Physiology tests at Visit 2

For Visit 2, 103 subjects were able to perform spirometry. The following variables were not normally distributed and required analysis using non- parametric statistical tests:

• Post-bronchodilator FEV1 (litres)

• Post-bronchodilator FVC (litres)

• Post-bronchodilator FEV1:FVC.

Findings of Visit 2 data and analysis are presented in Table 58.

8.2.2.1. Post-bronchodilator FVC

There was no significant difference in the median post bronchodilator FVC (litres) between those with or without PPTB (Wilcoxon p=0.398). Similarly, no difference was found in the comparison of the three subgroups: NPTB, DPTB and PrPTB (Kruskal Wallis p=0.368).

There was also no difference in the mean post-bronchodilator FVC (as % predicted) between those with and without PPTB (Satterthwaite’s t-test for

unequal variances p=0.917). No difference was found between the three subgroups (ANOVA p=0.990).

8.2.2.2. Post-bronchodilator FEV1

There was no significant difference in the median post-bronchodilator FEV1 (litres), between those with or without PPTB (Wilcoxon p=0.440), and no significant difference on three-group analysis of the NPTB, DPTB and PrPTB groups (Kruskal Wallis p=0.617).

FEV1 (% predicted) was both normally distributed and had equal variance. Thus, one sample t-test and ANOVA tests were used. The difference in the FEV1 (% predicted) between those with NPTB (mean FEV1 75.1%) and those with PPTB (mean FEV1 67.0%) was not significant (t-test p=0.090) [see Figure 43]. On three-group analysis, the difference between the NPTB (mean 75.1% predicted), DPTB (mean 63.0%) and PrPTB groups (mean 71.8%) was also not significant (ANOVA p=0.0529) [see Figure 44]. Using the Bonferroni correction, the difference between each pair of means was as follows:

• Difference between NPTB and DPTB: p=0.065

• Difference between NPTB and PrPTB: p=1.000

• Difference between DPTB and PrPTB: p=0.250.

n=31 n=72 0 50 100 150 FEV1 (% predicted) No Previous TB Previous TB (n=103) t-test: p= 0.0897 at Visit 2

Post bronchodilator FEV1 (percentage predicted)

Figure 43: Post-bronchodilator FEV1 (% predicted) at Visit 2

according to PPTB status: NPTB vs. PPTB. n=31 n=39 n=33 0 50 100 150 FEV1 (% predicted)

No Previous TB Definite TB Probable TB (n=103)

ANOVA: p = 0.0529

at Visit 2

Post bronchodilator FEV1 (percentage predicted)

Figure 44: Post-bronchodilator FEV1 (% predicted) at Visit 2 according to PPTB status: three- group analysis.

Table 58: Comparison of the results of lung physiology at Visit 2 according to previous PTB status: PPTB vs. NPTB and by subgroups.

NPTB sd PPTB sd p-value test NPTB sd DPTB sd PrPTB sd p-value test

(n) (31) (72) (31) (39) (33)

Post BD FVC (L) - mean 2.76 0.849 3.00 1.051 n/a 2.76 0.849 3.11 1.049 2.87 1.053 n/a

Post BD FVC (L) - median 2.80 - 2.83 - 0.398 Wilcoxon 2.80 - 3.22 - 2.65 - 0.368 Kwallis

Post BD FVC (%) - mean 96.29 11.335 95.99 17.490 0.917 Satterthwaite t-test

96.29 11.335 95.79 19.195 96.21 15, 532 0.990 ANOVA

Post BD FEV1 (L) -mean 1.74 0.638 1.67 0.746 n/a n/a 1.74 0.638 1.64 0.797 1.70 0.693 n/a n/a

Post BD FEV1 (L) - median 1.68 - 1.44 - 0.440 Wilcoxon 1.68 - 1.41 - 1.49 - 0.617 Kwallis

Post BD FEV1 (%) -mean 75.06 18.282 67.04 23.126 0.090 t-test 75.06 18.282 62.95 24.880 71.88 20.172 0.053 ANOVA

Post BD FEV1:FVC - mean 0.63 0.131 0.56 0.141 n/a n/a 0.63 0.131 0.52 0.133 0.60 0.138 n/a n/a

Post BD FEV1:FVC - median 0.67 - 0.60 - 0.012 Wilcoxon 0.67 - 0.54 - 0.63 - 0.002 Kwallis

Reversibility

Litres - median 0.20 0.156 0.19 0.168 0.730 Wilcoxon 0.20 0.16 0.16 0.148 0.19 0.190 0.879 Kwallis

% change 11.76 13.708 11.99 16.708 0.994 Wilcoxon 11.76 13.71 11.77 18.148 12.63 15.106 1.000 Kwallis

Significant reversibility*

Number of subjects 13 - 26 - 13 - 12 - 14 -

% (0.42) - (0.36) - 0.576 Chi2 0.42 - 0.31 - 0.42 - 0.511 Chi2

DLCO (mL/min/mmHg) 18.06 5.483 15.16 4.954 0.010 t-test 18.06 5.483 14.93 4.754 15.44 5.242 0.033 ANOVA

DLCO (%) 79.52 23.659 64.85 19.553 0.002 t-test 79.52 23.659 61.72 15.285 68.55 23.341 0.003 ANOVA *Significant reversibility = change in FEV1 of >200mL & >12%

8.2.2.3. Rate of decline in FEV1

The rate of decline in FEV1 between the BOLD 2005 study and Visit 1 spirometry of the Follow-up study (2010) are presented in Table 60. No difference in either the absolute decline in FEV1 or the rate of decline was found between subjects with and without PPTB. The FEV1 declined by a median of 119 mL (16.8 mL/yr) in those with NPTB and by 170 mL (32.7 mL/yr) in those with PPTB (Wilcoxon p=0.283). There was also no difference in the rate of decline between the subgroups.

