-fast bacilli (AFB) stain of the pleural fluid or pleural biopsy specimen, or granuloma in the pleural biopsy specimen. Probable cases included those with exudative pleural effusions with a >10 lymphocyte-predominant mm purified protein derivative (PPD) skin test result and resolution of clinical symptoms with treatment for tuberculosis. The radiologists' description of the chest radiograph was reviewed. Follow-up radiograph after treatment was catego¬ rized as follows: (1) complete resolution; (2) improved with small residual blunting of the costophrenic angle; (3) no

improvement; or (4) worsening.

CHEST/112/2/AUGUST, 1997

393

Descriptive statistics, including percentage and mean±SEM, used to express the data. Cases were divided into two groups according to the serum CD4 count; patients with a CD4

were

<200/jjlL were compared to patients with a CD4 count of >200/|nL. Pleural fluid and other parametric features were compared between these two groups using the two-sample t test.

count

X2 analysis was used to compare dichotomous variables.

through

1994, there were 2,817 cases

sex partners including homosexuality (six), multiple unknown and (three), (four). Six of the prostitutes had moved from New York City. recently patients were 20 men and two women. Nineteen were

There black and three were white. Clinical features of the patients are presented in Table 1. Extrathoracic tuberculosis was seen in 5 of 22 (23%) patients. The CD4 count was <200/ijlL in 10 of 19 (53%) patients. The chest radiograph and pleural fluid character¬ istics are shown in Tables 2 and 3. The typical chest showed a moderate to large unilateral radiograph effusion with ipsilateral lower lobe infiltrates. pleural The fluid was usually lymphocyte predominant but there was a wide range from 3 to 100% lymphocytes. Six of 15 (40%) patients with effusions had a glucose level <60 mg/dL, but only two had a glucose level

mg/dL.

Diagnostic tests are presented in Table 4. All five patients with positive sputum smears had parenchyTable 1.Presenting Clinical Features of AIDS Patients With Tuberculous Pleuritis No.

Age, yrs

22

Fever, temperature >38°C

Weight loss, >2.25 kg Cough Chest pain

Dyspnea

PPD, >10 mm

Albumin, <3.5 g/dL CD4+

394

lymphocytes, /uX

(%)

15/18 (83) 17/22 (77) 17/22 (77) 8/22 (36) 5/22 (23)

12/19(63) 18/20 (90) 19

Effusion only

Parenchymal changes+effusion Lower lobe infiltrate

of tuberculosis in non-AIDS patients in South Caro¬ lina. Pleural involvement was diagnosed in 169 of 2,817 (6%) cases. There were 202 AIDS patients with tuberculosis. Twenty-two of 202 (11%) of the AIDS patients with tuberculosis had pleural involve¬ ment compared to 6% pleural involvement in nonAIDS patients (p=0.01). There were 19 definite cases and three probable cases of AIDS tuberculous this time, there were 4,552 newly pleuritis. During cases of AIDS. diagnosed The AIDS risk factors for the 22 cases of AIDS tuberculous pleuritis included IV drug abuse (nine),

<40

(%) 6/22 (27) 16/22 (73) No.

(12)

Upper lobe infiltrate (2)

Results

From 1988

Table 2.Presenting Chest Radiographic Findings and Resolution in AIDS Patients With Tuberculous Pleuritis

Mean±SEM

Range

37±2 101.8+0.4 17±3

24-58 98-104 0-58

13.4±3.1 2.6±0.2 259±51

0-45 1.1-4.0 28-740

Miliary (2) Adenopathy Effusion side Right

4/22

(18)

9/22 (41) 12/22 (54) 1/22 (5)

Left Bilateral Effusion size Small Moderate

1/22 (5) 10/22 (45)

Large

11/22(50)

Resolution

Complete Improved (residual angle blunting

7/20 (35) 10/20 (50) 2/20 (10) 1/20 (5)

No improvement Worse

one with a miliary pattern. changes,these including two of five Only complained of cough. Two of seven patients with a positive sputum culture had no parenchymalin changes. Bronchoscopy results were diagnostic three of five patients in whom it was Pleural fluid culture was positive in 9 of performed. 14 (64%) patients. The incidence in non-AIDS cases in South Carolina during the study period was 53% (p=not significant). Treatment was supervised in eight and unsupervised in the remainder. Patients received two to four drugs for an average of 11 months (range, 9 to 18

mal

Table 3- -Pleural Fluid Characteristics in Tuberculous Pleuritis in MDS* No.

