Diagnosis, Treatment and Outcomes of Latent Tuberculosis Infection (LTBI) in the Household Contact Investigation Program

Yong-joon Park; jin-a Park; Yunhyung Kwon; Eunhye Shim; Ji-ae Shim; Sun-young Jung; Jae Chol Choi

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Epidemiology and Surveillance

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Public Health Weekly Report 2021; 14(19): 1245-1263

Published online May 6, 2021

Diagnosis, Treatment and Outcomes of Latent Tuberculosis Infection (LTBI) in the Household Contact Investigation Program

Park Yong-joon¹, Park jin-a¹, Kwon Yunhyung¹, Shim Eunhye¹, Shim Ji-ae², Jung Sun-young³, Choi Jae Chol³

¹Division of Tuberculosis Prevention and Control, Bureau of Infectious Disease Policy, Korea Disease Control and Prevention Agency (KDCA)
²Division of Infectious Disease Response Chungcheong Regional Center for Disease Control and Prevention, KDCA
³Chung-Ang University hospital

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Tuberculosis (TB), a respiratory infectious disease, is known to spread tuberculosis to family members who share in the same space for extended periods of time. In response to the rise in TB cases among family members, the Korea Disease Control and Prevention Agency (KDCA) created the Household Contact Investigation Program. The program is at the core of the KDCA’s National Tuberculosis Management Project that aims to detect and treat additional TB patients and latent TB infection(LTBI) through quick contact investigation.
o detect and treatment additional tuberculosis patients and latent tuberculosis infection (LTBI) through a quick contact investigation.
This study aimed to identify the epidemiological characteristics of household contacts of TB patients, evaluate the effectiveness in preventing the spread of TB according to whether TB patients are treated or not, and explore factors related to the adverse effects and elimination of LTBI.
The subjects of the study were examined as household contacts in the KDCA’s TB management data from 2015 to 2018, and were analyzed in connection with the data of the National Health Insurance Service (NHIS).
The risk of TB spreading among non-participants in the Household Contact Investigation Program was 7.4 times higher than that of participants in the program. TB patients who did not receive treatment for LTBI, were 7.29 times higher than TB patients who completed treatment and 2.47 times higher than TB patients who stopped treatment. The risk of suspension of treatment for LTBI was higher among TB patients aged 76 or older and among TB patients with diabetes. Furthermore, the risk of experiencing the side effects associated with LTBI treatment, was higher in all adult age groups aged 19-35, 36-65, and 75 or older than among children under the age of five. Side effect risks were 9.09 times higher in the age 75 or older group than among children in the under 5 years of age group. This study found that the risk of side effects of LTBI treatment at 66-75 years of age was lower than the risk at 36-65 years of age, given the recommendations for the treatment of LTBI.
This study concluded that, because the treatment of LTBI reduces the risk of TB, it should be actively recommended to contacts of people diagnosed with LTBI. This study recommended that medical institutions actively manage the side effects among certain age groups and among individuals with an underlying disease.

Key words Latent tuberculosis infection (LTBI), Household contacts investigation, Treatment of LTBI

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Table 1. The incidence of active tuberculosis by category of close contacts

	Not performed contact investigation (n=321) No. (%)	Subjects for TB screening
		Performed LTBI screening					Not performed LTBI screening (n=45,969) No. (%)
		Positive for LTBI screening			Negative for LTBI screening
		Performed treatment		Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
		Completed (n=9,584) No. (%)	Stopped treatment (n=2,329) No. (%)	Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
Total	16 (4.98)	23 (0.24)	16 (0.69)	151 (1.63)	166 (0.39)	11 (0.12)	572 (1.24)
≤ 1 year	15 (4.67)	5 (0.05)	2 (0.09)	82 (0.89)	79 (0.19)	6 (0.06)	199 (0.43)
1-2 years	1 (0.31)	6 (0.06)	8 (0.34)	47 (0.51)	50 (0.12)	1 (0.01)	144 (0.31)
2-3 years	0 (0.00)	4 (0.04)	2 (0.09)	16 (0.17)	19 (0.04)	2 (0.02)	144 (0.31)
> 3years	0 (0.00)	8 (0.08)	4 (0.17)	6 (0.06)	18 (0.04)	2 (0.02)	85 (0.18)

