Patient enrollment
A total of 14946 pulmonary TB patients have been documented in the two hospitals, 392 (2.62%) of them had acute miliary TB. 282 (71.94%) miliary TB patients undertook lumbar punctures or/and neuroimaging for the assessment of CNS involvement. Of these 282 patients, 87.59% (247/282) had CNS involvement. Totally, 8.50% (21/247) patients were definite cases by detection of Mtb in CSF, among which 19 were in CSF abnormal group and 2 in CSF normal group. The other 226 enrolled patients had clinical diagnosis.
Demographic Characteristics And Clinical Features
Among the 392 miliary TB, the male to female ratio was 1.24. The median age was 36 yrs (range 15–87), and 18–39 yrs group accounted for 53.06% of all enrolled patients. The most frequent symptom of TB was fever (90.56%), followed by cough (46.68%). The most common symptoms suggestive of CNS-TB were headache (40.31%), vomiting (25.00%) and meningeal signs (17.09%). All the patients were HIV-uninfected (Table 1).
Table 1
Demographic and clinical characteristics of 392 individuals with acute miliary tuberculosis
Characteristics | Overall | Beijing Chest Hospital | Henan Chest Hospital |
Total | 392 | 321 | 71 |
Sex | | | |
male | 217(55.36) | 175 (54.52) | 42(59.15) |
female | 175(44.64) | 146 (45.48) | 29(40.85) |
Age, median (range), yr | 36(15–87) | 30 (15–86) | 43(17–87) |
Age categories years | | | |
15–18 | 18(4.59) | 16 (4.98) | 2(2.82) |
18–39 | 208(53.06) | 180 (56.07) | 28(39.44) |
40–59 | 74(18.88) | 63 (19.63) | 11(15.49) |
༞60 | 92(23.47) | 62 (19.31) | 30(42.25) |
HIV status | | | |
Negative | 392(100.00) | 321 (100.00) | 71(100.00) |
Positive | 0 | 0 | 0 |
Presenting symptoms | | | |
Fever | 355(90.56) | 291 (90.65) | 64(90.14) |
Cough | 183(46.68) | 155 (48.29) | 28(39.44) |
Weight loss | 149(38.01) | 147 (45.79) | 2(2.82) |
Headache | 158(40.31) | 133 (41.43) | 25(35.21) |
Vomiting | 98(25.00) | 81(25.23) | 17(23.94) |
Confusion | 61(15.56) | 50(15.58) | 11(15.49) |
Altered consciousness | 31(7.91) | 20 (6.23) | 11(15.49) |
Convulsion | 12(3.06) | 9(2.80) | 3(4.23) |
Seizures | 8(2.04) | 6(1.87) | 2(2.82) |
Meningeal sign | 67(17.09) | 59 (18.38) | 8(11.27) |
Cranial nerve palsy | 42(10.71) | 35 (10.90) | 7(9.86) |
Coma | 16(4.08) | 14(4.36) | 2(2.82) |
Paraplegia | 9(2.30) | 8 (2.49) | 1(1.41) |
Bacteriological Findings
In total, 317 miliary TB were subjected to at least one kind of bacteriological test with sputum and/or blood and/or CSF. 151 (47.63%) of them produced positive outcomes by either tests (Table 2). Xpert MTB/RIF (Xpert) (Cepheid, Sunnyvale, USA) acquired highest positivity with sputum, followed by conventional PCR (Daan gene Ltd., Guangzhou, China), culture and MeltPro TB (Zeesan Biotech, Xiamen, China). Altogether, 59.65% (134/225) of miliary TB demonstrated bacteriological evidence of TB. CSF testing yielded much lower positivity compared with sputum for all the methods performed. Only 11.63% (15/129) of CSF were positive for Xpert, whereas the other tests were even lower. As a consequence, only 8.82% of the miliary TB had definite CNS-TB.
Table 2
Microbiological findings for miliary tuberculosis and cerebrospinal fluid examination
Specimen | Smear (%) | Culture (%) | Xpert (%) | PCR (%) | MeltPro TB (%) | Total |
Sputum | 47/179(26.26) | 80/161(49.69) | 67/109(61.47) | 37/70(52.86) | 30/66(45.45) | 134/225(59.56) |
Blood | — | 4/32(12.50) | — | — | — | 4/32(12.50) |
CSF | 2/206(0.97) | 6/87(6.90) | 15/129(11.63) | 9/188(4.79) | — | 21/238(8.82) |
Total | 49/287(17.07) | 89/219(40.64) | 77/166(46.39) | 46/218(21.10) | 30/66(45.45) | 151/317(47.63) |
Csf Biochemistry Test Findings
Assessment of CNS involvement with a lumbar puncture was undertaken in 60.71% (238/392) miliary TB patients. CSF abnormalities were detected in 146 patients overall. Headache, vomiting, confusion, altered consciousness, meningeal sign and cranial nerve palsy were noted in a much higher proportion among CSF abnormal patients than among CSF normal cases (Table 3).
