Long-term mortality in patients with pulmonary and extrapulmonary tuberculosis: a Danish nationwide cohort study

Figures & data

Figure 1 Summary of study design.

Notes: Nationwide cohort study of long-term mortality in patients with TB, Denmark, 1977–2008.
Abbreviations: EPTB, extrapulmonary tuberculosis; LFU, lost to follow-up; PTB, pulmonary tuberculosis; TB, tuberculosis; yrs, years.

Table 1 Characteristics of PTB and EPTB patient cohorts, population comparison cohorts, and sibling cohorts

	PTB patients	PTB population controls	Siblings of PTB patients	Siblings of PTB population controls	EPTB patients	EPTB population controls
Total number, n (%)	6,402 (25.0)	19,206 (75.0)	1,990 (14.6)	11,679 (85.4)	1,889 (25.0)	5,667 (75.0)
Males, n (%)	3,855 (60.2)	11,565 (60.2)	1,055 (53.0)	6,244 (53.5)	816 (43.2)	2,448 (43.2)
Immigrants, n (%)	2,326 (36.3)	0	405 (20.4)	0	1,242 (65.7)	0
Observation time (total), years	64,212	234,484	19,268	12,449	20,339	67,272
Observation time, median (IQR), years	8.1 (3.7–14.1)	10.5 (5.5–17.2)	8.3 (4.1–13.3)	9.7 (5.4–14.2)	9.3 (4.8–14.7)	10.4 (5.9–15.8)
Observation time (total), years, Danes	40,398				7,291
Observation time, median (IQR), years, Danes	7.8 (3.4–14.2)				9.1 (4.6–16.4)
Observation time (total), years, immigrants	23,814				13,047
Observation time, median (IQR), years, immigrants	8.7 (4.3–13.8)				9.4 (5.0–13.8)
Lost to follow-up during study period, n (%)	79 (1.2)	4 (0.01)	7 (0.4)	5 (0.01)	34 (1.8)	2 (0.001)
Emigrated during study period, n (%)	281 (4.4)	204 (1.1)	54 (2.7)	198 (1.7)	158 (8.4)	62 (1.1)
Age at diagnosis, median (IQR), years	42.8 (30.1–58.6)	42.8 (30.1–58.6)	31.7 (25.3–38.4)	31.5 (24.0–38.2)	38.8 (28.9–60.2)	38.8 (28.9–60.2)
Age at diagnosis by age intervals, n (%)
16–30 years	1,570 (24.5)	4,710 (24.5)	889 (44.7)	5,043 (43.2)	540 (28.6)	1,620 (28.6)
31–60 years	3,357 (52.4)	10,071 (52.4)	1,101 (55.3)	6,636 (56.8)	874 (46.3)	2,622 (46.3)
>61 years	1,475 (23.0)	4,425 (23.0)	0	0	475 (25.1)	1,425 (25.1)
Patients diagnosed by decade, n (%)
1977–1986	2,026 (31.6)	6,078 (31.6)			548 (29.0)	1,644 (29.0)
Immigrants, n (%)	383 (18.9)	0			168 (30.7)	0
1987–1996	1,500 (23.4)	4,500 (23.4)			463 (24.5)	1,389 (24.5)
Immigrants, n (%)	605 (40.3)	0			326 (70.4)	0
1997–2008	2,876 (44.9)	8,628 (44.9)			878 (46.5)	2,634 (46.5)
Immigrants, n (%)	1,338 (46.5)	0			748 (85.2)	0
Age at diagnosis by decade, median (IQR), years
1977–1986	52.6 (34.7–65.9)	52.6 (34.7–65.9)			57.6 (36.3–70.4)	57.6 (36.3–70.4)
1987–1996	41.2 (29.7–57.6)	41.2 (29.7–57.6)			36.3 (27.2–60.6)	36.3 (27.2–60.6)
1997–2008	39.5 (28.9–51.5)	39.5 (28.9–51.5)			34.6 (28.1–46.0)	34.6 (28.1–46.0)
Modified Charlson Comorbidity Index, n (%)
None (score 0)	5,498 (85.9)	17,744 (92.4)	1,897 (95.3)	11,254 (96.4)	1,680 (88.9)	5,231 (92.3)
Low (score 1–2)	791 (12.4)	1,340 (7.0)	85 (4.3)	385 (3.3)	177 (9.4)	408 (7.2)
High (score≥3)	113 (1.8)	122 (0.6)	8 (0.4)	40 (0.3)	32 (1.7)	28 (0.5)
Hospital admission in 5 years prior to TB
Total patients, n (%)	2,677 (41.8)	5,589 (29.1)	660 (33.2)	3,695 (31.6)	871 (46.1)	1,854 (32.7)
Infectious diseases	176 (2.7)	171 (0.9)	55 (2.8)	116 (1.0)	58 (3.1)	59 (1.0)
Pulmonology	426 (6.7)	403 (2.1)	50 (2.5)	255 (2.2)	61 (3.2)	131 (2.3)
Endocrinology	133 (2.1)	192 (1.0)	16 (0.8)	82 (0.7)	43 (2.3)	51 (0.9)
Gastroenterology	491 (7.7)	834 (4.3)	77 (3.9)	369 (3.2)	134 (7.1)	246 (4.3)
Psychiatry	225 (3.5)	116 (0.6)	29 (1.5)	91 (0.8)	9 (0.5)	37 (0.7)
Cardiovascular	320 (5.0)	824 (4.3)	38 (1.9)	166 (1.4)	88 (4.7)	227 (4.0)
Alcohol-related	152 (2.4)	51 (0.3)	10 (0.5)	24 (0.2)	2 (0.1)	9 (0.2)
Injury or poisoning	677 (10.6)	1,105 (5.8)	158 (7.9)	704 (6.0)	106 (5.6)	306 (5.4)
Neurology	90 (1.4)	167 (0.9)	20 (1.0)	97 (0.8)	20 (1.1)	56 (1.0)
Malignant neoplasm prior to study inclusion, n (%)	248 (3.9)	565 (2.9)	17 (0.9)	97 (0.8)	61 (3.2)	190 (3.4)
HIV diagnosis before or at time of TB diagnosis, n (%)	107 (1.7)	28 (0.001)	9 (0.5)	14 (0.1)	18 (1.2)	6 (0.001)
Medical history of TB before study inclusion, n (%)	0	0	163 (8.2)	17 (0.1)	0	0