Table 2. Baseline characteristics of close contacts and index patients

Characteristics		Close contacts	Index patients
Characteristics		No. (%)	No. (%)
Total		120,676 (100.0)	58,164 (100.0)
Sex	Male	50,123 (41.5)	35,364 (60.8)
Sex	Female	70,553 (58.5)	22,800 (39.2)
Age	≤ 5 years old	7,664 (6.4)	30 (0.1)
	6–18 years old	16,515 (13.7)	1,616 (2.8)
	19–35 years old	21,874 (18.1)	8,954 (15.4)
	36–65 years old	55,749 (46.2)	23,956 (41.2)
	66–75 years old	11,049 (9.2)	9,953 (17.1)
	76 ≤ years old	7,825 (6.5)	13,655 (23.5)
	Mean±SD	41.98±22.46	57.27±20.28

Table 3. Baseline characteristics of close contacts

	Characteristics	No. (%)
Relationship	Spouse	35,218 (29.2)
	Brothers and Sisters (siblings)	6,297 (5.2)
	Parents and Children	56,668 (47.0)
	Grandparents and Grandchildren	10,516 (8.7)
	Others (other relatives)	11,977 (9.9)
Years of contact investigation	Not done	322 (0.3)
	2015	31,914 (26.4)
	2016	34,754 (28.8)
	2017	28,336 (23.5)
	2018	25,350 (21.0)
Comorbidity^*	Chronic lung disease	31,187 (25.8)
	Diabetes	12,952 (10.7)
	Renal failure	847 (0.7)
	Liver disease	5,890 (4.9)
	AIDS	24 (0.0)
	Cancer	4,249 (3.5)
	Rheumatic disease	3,260 (2.7)
	Alcohol intoxication	1,063 (0.9)
	Use of steroid	49,746 (41.2)

*Comorbidity: variables form National Health Insurance Service

Table 4. Baseline characteristics of index patients

	Characteristics	No. (%)
Number of contacts	Mean	2.07
	Standard deviation	1.47
	Minimum	1
	Median	1
	Maximum	100
	First quartile	1
	Third quartile	3
Evidence of symptoms	Yes	41,010 (70.5)
Evidence of symptoms	No	17,154 (29.5)
Symptoms	Sough	29,126 (50.1)
	Sputum	19,950 (34.3)
	Hemoptysis	2,604 (4.5)
	Weight loss	5,320 (9.1)
Cavity on chest PA	Absent	42,845 (73.7)
	Present	13,201 (22.7)
	Missing	2,118 (3.6)
Acid fast bacilli smear result	Positive	22,887 (39.3)
	Negative	33,477 (57.6)
	Others (Undetermined, Not-done, Missing)	1,800 (3.1)