Table 3
The presenting symptoms in 238 miliary tuberculosis with lumbar puncture
Methods | CSF normal (n = 92) | CSF abnormal (n = 146) | P values* |
With CNS diagnosis (n = 57) | Without CNS diagnosis (n = 35) | Total |
Fever | 32(91.43%) | 50(87.72%) | 82(89.13%) | 140(95.89%) | 0.043 |
Cough | 20(57.14%) | 28(49.12%) | 48(52.17%) | 57(39.04%) | 0.047 |
Weight loss | 15(42.86%) | 23(40.35%) | 38(44.19%) | 61(41.78%) | 0.942 |
Headache | 6(17.14%) | 20(35.09%) | 26(28.26%) | 108(73.97%) | <0.001 |
Vomiting | 3(8.57%) | 10(17.54%) | 13(14.13%) | 66(45.21%) | <0.001 |
Confusion | 0 | 2(3.51%) | 2(2.33%) | 42(28.77%) | <0.001 |
Altered consciousness | 0 | 5(8.77%) | 5(5.81%) | 22(15.07%) | 0.022 |
Convulsion | 0 | 3(5.26%) | 3(3.49%) | 6(4.11%) | 0.738 |
Seizures | 0 | 1(1.75%) | 1(1.16%) | 2(1.44%) | 0.849 |
Meningeal sign | 1(2.86%) | 5(8.77%) | 6(6.52%) | 45(30.82%) | <0.001 |
Cranial nerve palsy | 2(5.71%) | 2(3.51%) | 4(4.65%) | 21(14.38%) | 0.014 |
Coma | 0 | 2(3.51%) | 2(2.33%) | 10(6.85%) | 0.108 |
Paraplegia | 0 | 0 | 0 | 8(5.48%) | 0.022 |
CSF: cerebrospinal fluid, CNS: central nervous system |
*Comparison between CSF normal and abnormal groups. |
There was no significant difference between CSF normal patients with or without CNS involvement groups |
Radiographic Image Findings
Among 223 miliary TB, neuroimaging examinations, cerebral CT, contrast-enhanced CT, MRI and contrast-enhanced MRI were performed for 49, 8, 219 and 177 patients, respectively. The most common abnormality on neuroimaging was the presence of miliary pattern of brain, followed by meningeal enhancement (Table 4).
Table 4
Radiographic findings of 247 miliary tuberculosis patients with central nervous system involvement
Characteristics | CT (n = 49, %) | Contrast-enhanced CT (n = 8, %) | MRI (n = 219, %) | Contrast-enhanced MRI (n = 177, %) |
Meningeal TB | | | | |
meningeal enhancement | 4(8.16) | 1(12.50) | 39(17.81) | 50(28.25) |
meningeal tuberculomas | 0 | 0 | 8(3.76) | 19(10.73) |
Meningeal abscess | 0 | 0 | 1(0.46) | 2(1.13) |
Brain parenchymal TB | | | | |
Miliary pattern of brain | 17(34.69) | 7(87.50) | 184(84.02) | 157(88.70) |
Tuberculous encephalitis | 0 | 0 | 6(2.74) | 1(0.46) |
Mixed intracranial TB | 3(6.12) | 0 | 19(8.68) | 37(20.90) |
Overall Sensitivity For Identification Cns Involvement Among Miliary Tb
Among the 247 miliary TB with CNS involvement, contrast-enhanced MRI (96.05%, 170/177) and MRI (93.15%, 204/219) were significantly more sensitive than CSF examination (71.92%, 146/203, P<0.001) and CT (34.69%, 17/49, P<0.001). The sensitivity of CSF examination was superior to CT scan (P<0.001). Contrast-enhanced MRI had higher sensitivity than MRI, but the differences were not significant (P = 0.211) (Table 5). Among patients with or without CNS symptom, MRI and contrast-enhanced MRI had more than 90% abnormal manifestations, whereas the abnormal rates for CT were much lower for both groups (Table 5). Surprisingly, 5 out of 7 patients without CNS symptom had abnormal CT imaging, whereas only 12 out of 42 patients with CNS symptom had abnormal CT imaging. However, the patient number for non-CNS symptom group was too small to draw any conclusion.
Table 5
The abnormal rate of cerebrospinal fluid or radiographic imaging stratified by central nervous system symptoms for miliary tuberculosis patients with central nervous system involvement
Methods | Total | Without CNS symptoms (n = 73) | With CNS symptoms (n = 174) | P values |
CSF | 146/203(71.92) | 24/56(42.86) | 122/147(82.99) | <0.001 |
CT | 17/49(34.69) | 5/7(71.43) | 12/42(28.57) | 0.027 |
MRI | 204/219(93.15) | 67/70(94.03) | 137/149(91.95) | 0.303 |
Contrast-enhanced MRI | 170/177(96.05) | 55/57(96.43) | 115/120(95.80) | 0.834 |
Among the 146 CSF abnormal CNS-TB, 28.5% (10/35) of the patients had cerebral CT scanning which presented abnormal images, while these percentages for contrast-enhanced CT, MRI and contrast-enhanced MRI were 80% (4/5), 92.00% (115/125), and 95.00% (95/100), respectively. In addition, among the 57 CNS TB with normal CSF outcomes, CT, contrast-enhanced CT, MRI and contrast-enhanced MRI detected 36.36% (4/11), 100% (3/3), 98.04% (50/51), 100% (38/38) patients. Notably, among 8 patients with CNS symptom but with normal CT images and normal CSF outcomes, lesions in brains were identified in 4 patients using MRI and contrast-enhanced MRI. Another patient, using contrast-enhanced CT, also showed cerebral abnormality.
Stratification analysis was conducted further by dividing the miliary TB into definite or clinically diagnosed CNS-TB groups. MRI and contrast-enhanced MRI demonstrated similar sensitivities among both groups, the positive rates were all greater than 90%, and no significant difference was observed. CSF examination had higher sensitivity for the definite CNS-TB group (90.48%, 19/21) than for clinically diagnosed group (69.78%, 127/182; P = 0.046). Whereas CT scan had lower sensitivities for both groups (50.00%, 2/4 vs 33.33%, 15/45; P = 0.502), and no significant difference was observed.