Abbreviations: EPTB, extrapulmonary tuberculosis; HIV, human immunodeficiency virus; IQR, interquartile range; PTB, pulmonary tuberculosis; TB, tuberculosis.

Figure 2 Kaplan–Meier survival curves.

Notes: Graphs depict long-term mortality in patients (dashed line) with PTB (A), and EPTB (B), compared with population controls (solid line), Denmark, 1977–2008.
Abbreviations: EPTB, extrapulmonary tuberculosis; PTB, pulmonary tuberculosis.

Table 2 All-cause mortality rate ratios in PTB and EPTB patients, population controls, and siblings, Denmark, 1977–2008

	PTB cohort			EPTB cohort			Siblings (n=1,990) of PTB patients versus siblings (n=11,679) of PTB controls; all born after January 1, 1952			PTB patients (n=1,019) versus their respective siblings (n=1,990); all born after January 1, 1952
	Number of patients who died	Number of controls who died	MRR (95% CI)	Number of patients who died	Number of controls who died	MRR (95% CI)	Number of siblings of patients who died (%)	Number of siblings of controls who died (%)	MRR (95% CI)a	Number of patients who died (%)	Number of siblings of patients who died (%)	MRR (95% CI)a
Overall	2,388 (37.3%)	4,683 (24.4%)	1.86 (1.77–1.96)	515 (27.3%)	1,379 (24.3%)	1.24 (1.12–1.37)	74 (3.7)	206(1.8)	2.16(1.62-2.87)	110(10.8)	74 (3.7)	3.55(2.57-4.91)
Overall for individuals born after January 1, 1952	271 (8.4)	193 (2.0)	4.62 (3.85–5.57)
MRR stratified on individual risk factors
Sex
Females	812	1,757	1.61 (1.48–1.75)	299	789	1.24 (1.09–1.42)	16	65	1.53 (0.86-2.73)	30	16	6.95(3.46-13.94)
Males	1,576	2,926	2.04 (1.92–2.17)	216	590	1.23 (1.05–1.43)	58	141	2.45(1.76-3.40)	80	58	2.86(1.98-4.12)
Age at diagnosis (years)
16–30	87	106	2.71 (2.04–3.59)	16	20	2.61 (1.35–5.04)	21	68	2.09(1.27-3.44)	29	21	2.93 (1.63-5.28)
0–10 years observation time	12	18	2.19 (1.05–4.55)	5	4	4.09 (1.10–15.25)
> 10 years observation time	0	1	n/a	0	0	n/a
31–60	1,104	1,464	2.80 (2.59–3.03)	140	310	1.50 (1.23–1.83)	53	138	2.17(1.54-3.08)	81	53	3.88 (2.63-5.72)
0–10 years observation time	500	306	5.87 (5.09–6.77)	36	73	1.64 (1.10–2.44)
>10 years observation time	184	198	3.44 (2.81–4.20)	20	29	2.39 (1.35–4.22)
>60	1,197	3,113	1.57 (1.47–1.68)	359	1,049	1.15 (1.02–1.29)	0	0	n/a	0	0	n/a
0–10 years	1,079	2,032	2.23 (2.07–2.40)	266	680	1.32 (1.14–1.52)
observation time
>10 years observation time	613	2,128	1.38 (1.26–1.50)	188	593	1.15 (0.98–1.36)
Ethnicity
Native Danes	2,119	4,147	1.94 (1.84–2.04)	429	1,158	1.27 (1.13–1.42)	72	206	2.38(1.78-3.18)	105	72	3.45 (2.48^.80)
Immigrantsb	269	536	1.71 (1.48–1.98)	86	221	1.26 (0.98–1.62)	2	0	n/a	5	2	5.85(1.12-30.61)
Modified Charlson
Comorbidity Index
Score 0	1,857	3,689	1.80 (1.70–1.90)	407	1,119	1.18 (1.06–1.33)
Score 1	460	902	2.20 (1.96–2.46)	90	234	1.46 (1.15–1.86)
Score 2	71	92	4.22 (3.09–5.75)	18	26	3.11 (1.70–5.67)