Color Yellow/turbid

Serosanguineous Lymph predominant

Cell count/juiL

predominant Lymph, % Eosinophils, >10% PMN

Mesothelial,

>5%

Glucose, mg/dL

LDH, IU/L

15 17

pH

LDH fluid/serum ratio Protein, g/dL 11 Protein fluid/serum ratio *

(%)

9/13 (69) 4/13 (31)

10/15 (67) 5/15 (33) 0/15

0/11 11

17 11

Mean±SEM

Range

3,380± 1,059

433-14,000

69±8

3-100

7.35: :0.05 67= :9 1,184 = :309 3.05^ :0.58 6.0= :0.5 0.75 = :0.03

7.04-7.5

4-114

253-7910 0.93-7.33 4.0-9.1 0.60-0.84

Lymph=lymphocyte; PMN=pol)rnorphonuclear leukocyte; LDH dehydogenase.

=

lactate

Clinical

Investigations

Table

+ + + +

4.Diagnostic Tests in Tuberculous Pleuritis in AIDS

Positive/Total (%) 5/21 (24)

Sputum AFB smear Sputum culture

Pleural fluid AFB smear Pleural fluid culture Pleural biopsy Granuloma present + AFB smear

+

culture

7/21 (33) 1/16 (6)

9/14 (64)

7/9 4/9 2/5

(78) (44) (40)

patients received daily therapy, biweekly treatment, and one received triweekly therapy. of clinical follow-up was 31 Average length months. Two of 22 (9%) patients died of tuberculo¬ sis; one died before the diagnosis was established months).

Fourteen

six received

and had not received antituberculous treatment, and the other died in the fourth month of treatment while receiving three-drug unsupervised daily ther¬ apy. It was later discovered that this patient had an isoniazid-resistant organism. Three patients died of other causes; one died during treatment and the other two died after successful treatment of tuber¬ culosis. Four patients were unavailable for follow-up after successful therapy. Thirteen patients were alive an average of 39 months after the diagnosis of tuberculous pleuritis. Therefore, antituberculous successful in 20 of the 21 therapy was considered (95%) patients who received treatment. When patients with a CD4 count <200/fxL were compared to patients with a CD4 count >200/|xL, no difference in pleural fluid characteristics or diag¬ nostic test results was found. There was a trend toward a smaller PPD reaction in those with a CD4 count <200/|ulL compared with those with a count >200/jjlL: 6 mm vs 16 mm (p=0.09). There also was a tendency for a smaller skin test reaction in the AIDS cases

cases (13.4±3.1 mm) compared to non-AIDS (17±0.7 mm) in South Carolina (p=0.07).

Discussion

Among

all patients with tuberculosis in South the Carolina, proportion with pleural involvement is greater in AIDS patients than in non-AIDS patients. This is an unexpected finding given the currently accepted pathophysiologic state of the disease. Since tuberculous pleurisy is thought to be primarily an immune reaction to tuberculin proteins in the pleu¬ ral space, a lower incidence in AIDS patients be¬ cause of impaired cell-mediated immunity would be expected. There are several possible explanations for our observation of an increased incidence of tuber¬ culous pleurisy in AIDS.

It has been suggested that AIDS patients with tuberculosis have a higher burden of microorganisms in the pleural space.14 Positive pleural fluid cultures have been reported in 30 to 60% of non-AIDS patients in older series.1517 Pleural fluid smear or culture was positive in 91% of HIV-positive patients described by Relkin et al.14 The latter series also found a significantly increased frequency of positive AFB smears of pleural tissue in HIV-positive pa¬

(69%) compared

HIV-negative patients pleural fluid cultures were positive significantly more often in HIV-posi¬ tive (44%) than in HIV-negative (15%) patients. We found pleural fluid culture positivity in 64% of HIV-positive patients. Although this was higher than tients

(21%). Gil

et

to

al18 also found

the incidence in South Carolina non-AIDS cases (53%) during the study period, the difference did not reach statistical significance. All five patients with a CD4 count <150/julL had a positive pleural fluid culture. A second possible explanation for an increased incidence of pleurisy in AIDS patients with tubercu¬ losis pertains to the pathophysiologic state of the disease. It may be that instead of being due to an immune reaction to tuberculin proteins in the pleu¬ ral space, tuberculous pleurisy represents a failure of the immune system in the pleural space. The failed immunity, which would likely be present more often in AIDS patients, could allow the organisms to persist in the pleural space for a longer duration. The immune reaction to PPD is

depressed

in AIDS.

Negative tuberculin skin tests are more common in patients with low CD4 counts and tuberculous effu¬ sions.8 Sixty-three percent of our patients had a positive PPD skin test, similar to the percentage reported by Kitinya and associates19 (64%), but that reported by Relkin and colleagues14 higher than (41%), Gil et al18 (20%)), or Ankobiah and associ¬ ates20 (12%). It is unclear what accounts for this difference. However, there was a tendency for a smaller skin test reaction in the AIDS patients (13.4±3.1 mm) compared to non-AIDS patients (17±0.7 mm) in South Carolina (p=0.07). Among our patients, 10 of 19 had a CD4 count <200/julL,

and there was a tendency for a smaller PPD response <200/julL than in those with a CD4 count >200/|jlL (6 mm vs 16 mm, Gil et al18 found significantly fewer positive p=0.09). skin tests in their HIV-positive patients than in the HIV-negative control subjects. However, there is other evidence that the immune system in the pleural space is functional. For example, there does not appear to be any significant defect in pleural formation even in patients with very low granuloma CD4 counts. Jones and colleagues8 found that the frequency of granuloma formation did not decrease in patients with a CD4 count