Table 5. Risk factors for the development of tuberculosis

Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	HR	95% CI		aHR	95% CI
Contacts	Status of LTBI	Not performed LTBI screening	572	164,339.53	3.48	1.00			1.00
		Not performed contact investigation	16	1,208.68	13.24	3.89	2.37	6.41	5.94	3.59	9.83
		No LTBI by 1-step	166	116,112.29	1.43	0.39	0.33	0.46	0.42	0.33	0.52
		No LTBI by 2-step	11	27,584.54	0.40	0.11	0.06	0.20	0.16	0.08	0.29
		LTBI with treatment discontinuation	16	6,678.06	2.40	0.66	0.40	1.08	0.57	0.34	0.96
		LTBI with treatment complete	23	26,537.56	0.87	0.24	0.16	0.36	0.25	0.16	0.39
		LTBI without treatment	151	23,327.45	6.47	1.72	1.44	2.07	1.58	1.30	1.93
	Sex	Male	407	151,295.65	2.69	1.00			-	-	-
	Sex	Female	548	214,492.45	2.55	0.95	0.84	1.08	-	-	-
	Age	Under 5	1	24,201.36	0.04	1.00			1.00
		6–18	80	51,868.83	1.54	37.26	5.20	267.19	24.68	3.44	176.81
		19–35	177	67,067.33	2.64	63.56	8.92	452.77	29.02	4.06	207.18
		36–65	384	168,207.33	2.28	54.84	7.72	389.55	14.96	2.09	106.94
		66–75	144	33,050.80	4.36	104.64	14.67	746.38	24.57	3.41	176.91
		Over 76	169	21,392.46	7.90	187.96	26.38	1,339.38	42.67	5.93	307.11
	Relationship to index patients	1st degree^*	878	298,094.68	2.95	1.00			1.00
	Relationship to index patients	2nd degree^†	77	67,693.43	1.14	0.39	0.31	0.49	0.48	0.38	0.61
	Comorbidities	Chronic lung disease	257	93,209.28	2.76	1.08	0.93	1.24	-	-	-
		Diabetes	163	37,399.45	4.36	1.80	1.52	2.13	1.15	0.96	1.38
		Renal failure	17	2,229.59	7.62	2.91	1.80	4.70	1.77	1.09	2.89
		Liver disease	53	17,061.02	3.11	1.19	0.91	1.57	-	-	-
		AIDS	0	71.06	0	0	0	3.02E+104	-	-	-
		Cancer	43	11,828.33	3.64	1.40	1.03	1.90	1.09	0.80	1.48
		Rheumatic disease	32	9,806.36	3.26	1.26	0.89	1.79E+00	-	-	-
		Use of steroids	15	3,145.55	4.77	1.84	1.10	3.06	1.58	0.95	2.63
Index	Cavity	Absence	406	153,859.13	2.64	1.03	0.90	1.17	-	-	-
	Cavity	Presence	547	267,824.49	2.04	1.00			1.00
	Sputum culture	Negative	386	85,194.74	4.53	2.23	1.95	2.54	1.69	1.48	1.94
	Sputum culture	Positive	107	98,735.09	1.08	1.00			1.00
	TB-PCR	Negative	809	245,640.55	3.29	3.03	2.48	3.71	1.74	1.40	2.16
	TB-PCR	Positive	118	107,655.41	1.10	1.00			1.00
	AFB smear	Negative	545	163,612.25	3.33	3.05	2.50	3.72	1.42	1.14	1.76
	AFB smear	Positive	257	203,820.39	1.26	1.00			1.00
	Symptoms	No	676	150,454.44	4.49	3.58	3.10	4.14	2.35	2.00	2.77
	Symptoms	Yes	817	103,754.80	7.87	1.00			1.00

*1st degree: Spouse / Brothers and Sisters (siblings) / Parents and Children

†2nd degree: Grandparents and Grandchildren / Others (other relatives)

Table 6. The risk of tuberculosis according to screening and treatment of latent tuberculosis infection in household contacts

Characteristics			No.	person-year	Incidence per 1000 PY	Hazard Ratio I	Hazard Ratio II (adjusted)
Screening		Performed	939	364,579.43	2.58	1.00	1.00
Screening		Not performed	16	1,208.68	13.24	5.38 (3.28-8.83)	7.40 (4.49-12.19)
Result of LTBI screening		Negative	177	143,696.83	1.23	1.00	1.00
Result of LTBI screening		Positive	190	56,543.07	3.36	2.71 (2.21-3.33)	2.28 (1.85-2.82)
Treatment of LTBI	case 1	treated	39	33,215.62	1.17	1.00	1.00
	case 1	Not treated	151	23,327.45	6.47	5.42 (3.81-7.71)	5.46 (3.76-7.92)
	case 2	Treatment complete	23	26,537.56	0.87	1.00	1.00
		Stopped treatment	16	6,678.06	2.40	2.78 (1.47-5.25)	2.47 (1.30-4.68)
		Not treated	151	23,327.45	6.47	7.34 (4.73-11.38)	7.29 (4.61-11.51)

Variables: sex, age, comorbidities (case 1: renal failure, alcohol intoxication, case 2: renal failure, diabetes), presence of cavity, culture result, smear result, presence of symptoms and tuberculosis-polymerase chain reaction result.