Notes:

a Adjusted for sex and age

b immigrant patients compared with their Danish population controls.

Abbreviations: CI, confidence interval; EPTB, extrapulmonary tuberculosis; MRR, mortality rate ratio; n/a, not applicable; PTB, pulmonary tuberculosis.

Table 3 Cause-specific mortality rate ratios in PTB and EPTB patients, population controls, and siblings, Denmark, 1977–2008

	PTB cohort				EPTB cohort				Siblings of PTB patents versus siblings of PTB controls				PTB patients versus their respective siblings
	Number of patients who died (n=2,388)	Number of controls who died (n=4,683)	MRR	95% CI	Number of patients who died (n=515)	Number of controls who died (n=1,379)	MRR	95% CI	Number of siblings of patients who died (n=74 total)	Number of siblings of controls who died (n=206 total)	MRRa	95% CI	Number of patients who died (n=110 total)	Number of siblings of patients who died (n=74 total)	MRRa	95% CI
Infectious diseases	156	31	18.38	12.50–27.02	14	8	5.79	2.43–13.80	7	2	10.53	1.76–63.00	11	7	10.56	2.33–17.83
Neoplasmsb	530	1,242	1.56	1.41–1.73	118	334	1.17	0.95–1.44	13	54	1.32	0.67–2.61	13	13	2.71	1.15–6.37
Malignant neoplasms of lip, oral cavity, and pharynx	28	22	4.65	2.66–8.12	0	7
Malignant neoplasms of digestive organs	128	349	1.34	1.10–1.65	34	72	1.56	1.04–2.35
Malignant neoplasms of respiratory and intrathoracic organs	191	303	2.30	1.92–2.76	25	72	1.15	0.73–1.81
Malignant neoplasms of bone and articular cartilage	1	3	1.22	0.13–11.70	1	1
Melanoma and other malignant neoplasms of skin	3	17	0.64	0.19–2.20	1	7	0.47	0.06–3.84
Malignant neoplasms of breast	27	63	1.57	1.00–2.46	10	23	1.44	0.68–3.02
Malignant neoplasms of female genital organs	13	57	0.83	0.46–1.52	5	31	0.53	0.21–1.37
Malignant neoplasms of male genital organs	24	100	0.88	0.56–1.37	7	20	1.16	0.49–2.74
Malignant neoplasms of urinary tract	21	74	1.04	0.64–1.68	5	28	0.59	0.23–1.53
Malignant neoplasms of central nervous system	7	32	0.80	0.35–1.81	2	4
Malignant neoplasms of thyroid and other endocrine organs	0	3			1	0
Malignant hematologic neoplasms	37	87	1.55	1.06–2.28	15	25	1.98	1.05–3.76
Malignant neoplasm of other and ill-defined sites	50	125	1.46	1.05–2.03	10	43	0.75	0.38–1.49
Benign neoplasms	0	7			2	1
Hematologic diseases	10	15	2.43	1.09–5.42	1	3	1.10	0.11–10.60	0	3			1	0
Endocrine diseases	67	123	1.99	1.48–2.68	17	35	1.61	0.90–2.87	1	4	1.76	0.20–15.75	3	1	5.41	0.56–52.29
Psychiatric disorders (including those caused by alcohol and/or drug abuse)	108	142	2.78	2.16–3.57	8	27	0.98	0.45–2.16	12	15	4.66	2.09–10.37	11	12	2.44	0.97–6.09
Neurologic diseases	21	73	1.05	0.65–1.71	9	14	2.13	0.92^.91	0	6			1	0
Cardiovascular diseases	573	1,761	1.19	1.08–1.3 1	191	582	1.09	0.92–1.28	5	26	1.35	0.52–3.52	II	5	3.87	1.34–11.21
Respiratory diseases	353	432	2.98	2.59–3.43	40	141	0.94	0.66–1.33	3	5	1.40	0.16–11.95	7	3	15.37	1.87–126.61
Gastrointestinal diseases	178	210	3.10	2.53–3.78	27	43	2.08	1.28–3.36	10	17	4.17	1.82–9.53	25	10	6.49	2.80–15.05
Dermatologic diseases	0	2			2	2	3.31	0.47–23.48	0	0			0	0
Rheumatologic diseases	12	17	2.58	1.23–5.40	1	8	0.41	0.05–3.31	0	0			1	0
Genitourinary diseases	22	78	1.03	0.64–1.65	12	16	2.48	1.17–5.24	0	1			0	0
Injury or poisoning	150	219	2.50	2.03–3.08	27	72	1.24	0.80–1.93	12	54	1.57	0.84–2.93	14	12	2.00	0.92–4.32
Not classified elsewhere	155	244	2.32	1.90–2.84)	32	79	1.34	0.89–2.02	0	9			8	0
Unknown	51	89	2.09	1.48–2.95	14	15	3.09	1.49–6.40	11	7	11.06	4.29–28.52	3	11	0.47	0.13–1.70
Congenital cause of death	2	5			1	0			0	3			1	0
Pregnancy-related death	0	0			1	0			0	0			0	0

