Corticosteroids for tuberculous pleurisy

Hannah Ryan; Jinho Yoo; Padmapriya Darsini

doi:10.1002/14651858.CD001876.pub3

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Figure 1

Study flow diagram.

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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included trials.

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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included trial.

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Analysis 1.1

Comparison 1 Corticosteroids versus control (placebo or no steroids), Outcome 1 Residual pleural effusion on chest X‐ray.

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Analysis 1.2

Comparison 1 Corticosteroids versus control (placebo or no steroids), Outcome 2 Pleural changes at the end of treatment (pleural thickening and pleural adhesions).

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Analysis 1.3

Comparison 1 Corticosteroids versus control (placebo or no steroids), Outcome 3 Death from any cause.

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Analysis 1.4

Comparison 1 Corticosteroids versus control (placebo or no steroids), Outcome 4 Adverse events leading to study drug discontinuation.

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Analysis 1.5

Comparison 1 Corticosteroids versus control (placebo or no steroids), Outcome 5 HIV‐associated adverse events.

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Analysis 2.1

Comparison 2 Effect of study quality on the outcome residual pleural fluid on chest X‐ray, Outcome 1 Residual pleural fluid on chest X‐ray ‐ studies at high risk of selection bias excluded.

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Analysis 2.2

Comparison 2 Effect of study quality on the outcome residual pleural fluid on chest X‐ray, Outcome 2 Residual pleural fluid on chest X‐ray ‐ studies at high risk of selection bias included.