Table 7. Completion and discontinuation of LTBI treatment for each type of drug treatment

Characteristics			Treatment of LTBI	3HR	4R	6-9H
Treatment	Total		11,913	6,330	1,038	4,545
	completed Treatment		9,584 (80.4)	5,121 (80.9)	850 (81.9)	3,613 (79.5)
	Stopped treatment		2,329 (19.6)	1,209 (19.1)	188 (18.1)	932 (20.5)
Reasons for discontinuation	Side effects	Total	633 (57.3)	407 (61.0)	57 (54.3)	169 (50.8)
		Hepatotoxicity	230 (20.8)	151 (22.6)	20 (19.0)	59 (17.7)
		Skin reactions	233 (21.1)	132 (19.8)	18 (17.1)	83 (24.9)
		Platelet abnomality	38 (3.4)	22 (3.3)	1 (1.0)	15 (4.5)
		Gastroenteric trouble	50 (4.5)	41 (6.1)	4 (3.8)	5 (1.5)
		Pain	39 (3.5)	29 (4.3)	8 (7.6)	2 (0.6)
		Others	43 (3.9)	32 (4.8)	6 (5.7)	5 (1.5)
	Resistance		45 (4.1)	19 (2.8)	6 (5.7)	20 (6.0)
	Others^*		427 (38.6)	241 (36.1)	42 (40.0)	144 (43.2)

*Noncooperation, Unidentified, Interruption of one’s self

No reason for discontinuation of LTBI treatment 1,224 people(3HR 542 people, 4R 83 people, 6-9H 599 people)

Table 8. Analysis of the discontinuation factor for LTBI treatment

Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	2,329 (100.0)
	Male	4,298 (44.8)	1,034 (44.4)	0.696	1.00			-	-	-
	Female	5,286 (55.2)	1,295 (55.6)	1.02	0.93	1.12	-	-	-
Age	Mean±SD	30.82±23.26	35.36±22.34
	≤ 5 years old	1,835 (19.1)	284 (12.2)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	437 (18.8)		1.25	1.07	1.47	1.35	1.15	1.60
	19–35 years old	1,247 (13.0)	436 (18.7)		2.26	1.91	2.67	3.04	2.52	3.66
	36–65 years old	3,811 (39.8)	1,014 (43.5)		1.72	1.49	1.98	2.45	2.06	2.91
	66–75 years old	337 (3.5)	99 (4.3)		1.90	1.47	2.45	2.51	1.89	3.32
	76 ≤ years old	100 (1.0)	59 (2.5)		3.81	2.70	5.38	4.90	3.40	7.07
Comorbidity^*	Chronic lung disease	2,798 (29.2)	596 (25.6)	0.0005	0.83	0.75	0.93	0.90	0.81	1.00
	Diabetes	789 (8.2)	280 (12.0)	<.0001	1.52	1.32	1.76	1.26	1.07	1.47
	Renal failure	46 (0.5)	7 (0.3)	0.2433	0.63	0.28	1.39	-	-	-
	Liver disease	376 (3.9)	104 (4.5)	0.2326	1.15	0.92	1.43	-	-	-
	AIDS	3 (0.0)	1 (0.0)	0.7834	1.37	0.14	13.20	-	-	-
	Cancer	264 (2.8)	62 (2.7)	0.8061	0.97	0.73	1.28	-	-	-
	Rheumatic disease	162 (1.7)	55 (2.4)	0.0298	1.41	1.03	1.92	1.19	0.87	1.63
	Alcohol intoxication	56 (0.6)	16 (0.7)	0.5663	1.18	0.67	2.06	-	-	-
	Use of steroids	3,668 (38.3)	865 (37.1)	0.313	0.95	0.87	1.05	-	-	-
Therapy	6-9H	3,613 (37.7)	932 (40.0)	0.1756	1.00			-	-	-
	3HR	5,121 (53.4)	1,209 (51.9)		0.92	0.83	1.01	0.56	0.50	0.63
	4R	850 (8.9)	188 (8.1)		0.86	0.72	1.02	0.50	0.41	0.60