Notes:

a Adjusted for sex and age.

b Detailed neoplasm subanalysis not performed for sibling study populations due to small case numbers.

Abbreviations: CI, confidence interval; EPTB, extra-pulmonary tuberculosis; MRR, mortality rate ratio; PTB, pulmonary tuberculosis.

Table S1 Detailed cause-specific mortality rate ratios in PTB and EPTB patients compared with population controls, Denmark, 1977–2008

	PTB cohort				EPTB cohort
	Number of patients who died (n=2,388)	Number of controls who died (n=4,683)	MRR	95% CI	Number of patients who died (n=515)	Number of controls who died (n=1,379)	MRR	95% CI
Infectious diseases	156	31	18.38	12.50–27.02	14	8	5.79	2.43–13.80
Tuberculosis and HIV/AIDS	135	3	164.33	52.34–515.92	10	0
Other infectious diseases	21	28	2.95	1.66–5.24	4	8	1.89	0.55–6.46
Malignant neoplasms	530	1,242	1.56	1.41–1.73	118	334	1.17	0.95–1.44
Malignant neoplasms of lip, oral cavity, and pharynx	28	22	4.65	2.66–8.12	0	7
Lip, oral cavity	0	0
Tongue, palate, parotid gland	18	14	4.70	2.34–9.44
Tonsils and oropharynx	4	4	3.65	0.91–14.60
Nasopharynx	0	0
Hypopharynx	2	3	2.43	0.41–14.57
Unspecified cancer of the ear, nose, throat	4	1	14.61	1.63–130.69
Malignant neoplasms of digestive organs	128	349	1.34	1.10–1.65	34	72	1.56	1.04–2.35
Esophagus	29	31	3.42	2.06–5.67	1	12	0.28	0.04–2.12
Stomach	17	44	1.41	0.81–2.47	6	6	3.31	1.07–10.26
Small intestine	1	3	1.22	0.13–11.70	0	1
Colon	33	126	0.96	0.65–1.40	10	29	1.14	0.56–2.34
Rectum	17	54	1.15	0.67–1.98	7	6	3.86	1.30–11.48
Liver and gallbladder	13	30	1.58	0.83–3.03	3	3	3.31	0.67–16.39
Pancreas	16	55	1.06	0.61–1.85	6	14	1.42	0.54–3.69
Unspecified gastrointestinal cancer	2	6	1.22	0.25–6.03	1	1
Malignant neoplasms of respiratory and intra-thoracic organs	191	303	2.30	1.92–2.76	25	72	1.15	0.73–1.81
Nasal cavity and middle ear	0	1
Larynx	12	11	3.98	1.76–9.03
Lungs (including trachea)	171	278	2.25	1.86–2.72
Pleura, mediastinum and other ill-defined sites	8	13	2.25	0.93–5.42
Malignant neoplasms of bone and articular cartilage	1	3	1.22	0.13–11.70	1	1	3.31	0.21–52.88
Melanoma and other malignant neoplasms of skin	3	17	0.64	0.19–2.20	1	7	0.47	0.06–3.84
Malignant neoplasms of breast	27	63	1.57	1.00–2.46	10	23	1.44	0.68–3.02
Malignant neoplasms of female genital organs	13	57	0.83	0.46–1.52	5	31	0.53	0.21–1.37
Malignant neoplasms of male genital organs	24	100	0.88	0.56–1.37	7	20	1.16	0.49–2.74
Malignant neoplasms of urinary tract	21	74	1.04	0.64–1.68	5	28	0.59	0.23–1.53