CHEST/112/2/AUGUST, 1997

395

with the peripheral CD4 cell count and speculated that mechanisms independent of the CD4 cell were responsible for granuloma formation. It is not known if there is a minimum CD4 count necessary to form granulomata. Although we found no relationship between serum CD4 count and pleural fluid cell count or lymphocyte percentage, the cell type (CD4 vs CD8) of pleural lymphocytes in AIDS tuberculous pleuritis has never been described (to our knowl¬

edge). The size of pleural effusions in AIDS tuberculous third possible explanation. Be¬ provides a effusions pleurisytuberculous in AIDS patients are cause moderate to large in size,2 it is less likely typically would go undetected and more likely that they they would be thoroughly evaluated. However, this fea¬ ture of the effusions has not been noted by all investigators.13'20 It has been shown that AIDS pa¬ of causes have tients with effusions from

a

variety

lower serum albumin levels than those without effu¬ sions.2 Hypoalbuminemia, which may be a contrib¬ uting factor in the formation and large size of pleural effusions, may lead to the increased incidence that we have noted in the AIDS patients. It is possible that HIV-positive patients who have effusions receive a more complete evaluation pleural in search of other diagnoses. Small effusions in non-AIDS patients may not always be evaluated or may be overlooked. However, this is unlikely since the incidence of tuberculous pleurisy in our nonAIDS patients is similar to national rates. It is also that some of our non-AIDS patients were possible undetected HIV-positive individuals. If this actually were the case, however, it would further increase the difference in incidence between the two populations. Only recently has indetailed information about tuberculous pleurisy HIV-positive patients been reported.5'141821 In most respects, the clinical features of tuberculous pleurisy in AIDS and non-AIDS are similar.20 IV drug abuse was the most frequent AIDS risk factor in our patients, a Patients develop by others.1420 finding reported illness with cough and may also an acute febrile have chest pain and dyspnea. Weight loss and low albumin concentrations were particularly promi¬ nent in

our

patients (Table 1).

Our

patients were

younger and had the same mean age as those described by Relkin et al14 (37 years in HIV-

positive patients

vs

52 years in

HIV-negative

tu¬

pleuritisinfiltrate patients, p<0.05). accompanied the effu¬ parenchymal sion in 16 of 22 cases. In 12 of these 16 (75%), the infiltrate was lower lobe in location, resembling primary disease (Table 2). Other investigators have noted a significant lower lobe predominance

berculous A

of infiltrates in

396

HIV-positive patients with tuber¬

culous

pleurisy.13in This

often than ex¬ and is contrast to non-AIDS where pected infiltrates are found in the upper lobe in three fourths of patients. In our series, only patients with parenchymal changes had positive sputum AFB smears. However, three of eight patients without parenchymal changes had positive cultures of sputum or bronchoscopy specimens. Gil et al18 found that sputum cultures were positive more often in HIV-positive (40%) patients than HIV-negative (13%) patients with pleu¬ ritis (p<0.05). Sputum AFB smears are more often positive in patients with AIDS tuberculous pleuritis with low CD4 cell counts.8 Pleural fluid chemistry values in those with AIDS tuberculous pleurisy are similar to those reported in non-AIDS individuals. The effusion was lymphocyte in two thirds of our patients, and all predominant effusions were exudates by usual criteria (Table 3). A glucose level <60 mg/dL was present in 40% of our AIDS cases; this incidence is similar to that reported in

was more

HIV-negative cases (30%).22

In our nine patients who had a pleural biopsy, four were AFB smear positive, two were culture positive,

and granulomata were seen in seven. Pleural granu¬ lomata were present in a similar percentage in the series of Relkin and colleagues14 and were not affected by HIV status (88% HIV-positive vs 71% HIV-negative, p=not significant). A report from Tanzania also concluded that there was no significant difference in the yield by any diagnostic procedure between HIV-positive and HIV-negative patients.5 However, Gil and coworkers18 found that granulo¬ mata were present on pleural biopsy specimens less often in HIV-positive patients than in HIV-negative patients (44% vs 84%), p<0.05). Regardless of their subjects' HIVthatstatus, all of these studieshasare thein accordance pleural histologic study

diagnostic yield. highest Treatment for tuberculous

pleurisy was usually

successful. Of our 22 patients, most were known survivors after successful treatment. Only one died of tuberculosis during treatment and there were no tuberculosis deaths after completing therapy. The clinical and microbiological response to treatment of tuberculosis seems to be the same in AIDS patients as in non-AIDS patients. However, the high rate of drug resistance in the AIDS population (7oneto of12%) our as illustrated by may complicate therapy,

patients.

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