*Comorbidity: variables from the National Health Insurance Service

Table 9. Analysis of adverse drug reactions to LTBI treatment

Characteristics		Treatment of LTBI		P-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		No side effects	No. (%) Side effects^* No. (%)	P-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	633 (100.0)
	Male	4,298 (44.8)	225 (35.5)	<.0001	1.00			1.00
	Female	5,286 (55.2)	408 (64.5)		1.47	1.25	1.74	1.27	1.07	1.51
Age	Mean±SD	30.82±23.26	43.49±20.45
	≤ 5 years old	1,835 (19.1)	48 (7.6)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	50 (7.9)		0.85	0.57	1.27	0.91	0.61	1.37
	19–35 years old	1,247 (13.0)	100 (15.8)		3.07	2.16	4.36	3.56	2.44	5.21
	36–65 years old	3,811 (39.8)	380 (60.0)		3.81	2.81	5.17	4.38	3.09	6.21
	66–75 years old	337 (3.5)	32 (5.1)		3.63	2.29	5.76	3.82	2.31	6.31
	76 ≤ years old	100 (1.0)	23 (3.6)		8.79	5.14	15.03	9.09	5.12	16.15
Comorbidity^†	Chronic lung disease	2,798 (29.2)	175 (27.6)	0.4062	0.93	0.78	1.11	-	-	-
	Diabetes	789 (8.2)	98 (15.5)	<.0001	2.00	1.60	2.51	1.21	0.94	1.55
	Renal failure	46 (0.5)	5 (0.8)	0.2839	1.69	0.67	4.25	-	-	-
	Liver disease	376 (3.9)	41 (6.5)	0.0017	1.73	1.25	2.41	1.09	0.77	1.53
	AIDS	3 (0.0)	1 (0.2)	0.1187	5.28	0.55	50.75	-	-	-
	Cancer	264 (2.8)	23 (3.6)	0.1949	1.34	0.87	2.07	-	-	-
	Rheumatic disease	162 (1.7)	24 (3.8)	0.0001	2.28	1.47	3.52	1.41	0.90	2.20
	Alcohol intoxication	56 (0.6)	8 (1.3)	0.0358	2.16	1.03	4.53	-	-	-
	Use of steroids	3,668 (38.3)	297 (46.9)	<.0001	1.43	1.22	1.68	1.31	1.11	1.54

*Hepatotoxicity, Skin reactions, Platelet abnormality, Gastroenteric trouble, Pain, Others

†Comorbidity: variables from the National Health Insurance Service

Figure 1. Flowchart of the study population according to contact investigations, Latent tuberculosis infection (LTBI) tests, and LTBI treatment

References

Sections

Abstract
Reference

World Health Organization. Global tuberculosis report 2020.
Korea Centers for Diseases Control and Prevention. 2019 Annual report on the notified tuberculosis in Korea 2019. KCDC; 2020.
Shim TS, Koh WJ, Yim JJ, Lew WJ. Treatment of latent tuberculosis infection in Korea. Tuberc Respir Dis 2008;65:79-90.
Greg J. Fox, Nguyen V. Nhung, et al. Household- Contact Investigation for Detection of Tuberculosis in Vietnam. N Engl J Med 2018;378:221-229.
Lobue P, Menzies D. Treatment of latent tuberculosis infection: an update. Respirology 2010;15:603-622.
Haileyesus Getahun, Alberto Matteelli, et al. Latent Mycobacterium tuberculosis Infection. N Engl J Med 2015;372(22):2127-2135.
Joint Committee for the Development of Korean Guideline for Tuberculosis; Korean Centers for Disease Control and Prevention. Korean guidelines for tuberculosis, 3rd ed. Seoul: Medrang Inforang Ltd.; 2017.

Epidemiology and Surveillance

Public Health Weekly Report 2021; 14(19): 1245-1263

Published online May 6, 2021

Diagnosis, Treatment and Outcomes of Latent Tuberculosis Infection (LTBI) in the Household Contact Investigation Program

Park Yong-joon¹, Park jin-a¹, Kwon Yunhyung¹, Shim Eunhye¹, Shim Ji-ae², Jung Sun-young³, Choi Jae Chol³

Abstract

Keywords: Latent tuberculosis infection (LTBI), Household contacts investigation, Treatment of LTBI

Body

Table 1 The incidence of active tuberculosis by category of close contacts

	Not performed contact investigation (n=321) No. (%)	Subjects for TB screening
		Performed LTBI screening					Not performed LTBI screening (n=45,969) No. (%)
		Positive for LTBI screening			Negative for LTBI screening
		Performed treatment		Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
		Completed (n=9,584) No. (%)	Stopped treatment (n=2,329) No. (%)	Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
Total	16 (4.98)	23 (0.24)	16 (0.69)	151 (1.63)	166 (0.39)	11 (0.12)	572 (1.24)
≤ 1 year	15 (4.67)	5 (0.05)	2 (0.09)	82 (0.89)	79 (0.19)	6 (0.06)	199 (0.43)
1-2 years	1 (0.31)	6 (0.06)	8 (0.34)	47 (0.51)	50 (0.12)	1 (0.01)	144 (0.31)
2-3 years	0 (0.00)	4 (0.04)	2 (0.09)	16 (0.17)	19 (0.04)	2 (0.02)	144 (0.31)
> 3years	0 (0.00)	8 (0.08)	4 (0.17)	6 (0.06)	18 (0.04)	2 (0.02)	85 (0.18)