Malignant neoplasms of central nervous system	7	32	0.80	0.35–1.81	2	4	1.65	0.30–9.03
Malignant hematologic neoplasms	37	87	1.55	1.06–2.28	15	25	1.98	1.05–3.76
Myeloma	3	16	0.68	0.20–2.35	0	4
Lymphoma	11	21	1.91	0.92–3.97	4	10	1.32	0.41–4.22
Leukemia	23	50	1.68	1.03–2.75	11	11	3.31	1.43–7.63
Malignant neoplasms of other and ill-defined sites	50	125	1.46	1.05–2.03	10	43	0.75	0.38–1.49
Benign neoplasms	0	7			2	1
Hematologic diseases	10	15	2.43	1.09–5.42	1	3	1.10	0.11–10.60
Endocrine diseases	67	123	1.99	1.48–2.68	17	35	1.61	0.90–2.87
Diabetes mellitus	56	92	2.22	1.59–3.10	15	25	1.98	1.05–3.76
Psychiatric disorders	108	142	2.78	2.16, 3.57	8	27	0.98	0.45, 2.16
Caused by alcohol and/or drugs	87	41	7.75	5.35, 11.23
Other psychiatric disorders	21	101	0.76	0.47, 1.21
Neurologic diseases	21	73	1.05	0.65, 1.71	9	14	2.13	0.92, 4.91
Cardiovascular diseases	573	1761	1.19	1.08, 1.31	191	582	1.09	0.92, 1.28
Respiratory diseases	353	432	2.98	2.59, 3.43	40	141	0.94	0.66, 1.33
Acute infections of the upper respiratory tract	5	7	2.61	0.83, 8.22	0	0
Pneumonia and bronchitis	79	135	2.14	1.62, 2.82	14	48	0.96	0.53, 1.75
Chronic illness of the lower respiratory tract	241	260	3.38	2.84, 4.03	23	84	0.91	0.57, 1.44
Diseases involving pleura, lung abscesses or edema	28	30	3.41	2.04, 5.70	3	9	1.10	0.30, 4.07
Gastrointestinal diseases	178	210	3.10	2.53, 3.78	27	43	2.08	1.28, 3.36
Liver disease	113	62	6.66	4.88, 9.07	6	17	1.17	0.46, 2.96
Esophagus, stomach, duodenum	14	64	0.80	0.45, 1.42	7	14	1.65	0.67, 4.10
Inflammatory bowel disease	0	4			0	0
Ileus, diverticulitis, abscess, peritonitis	25	41	2.23	1.35, 3.66	8	8	3.31	1.24, 8.81
Pancreas and gall-bladder disease	22	22	3.65	2.02, 6.59	3	1	9.92	1.03, 95.39
Other gastrointestinal disease, including hemorrhage	4	17	0.86	0.29, 2.55	3	3	3.31	0.67, 16.39
Dermatologic diseases	0	2			2	2	3.31	0.47, 23.48
Rheumatic diseases	12	17	2.58	1.23, 5.40	1	8	0.41	0.05, 3.31
Genitourinary diseases	22	78	1.03	0.64, 1.65	12	16	2.48	1.17, 5.24
Injury or poisoning	150	219	2.50	2.03, 3.08	27	72	1.24	0.80, 1.93
Not classified elsewhere	155	244	2.32	1.90, 2.84	32	79	1.34	0.89, 2.02
Unknown	51	89	2.09	1.48, 2.95	14	15	3.09	1.49, 6.40
Congenital cause of death	2	5			1	0
Pregnancy related death	0	0			1	0

Abbreviations: CI, confidence interval; EPTB, extrapulmonary tuberculosis; MRR, mortality rate ratio; PTB, pulmonary tuberculosis; HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome.