Pleurisy

Objective: To investigate the incidence, clinical features, and treatment of tuberculous pleurisy in AIDS 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 [+ or -] 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 [is greater than or equal to] 200/[Mu]L to patients with CD4 count [less than] 200/[mu]L. 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 good for most patients. (CHEST 1997; 112:393-97)

Key words: AIDS; pleurisy; tuberculosis

Abbreviations: AFB=acid-fast bacilli; PPD=purified protein derivative

Tuberculosis is the most common cause of pleural effusions in HIV-positive patients in Africa[1] 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;[5-7] those with lower CD4 cell counts have more extrapulmonary manifestations.[8] However, the incidence of tuberculous pleurisy in HIV-positive patients has been reported as higher,[9] lower,[10] and the same[7,11-13] as in HIV-negative patients. The incidence varies considerably in different parts of the world. Jones et al[8] reported that HIV-positive patients with tuberculosis and lower CD4 cell counts have fewer pleural effusions. Other aspects of this disease are equally controversial. Our observations, 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 confidentiality was maintained. These cases were reviewed retrospectively 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 sputum 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 lymphocyte-predominant exudative pleural effusions with a [greater than] 10 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 categorized as follows: (1) complete resolution; (2) improved with small residual blunting of the costophrenic angle; (3) no improvement; or (4) worsening.

Descriptive statistics, including percentage and mean [+ or -] SEM, were used to express the data. Cases were divided into two groups according to the serum CD4 count; patients with a CD4 count <200/[mu]L were compared to patients with a CD4 count of [is greater than or equal to] 200/[mu]L. Pleural fluid and other parametric features were compared between these two groups using the two-sample t test. [Chi.sup.2] analysis was used to compare dichotomous variables.

Results

From 1988 through 1994, there were 2,817 cases of tuberculosis in non-AIDS patients in South Carolina. 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 involvement compared to 6% pleural involvement in non-AIDS patients (p=0.01). There were 19 definite cases and three probable cases of AIDS tuberculous pleuritis. During this time, there were 4,552 newly diagnosed cases of AIDS.

The AIDS risk factors for the 22 cases of AIDS tuberculous pleuritis included IV drug abuse (nine), homosexuality (six), multiple sex partners including prostitutes (three), and unknown (four). Six of the patients had recently moved from New York City. There were 20 men and two women. Nineteen were 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 [less than] 200/[Mu]L in 10 of 19 (53%) patients.

[TABULAR DATA NOT REPRODUCIBLE IN ASCII]

The chest radiograph and pleural fluid characteristics are shown in Tables 2 and 3. The typical chest radiograph showed a moderate to large unilateral pleural effusion with ipsilateral lower lobe infiltrates. 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 [less than] 60 mg/dL, but only two had a glucose level [less than] 40 mg/dL.

Diagnostic tests are presented in Table 4. All five patients with positive sputum smears had parenchymal changes, including one with a miliary pattern. Only two of these five complained of cough. Two of seven patients with a positive sputum culture had no parenchymal changes. Bronchoscopy results were diagnostic in three of five patients in whom it was performed. Pleural fluid culture was positive in 9 of 14 (64%) patients. The incidence in non-AIDS cases in South Carolina during the study period was 53% (p=not significant).

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

Discussion

Among all patients with tuberculosis in South Carolina, the 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 pleural space, a lower incidence in AIDS patients because of impaired cell-mediated immunity would be expected. There are several possible explanations for our observation of an increased incidence of tuberculous 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.[15-17] 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 patients (69%) compared to HIV-negative patients (21%). Gil et al[18] also found pleural fluid cultures were positive significantly more often in HIV-positive (44%) than in HIV-negative (15%) patients. We found pleural fluid culture positivity in 64% of HIV-positive patients. Although this was higher than 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 [less than] 150/[Mu]L had a positive pleural fluid culture.

A second possible explanation for an increased incidence of pleurisy in AIDS patients with tuberculosis 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 pleural 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 effusions.[8] Sixty-three percent of our patients had a positive PPD skin test, similar to the percentage reported by Kitinya and associates[19] (64%), but higher than that reported by Relkin and colleagues[14] (41%), Gil et al[18] (20%), or Ankobiah and associates[20] (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 [+ or -] 3.1 mm) compared to non-AIDS patients (17 [+ or -] 0.7 mm) in South Carolina (p=0.07). Among our patients, 10 of 19 had a CD4 count [less than] 200/[mu]L, and there was a tendency for a smaller PPD response in patients with a CD4 count [less than] 200/[Mu]L than in those with a CD4 count [greater than] 200/[Mu]L (6 mm vs 16 mm, p=0.09). Gil et al[18] found significantly fewer positive 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 granuloma formation even in patients with very low CD4 counts. Jones and colleagues[8] found that the frequency of granuloma formation did not decrease 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 knowledge).

The size of pleural effusions in AIDS tuberculous pleurisy provides a third possible explanation. Because tuberculous effusions in AIDS patients are typically moderate to large in size,[2] it is less likely they would go undetected and more likely that they would be thoroughly evaluated. However, this feature of the effusions has not been noted by all investigators.[13,20] It has been shown that AIDS patients with effusions from a variety of causes have lower serum albumin levels than those without effusions.[2] Hypoalbuminemia, which may be a contributing 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 pleural effusions receive a more complete evaluation 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 non-AIDS patients is similar to national rates. It is also possible that some of our non-AIDS patients were actually undetected HIV-positive individuals. If this were the case, however, it would further increase the difference in incidence between the two populations.

Only recently has detailed information about tuberculous pleurisy in HIV-positive patients been reported.[5,14,18-21] 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 finding reported by others.[14, 20] Patients develop an acute febrile illness with cough and may also have chest pain and dyspnea. Weight loss and low albumin concentrations were particularly prominent in our patients (Table 1). Our patients were younger and had the same mean age as those described by Relkin et al[14] (37 years in HIV-positive patients vs 52 years in HIV-negative tuberculous pleuritis patients, p [less than] 0.05).

A parenchymal infiltrate accompanied the effusion 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 of infiltrates in HIV-positive patients with tuberculous pleurisy.[13] This was more often than expected and is in contrast to non-AIDS where 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 al[18] found that sputum cultures were positive more often in HIV-positive (40%) patients than HIV-negative (13%) patients with pleuritis (p [less than] 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 predominant in two thirds of our patients, and all effusions were exudates by usual criteria (Table 3). A glucose level [less than] 60 mg/dL was present in 40% of our AIDS cases; this incidence is similar to that reported in 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 granulomata were present in a similar percentage in the series of Relkin and colleagues[14] 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 coworkers[18] found that granulomata were present on pleural biopsy specimens less often in HIV-positive patients than in HIV-negative patients (44% vs 84%, p [less than] 0.05). Regardless of their subjects' HIV status, all of these studies are in accordance that pleural histologic study has the highest diagnostic, yield.

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 (7 to 12%) may complicate therapy, as illustrated by one of our patients.

References

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