Table 2 Baseline characteristics of close contacts and index patients

Characteristics		Close contacts	Index patients
Characteristics		No. (%)	No. (%)
Total		120,676 (100.0)	58,164 (100.0)
Sex	Male	50,123 (41.5)	35,364 (60.8)
Sex	Female	70,553 (58.5)	22,800 (39.2)
Age	≤ 5 years old	7,664 (6.4)	30 (0.1)
	6–18 years old	16,515 (13.7)	1,616 (2.8)
	19–35 years old	21,874 (18.1)	8,954 (15.4)
	36–65 years old	55,749 (46.2)	23,956 (41.2)
	66–75 years old	11,049 (9.2)	9,953 (17.1)
	76 ≤ years old	7,825 (6.5)	13,655 (23.5)
	Mean±SD	41.98±22.46	57.27±20.28

Table 3 Baseline characteristics of close contacts

	Characteristics	No. (%)
Relationship	Spouse	35,218 (29.2)
	Brothers and Sisters (siblings)	6,297 (5.2)
	Parents and Children	56,668 (47.0)
	Grandparents and Grandchildren	10,516 (8.7)
	Others (other relatives)	11,977 (9.9)
Years of contact investigation	Not done	322 (0.3)
	2015	31,914 (26.4)
	2016	34,754 (28.8)
	2017	28,336 (23.5)
	2018	25,350 (21.0)
Comorbidity^*	Chronic lung disease	31,187 (25.8)
	Diabetes	12,952 (10.7)
	Renal failure	847 (0.7)
	Liver disease	5,890 (4.9)
	AIDS	24 (0.0)
	Cancer	4,249 (3.5)
	Rheumatic disease	3,260 (2.7)
	Alcohol intoxication	1,063 (0.9)
	Use of steroid	49,746 (41.2)

*Comorbidity: variables form National Health Insurance Service.

Table 4 Baseline characteristics of index patients

	Characteristics	No. (%)
Number of contacts	Mean	2.07
	Standard deviation	1.47
	Minimum	1
	Median	1
	Maximum	100
	First quartile	1
	Third quartile	3
Evidence of symptoms	Yes	41,010 (70.5)
Evidence of symptoms	No	17,154 (29.5)
Symptoms	Sough	29,126 (50.1)
	Sputum	19,950 (34.3)
	Hemoptysis	2,604 (4.5)
	Weight loss	5,320 (9.1)
Cavity on chest PA	Absent	42,845 (73.7)
	Present	13,201 (22.7)
	Missing	2,118 (3.6)
Acid fast bacilli smear result	Positive	22,887 (39.3)
	Negative	33,477 (57.6)
	Others (Undetermined, Not-done, Missing)	1,800 (3.1)