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Steroids compared with placebo for pleural TB
Patient or population: adults and adolescents with pleural TB Settings: hospital care and community follow‐up Intervention: corticosteroids Comparison: placebo
Outcomes	Illustrative comparative risks¹ (95% CI)		Relative effect (95% CI)	Number of participants (trials)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Control	Corticosteroids
Residual pleural fluid on chest X‐ray at 8 weeks	62 per 100	33 per 100 (23 to 48)	RR 0.54 (0.37 to 0.78)	237 (2 trials)	⊕⊕⊝⊝^1,2,3,4 low
Residual pleural fluid on chest X‐ray at 24 weeks	29 per 100	10 per 100 (5 to 19)	RR 0.35 (0.18 to 0.66)	237 (2 trials)	⊕⊕⊝⊝^1,2,3,4 low
Pleural changes at the end of follow‐up (pleural adhesions or pleural thickening on chest X‐ray; follow‐up 6 to 24 months)	50 per 100	36 per 100 (29 to 46)	RR 0.72 (0.57 to 0.92)	393 (5 trials)	⊕⊕⊝⊝^5,6,7 low
Long‐term functional respiratory impairment (> 6 months)	—	—	Average percentage predicted FVC similar in corticosteroid and control groups.	187 (2 trials)	⊕⊝⊝⊝⁸ very low
Adverse events leading to treatment discontinuation (follow‐up 6 to 24 months)	1 per 100	3 per 100 (1 to 7)	RR 2.78 (1.11 to 6.94)	590 (6 trials)	⊕⊕⊝⊝^9,10 low
HIV‐related infections (cryptococcal meningitis)	5 per 100	3 per 100 (1 to 12)	RR 0.59 (0.15 to 2.42)	103 (1 trial)	⊕⊝⊝⊝^11,12 very low
HIV‐related cancer (Kaposi's sarcoma)	14 per 1000¹³	180 per 1000 (1 to 316)	RR 12.87 (0.73 to 225.40)	103 (1 trial)	⊕⊝⊝⊝^14,15 very low
¹The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). Abbreviations: CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development and Evaluation; RR: risk ratio; TB: tuberculosis; FVC: forced vital capacity.
GRADE Working Group grades of evidence High quality: further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: we are very uncertain about the estimate.
¹Downgraded by one for risk of bias: of the four trials that reported this outcome, we excluded two trials from the final analysis due to high risk of selection bias, after a subgroup analysis suggested the pooled estimate including these studies could be misleading (Bang 1997; Lee 1999). We judged this to be our best estimate of effect. However because we excluded trials from this analysis this generates uncertainty, so we have downgraded the quality of the evidence. ²Not downgraded for inconsistency: heterogeneity in the original meta‐analysis was likely due to differences in study quality. A subgroup analysis showed that statistical heterogeneity disappeared when we excluded trials that were at high risk of selection bias. ³Downgraded by one for imprecision: the CI around the summary effect estimate is wide due to the small number of participants and events in each included trial. ⁴Not downgraded for indirectness: the included trials were performed in different settings and time periods and used widely available drugs and diagnostic techniques. Although the trials did not include children, we did not downgrade as pleural TB is less common in children than in adults. One trial included HIV‐positive people, Elliott 2004, and this trial contributed most of the participants in the meta‐analysis. When making recommendations relating to the use of corticosteroids for pleural TB in children or in HIV‐negative adults, guideline panels may wish to consider downgrading for indirectness. ⁵Downgraded by one for serious risk of bias: we assessed two trials as at high risk of bias for randomization method (Bang 1997; Lee 1999), and the other three trials were at unclear risk of bias (Galarza 1995; Lee 1988; Wyser 1996). Only Wyser 1996 reported that outcome assessors were blinded to the treatment allocation. ⁶Downgraded by one for serious imprecision: the CI around the summary effect estimate is wide, ranging from a maximum risk reduction with steroids of 43% to a minimum risk reduction of 7%, which may not be clinically significant when weighed against possible harms of steroids. ⁷Not downgraded for indirectness: the trials were performed in a variety of settings, and all used drugs and diagnostic techniques that are widely available. We did not include any HIV‐positive people in this meta‐analysis, so when making recommendations regarding the use of corticosteroids in HIV‐positive people with TB pleurisy, guideline panels may wish to consider downgrading for indirectness. Only one trial included children aged over 11 years of age (Galarza 1995), but we did not downgrade as pleural TB is not common in children. ⁸Two of the six trials reported pulmonary function tests at the end of treatment (Galarza 1995; Wyser 1996), but data were insufficient to combine these outcomes in a meta‐analysis. The data are in Table 7, and suggest that in these trials there was little or no difference in mean percentage predicted FVC at the end of treatment. The number of participants in each group with pulmonary function tests suggestive of a functional respiratory impairment are not reported. ⁹Downgraded by one for risk of bias: there were concerns about randomization method and allocation concealment. Additionally, reporting of adverse events varied significantly across the trials, and some trials only reported on adverse events in the steroid group, and it is likely that some trials did not detect or report all adverse events. ¹⁰Downgraded by one for serious imprecision: the CI around the summary effect estimate is wide, with a maximum increased risk of adverse effects leading to study drug discontinuation of nearly 700% and a minimum increased risk of 12%, which may not be clinically significant when weighed against possible benefits of steroids. ¹¹Downgraded by two for serious imprecision: the CI around the summary effect estimate is very wide, and possible effects range from large benefits to significant harms. ¹²Downgraded by one for indirectness: only one trial included HIV‐positive people and assessed HIV‐related adverse events (Elliott 2004). Participants in this trial were not treated with antiretroviral therapy, which is known to prevent cryptococcal meningitis in HIV‐positive people; therefore this estimate may not be applicable to HIV‐positive people on antiretroviral therapy. This trial did not include any children. ¹³Prevalence of Kaposi's sarcoma of 1.4% in HIV‐positive adults on clinic enrolment taken from Semeere 2016, a multi‐centre prospective cohort study performed in Uganda and Kenya. ¹⁴Downgraded by two for serious imprecision: the CI around the summary effect estimate is very wide, and possible effects range from large benefits to significant harms. ¹⁵Downgraded by one for indirectness: only one trial included HIV‐positive people and assessed HIV‐related adverse events (Elliott 2004). Participants in this trial were not treated with antiretroviral therapy, which is known to treat and prevent Kaposi's sarcoma in HIV‐positive people, therefore this estimate may not be applicable to HIV‐positive people on antiretroviral therapy. This trial did not include any children.

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Table 1. Theoretical framework describing differences between isolated tuberculous pleurisy and pulmonary TB with tuberculous pleurisy (pleuro‐pulmonary TB)

Clinical Feature	Isolated pleural TB	Pleuro‐pulmonary TB
Sputum microscopy/culture	Negative	Some positive
Pleural fluid	Usually demonstrates exudative effusion Usually negative for M. tuberculosis on smear and culture	Usually demonstrates exudative effusion Usually negative for M. tuberculosis on smear and culture
Chest X‐ray	Discrete pleural effusion, or pleural thickening, or both	Pleural effusion with other changes such as consolidation, cavities, atelectasis, or hilar enlargement
Chest computed tomography (CT)	May demonstrate underlying lung infection	Demonstrates underlying lung infection
Pathogenesis	Predominantly driven by delayed type hypersensitivity reaction	Predominantly driven by TB infection of the lung
Prognosis	Most people will improve with no antituberculous treatment (ATT), but may experience a relapse of TB infection	People may deteriorate and die without ATT

Table 1. Theoretical framework describing differences between isolated tuberculous pleurisy and pulmonary TB with tuberculous pleurisy (pleuro‐pulmonary TB)

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Table 2. Summary of characteristics of included studies

Trial	Country	Year	Participants		Adults or children	HIV status	ATT regimen	Therapeutic thoracocentesis performed
Trial	Country	Year	Steroid group	Control group	Adults or children	HIV status	ATT regimen	Therapeutic thoracocentesis performed
Bang 1997	South Korea	1991 to 1994	34	50	Adults	Not reported	2RHZE/7RHE	No
Elliott 2004	Uganda	1998 to 2002	99	98	Adults	Positive	2RHZE/4RH	No
Galarza 1995	Spain	1985 to 1992	57	60	Both	Negative	6RH	Yes
Lee 1988	Taiwan	1983 to 1987	21	19	Adults	Not reported	3RHE/6‐9RH	No
Lee 1999	South Korea	1990 to 1997	50	32	Adults	Not reported	6RHZE or 2RHZS/4RHZ	No
Wyser 1996	South Africa	1994 to 1995	34	36	Adults	Negative	6RHZ	Yes
Abbreviations: ATT: antituberculous treatment; E: ethambutol; H: isoniazid; R: rifampicin; S: streptomycin; Z: pyrazinamide.

Table 2. Summary of characteristics of included studies

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Table 3. Diagnostic testing in included trials

Trial	Diagnostic criteria for pleural TB	Other diagnostic tests
Bang 1997	Microscopy positive for AFB or culture positive from sputum, pleural fluid, or pleural biopsy.	Chest X‐ray
Elliott 2004	Positive culture from pleural biopsy, pleural fluid, or sputum, or histopathologic analysis of pleural biopsy consistent with tuberculous pleurisy	Chest X‐ray HIV test (rapid test and ELISA) Serum cryptococcal antigen test CD4⁺ cell count HIV viral load (plasma and pleural fluid) Serum glucose
Galarza 1995	At least one of the following Pleural exudate with positive culture Pleural biopsy culture positive Pleural biopsy with caseating granulomas with Langhans giant cells, Epithelioid cells and lymphocytes Compatible clinico‐radiological picture plus 2 or more of the following: age < 40 years, PPD > 6 mm or conversion using 5 units of tuberculin PPD‐S, lymphocytic pleural fluid (> 70% lymphocytes), pleural fluid levels of adenosine deaminase activity (ADA) > 60 U/mL	Chest X‐ray Simple spirometry (FVC and FEV₁) Serum biochemistry Full blood count HIV test
Lee 1988	Pleural biopsy reported as pleural TB or chronic granulomatous inflammation	Chest X‐ray Unspecified diagnostic tests to exclude heart failure, malignancy, pneumonia, diabetes mellitus Chest ultrasound or CT scan in participants with persisting pleural effusion after 3 months
Lee 1999	TB on pleural biopsy, or pleural effusion plus AFB stain positive or culture positive from sputum, pleural fluid, or pleural biopsy	Chest X‐ray
Wyser 1996	Pleural biopsy with caseating granulomata with or without AFB on histological examination, or positive culture.	Chest X‐ray Unspecified tests to rule out pneumonia, empyema, malignancy, diabetes mellitus HIV test Thoracoscopy and bronchoscopy performed under general anaesthesia High‐resolution CT chest at three levels to measure pleural thickness Spirometry and body plethysmography
Abbreviations: ADA: adenosine deaminase activity; AFB: acid‐fast bacilli; CT: computed tomography; ELISA: enzyme‐linked immunosorbent assay; FEV₁: forced expiratory volume at one second; FVC: forced vital capacity; HIV: human immunodeficiency virus; PPD: purified protein derivative; PPD‐S: purified protein derivative‐standard; TB: tuberculosis