8.2.2.4. FEV1:FVC

The median FEV1:FVC was significantly lower in subjects with PPTB (median ratio 0.60) compared with those subjects with NPTB (median ratio 0.67) (Wilcoxon p=0.012) [see Figure 45].

Additionally, on three-group analysis, there was a significant difference in median FEV1:FVC between those with NPTB (median ratio 0.67), those with DPTB (median ratio 0.54) and those with PrPTB (median ratio 0.63) (Kruskal-Wallis Test p=0.002) [see Figure 46].

Comparing the median FEV1:FVC between the individual groups using the Wilcoxon test yielded the following results:

• Difference between NPTB and DPTB: p=0.0006

• Difference between NPTB and PrPTB: p=0.4011

n=31 n=72 .2 .4 .6 .8 FEV1:FVC Ratio No Previous TB Previous TB (n=103) Wilcoxon: p=0.0116 at Visit 2

Post bronchodilator FEV1:FVC Ratio

Figure 45: Post-bronchodilator FEV1:FVC at Visit 2 according to

PPTB status, NPTB vs. PPTB. n=31 n=39 n=33 .2 .4 .6 .8 FEV1:FVC Ratio

No Previous TB Definite TB Probable TB (n=103)

Kruskal-Wallis: p=0.0015

at Visit 2

Post bronchodilator FEV1:FVC Ratio

Figure 46: Post-bronchodilator FEV1:FVC at Visit 2 according to PPTB status: three-group analysis. 8.2.2.4. Bronchodilator responsiveness

Bronchodilator responses (change in FEV1 45 minutes after administration of 400 μg salbutamol and 80 μg ipratropium bromide anhydrous) were similar in those with and without PPTB, whether expressed in litres or percentage change. Additionally, there was no significant difference when three-group analysis was performed. Neither was there a difference in the proportion of subjects with significant reversibility (defined as a change in FEV1 of more than 200 mL and 12.0%) between subjects with and without PPTB, or in three-group analysis [see Table 58].

8.2.2.5. Diffusing capacity (DLCO)

A significantly higher mean DLCO (ml/min/mmHg) was found in subjects with

NPTB (18.06 mL/min/mmHg, sd=5.483) compared with PPTB (15.16 mL/min/mmHg, sd=4.954) (t-test p=0.0097) [see Figure 47]. The difference between DPTB (14.93 mL/min/mmHg, sd=4.754), PrPTB (15.44 mL/min/mmHg, sd=5.242) and NPTB groups (18.06 mL/min/mmHg, sd=5.483) was also significant (ANOVA p=0.003) [see Figure 48]. However, on Bonferroni correction only the difference between those with NPTB and DPTB remained (p=0.033).

(n=31) (n=72) 5 10 15 20 25 30 Dif

fusion capacity (mL/min/mmHg/L,stpd)

No Previous TB Previous TB

(n=103)

ttest: p=0.0097

at Visit 2

Diffusion Capacity

Figure 47: Diffusing capacity (mLl/min/mmHg) according to PPTB status : NPTB vs. PPTB. (n=31) (n=39) (n=33) 5 10 15 20 25 30 Dif

fusion capacity (mL/min/mmHg/L,stpd)

No Previous TB Definite TB Probable TB

(n=103)

ANOVA: 0.033

at Visit 2

Diffusion Capacity

Figure 48: Diffusing capacity (mL/min/mmHg) according to PPTB

status: three-group analysis.

DLCO, expressed as percentage of predicted, was also higher in subjects with

NPTB (79.5%, sd=23.7%) vs. those with PPTB (64.9%, sd=19.6%)

(t-test p=0.002) [see Figure 49]. It was also significantly different in three- group analysis between those with NPTB (79.5%, sd=23.7%), DPTB (61.7%, sd=15.3%) and PrPTB (68.6%, sd=23.3%) (ANOVA p=0.003) [see Figure 50]. The Bonferroni correction confirmed a significant difference only between those with NPTB and those with DPTB (p=0.002).

(n=31) (n=72) 0 50 100 150 Dif

fusion capacity (% predicted)

No Previous TB Previous TB (n=103)

ttest: 0.002

at Visit 2

Diffusion Capacity (percentage predicted)

Figure 49: Diffusing capacity (%predicted) according to PPTB status: NPTB vs. PPTB. (n=31) (n=39) (n=33) 0 50 100 150 Dif

fusion capacity (% predicted)

No Previous TB Definite TB Probable TB (n=103)

ANOVA: 0.003

at Visit 2

Diffusion Capacity (percentage predicted)

Figure 50: Diffusing capacity (%predicted) according to PPTB