Table 3. Diagnostic testing in included trials

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Table 4. Corticosteroid regimens in included studies

Trial	Steroid	Regimen
Bang 1997	Prednisolone	1 mg/kg twice daily, tapered by 10 mg each week until cessation
Elliott 2004	Prednisolone	50 mg daily for 2 weeks, 40 mg daily for 2 weeks, then 25 mg daily for 2 weeks, then 15 mg daily for 2 weeks, then stopped
Galarza 1995	Prednisone	1 mg/kg/day for 15 days, tapering over the next 15 days
Lee 1988	Prednisolone	0.75 mg/kg/day, tapered by 5 mg per week until discontinued once radiological improvement was seen
Lee 1999	Prednisolone	30 mg four times daily for 1 month and tapered over the following month
Wyser 1996	Prednisone	0.75 mg/kg/day for 2 to 4 weeks; dose tapered by 5 mg/day over 2 weeks after clinical and radiological improvement
Abbreviations: mg: milligrams

Table 4. Corticosteroid regimens in included studies

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Table 5. Results: Time to resolution of symptoms

	Trial	Indicator	Units	Corticosteroids	Control
Mean values	Bang 1997	“Fever, pleuritic pain, malaise and breathlessness”	Mean days to resolution	3.8 (N = 34)	7.4¹ (N = 50)
	Galarza 1995	“Fever duration”	Mean days	3.32 (N = 57)	4.15 (N = 60)
	Lee 1988	“Fever, pleuritic pain, malaise and breathlessness”	Mean days to resolution	2.4 (N = 21)	5.6 (N = 19)
Cut‐offs (categorical)	Elliott 2004	“Anorexia”	Number of participants with anorexia at 4 weeks	3/99 (3%)	18/98 (18.4%)
		“Cough”	Number of participants with cough at 4 weeks	35/99 (35.4%)	57/98 (58.2%)
		“Weight”	Mean weight in kg at 4 weeks	57	52.5
	Wyser 1996	Symptoms resolved in all patients (VAS score)	Weeks	12	16
Abbreviations: kg: kilograms; VAS: visual analogue scale ¹P < 0.05.

Table 5. Results: Time to resolution of symptoms

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Table 6. Time to resolution of pleural effusion on chest X‐ray

	Trial	Units	Corticosteroids	Control
Mean values	Bang 1997	Mean days to resolution	88 (N=34)	100 (N=50)
	Lee 1988	Mean days to resolution	54.5 (N=21)	123.2 (N=19)
	Galarza 1995	Reabsorption index¹ at 4 weeks	93%	89%²
Categorical values	Bang 1997	Number of participants with residual effusion at 4 weeks	26/34 (76.5%)	39/50 (78%)
		Number of participants with residual effusion at 8 weeks	19/34 (55.9%)	30/50 (60%)
		Number of participants with residual effusion at 24 weeks	2/34 (5.9%)	3/50 (6%)
	Elliott 2004	Number of participants with residual effusion at 4 weeks	38/99 (38.4%)	56/98 (57.1%)
		Number of participants with residual effusion at 8 weeks	25/99 (30.3%)	42/98 (56.1%)
		Number of participants with residual effusion at 24 weeks	10/99 (10.1%)	25/98 (25.5%)³
	Lee 1988	Number of participants with residual effusion at 4 weeks	9/21 (42.9%)	15/19 (78.9%)
		Number of participants with residual effusion at 8 weeks	5/21 (23.8%)	12/19 (63.2%)
		Number of participants with residual effusion at 24 weeks	1/21 (4.8%)	6/19 (31.6%)
	Lee 1999	Number of participants with residual effusion at 8 weeks	29/32 (90.6%)	49/50 (98%)
	Lee 1999	Number of participants with residual effusion at 24 weeks	20/32 (62.5%)	44/50 (88%)
Abbreviations: N: number of participants ¹Reabsorption index = (length of affected hemithorax/length of healthy hemithorax) x 100. ²P = 0.01. ³Data at this time point extrapolated from graph. Data for 4 weeks and 8 weeks from the trial authors (unpublished data).

Table 6. Time to resolution of pleural effusion on chest X‐ray

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Table 7. Pulmonary function at the end of treatment

Trial	Indicator	Units	Corticosteroids	Control
Galarza 1995	Percentage predicted FVC	Mean percentage predicted FVC	95% (N = 57)	95% (N = 60)¹
Wyser 1996	Percentage predicted FVC	Mean percentage predicted FVC	85% (N = 34)	80% (N = 36)²
Wyser 1996	Lung function impairment	Number of participants with restrictive PFT results	11/34 (33.3%)	14/36 (39.4%)³
Abbreviations: FVC: forced vital capacity; N: number of participants; PFT: pulmonary function tests ¹Range 65% to 130% in steroid group, 63% to 140% in placebo group. ²Read from graph, P = 0.65. ³P = 0.72. Results extrapolated from percentages.

Table 7. Pulmonary function at the end of treatment

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Table 8. Adverse events leading to discontinuation of the trial drug

Trial	Corticosteroid	Control
Bang 1997	1/34 (2.9%)¹	0/50
Elliott 2004	9/99 (9.1%)²	2/98 (2.0%)
Galarza 1995	0/57	NR
Lee 1988	1/21 (4.8%)³	NR
Lee 1999	NR	NR
Wyser 1996	4/34 (11.8%)	3/36 (8.3%)⁴
Abbreviations: NR: not reported ¹Aggravation of epigastric pain in one patient, steroids stopped, and patient withdrawn from the trial. ²Trial drug discontinued for hyperglycaemia (two participants), hypertension (three participants), herpes zoster (three participants), oesophageal candidiasis (one participant) in the corticosteroid group; in the placebo group hyperglycaemia (one participant) and hypertension (one participant). ³One participant developed moon facies, epigastric pain, and lower limb oedema, all of which resolved on tapering the dosage. ⁴Epigastric pain was the only adverse effect noted, and affected four participants in the steroid group and three in the control group.

Table 8. Adverse events leading to discontinuation of the trial drug

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Table 9. Results: HIV‐related adverse events

Trial	Indicator	Control (N/98)	Corticosteroid (N/99)
Elliott 2004	Kaposi’s sarcoma	0	6 (6.1%)
	Cryptococcal meningitis	5 (5.1%)	3 (3.0%)
	Oesophageal candidiasis	23 (23.5%)	35 (35.4%)
	Oral candidiasis	31 (32.6%)	31 (31.3%)
	Herpes zoster	19 (19.4%)	22 (22.2%)
	Oral or genital herpes simplex	20 (20.4%)	22 (22.2%)
	Gastroenteritis	28 (28.6%)	34 (34.3%)
Abbreviations: N: number of participants

Table 9. Results: HIV‐related adverse events

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Comparison 1. Corticosteroids versus control (placebo or no steroids)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Residual pleural effusion on chest X‐ray Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 At 4 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.49, 0.84]
1.2 At 8 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.37, 0.78]
1.3 At 24 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.18, 0.66]
2 Pleural changes at the end of treatment (pleural thickening and pleural adhesions) Show forest plot	5	393	Risk Ratio (M‐H, Fixed, 95% CI)	0.72 [0.57, 0.92]

3 Death from any cause Show forest plot	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.64, 1.31]

4 Adverse events leading to study drug discontinuation Show forest plot	6	590	Risk Ratio (M‐H, Fixed, 95% CI)	2.78 [1.11, 6.94]

5 HIV‐associated adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Cryptococcal meningitis	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Oesophageal candidiasis	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.3 Oral candidiasis	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.4 Gastroenteritis	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.5 Herpes simplex	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.6 Herpes zoster	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.7 Kaposi sarcoma	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Corticosteroids versus control (placebo or no steroids)

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Comparison 2. Effect of study quality on the outcome residual pleural fluid on chest X‐ray

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Residual pleural fluid on chest X‐ray ‐ studies at high risk of selection bias excluded Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 At 4 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.49, 0.84]
1.2 At 8 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.54 [0.37, 0.78]
1.3 At 24 weeks	2	237	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.18, 0.66]
2 Residual pleural fluid on chest X‐ray ‐ studies at high risk of selection bias included Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 At 4 weeks	3	321	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.52, 1.07]
2.2 At 8 weeks	4	403	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.47, 1.12]
2.3 At 24 weeks	4	403	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.30, 0.98]

Comparison 2. Effect of study quality on the outcome residual pleural fluid on chest X‐ray

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