Table 5 Risk factors for the development of tuberculosis

Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	HR	95% CI		aHR	95% CI
Contacts	Status of LTBI	Not performed LTBI screening	572	164,339.53	3.48	1.00			1.00
		Not performed contact investigation	16	1,208.68	13.24	3.89	2.37	6.41	5.94	3.59	9.83
		No LTBI by 1-step	166	116,112.29	1.43	0.39	0.33	0.46	0.42	0.33	0.52
		No LTBI by 2-step	11	27,584.54	0.40	0.11	0.06	0.20	0.16	0.08	0.29
		LTBI with treatment discontinuation	16	6,678.06	2.40	0.66	0.40	1.08	0.57	0.34	0.96
		LTBI with treatment complete	23	26,537.56	0.87	0.24	0.16	0.36	0.25	0.16	0.39
		LTBI without treatment	151	23,327.45	6.47	1.72	1.44	2.07	1.58	1.30	1.93
	Sex	Male	407	151,295.65	2.69	1.00			-	-	-
	Sex	Female	548	214,492.45	2.55	0.95	0.84	1.08	-	-	-
	Age	Under 5	1	24,201.36	0.04	1.00			1.00
		6–18	80	51,868.83	1.54	37.26	5.20	267.19	24.68	3.44	176.81
		19–35	177	67,067.33	2.64	63.56	8.92	452.77	29.02	4.06	207.18
		36–65	384	168,207.33	2.28	54.84	7.72	389.55	14.96	2.09	106.94
		66–75	144	33,050.80	4.36	104.64	14.67	746.38	24.57	3.41	176.91
		Over 76	169	21,392.46	7.90	187.96	26.38	1,339.38	42.67	5.93	307.11
	Relationship to index patients	1st degree^*	878	298,094.68	2.95	1.00			1.00
	Relationship to index patients	2nd degree^†	77	67,693.43	1.14	0.39	0.31	0.49	0.48	0.38	0.61
	Comorbidities	Chronic lung disease	257	93,209.28	2.76	1.08	0.93	1.24	-	-	-
		Diabetes	163	37,399.45	4.36	1.80	1.52	2.13	1.15	0.96	1.38
		Renal failure	17	2,229.59	7.62	2.91	1.80	4.70	1.77	1.09	2.89
		Liver disease	53	17,061.02	3.11	1.19	0.91	1.57	-	-	-
		AIDS	0	71.06	0	0	0	3.02E+104	-	-	-
		Cancer	43	11,828.33	3.64	1.40	1.03	1.90	1.09	0.80	1.48
		Rheumatic disease	32	9,806.36	3.26	1.26	0.89	1.79E+00	-	-	-
		Use of steroids	15	3,145.55	4.77	1.84	1.10	3.06	1.58	0.95	2.63
Index	Cavity	Absence	406	153,859.13	2.64	1.03	0.90	1.17	-	-	-
	Cavity	Presence	547	267,824.49	2.04	1.00			1.00
	Sputum culture	Negative	386	85,194.74	4.53	2.23	1.95	2.54	1.69	1.48	1.94
	Sputum culture	Positive	107	98,735.09	1.08	1.00			1.00
	TB-PCR	Negative	809	245,640.55	3.29	3.03	2.48	3.71	1.74	1.40	2.16
	TB-PCR	Positive	118	107,655.41	1.10	1.00			1.00
	AFB smear	Negative	545	163,612.25	3.33	3.05	2.50	3.72	1.42	1.14	1.76
	AFB smear	Positive	257	203,820.39	1.26	1.00			1.00
	Symptoms	No	676	150,454.44	4.49	3.58	3.10	4.14	2.35	2.00	2.77
	Symptoms	Yes	817	103,754.80	7.87	1.00			1.00

*1st degree: Spouse / Brothers and Sisters (siblings) / Parents and Children.

†2nd degree: Grandparents and Grandchildren / Others (other relatives).

Table 6 The risk of tuberculosis according to screening and treatment of latent tuberculosis infection in household contacts

Characteristics			No.	person-year	Incidence per 1000 PY	Hazard Ratio I	Hazard Ratio II (adjusted)
Screening		Performed	939	364,579.43	2.58	1.00	1.00
Screening		Not performed	16	1,208.68	13.24	5.38 (3.28-8.83)	7.40 (4.49-12.19)
Result of LTBI screening		Negative	177	143,696.83	1.23	1.00	1.00
Result of LTBI screening		Positive	190	56,543.07	3.36	2.71 (2.21-3.33)	2.28 (1.85-2.82)
Treatment of LTBI	case 1	treated	39	33,215.62	1.17	1.00	1.00
	case 1	Not treated	151	23,327.45	6.47	5.42 (3.81-7.71)	5.46 (3.76-7.92)
	case 2	Treatment complete	23	26,537.56	0.87	1.00	1.00
		Stopped treatment	16	6,678.06	2.40	2.78 (1.47-5.25)	2.47 (1.30-4.68)
		Not treated	151	23,327.45	6.47	7.34 (4.73-11.38)	7.29 (4.61-11.51)

Table 7 Completion and discontinuation of LTBI treatment for each type of drug treatment

Characteristics			Treatment of LTBI	3HR	4R	6-9H
Treatment	Total		11,913	6,330	1,038	4,545
	completed Treatment		9,584 (80.4)	5,121 (80.9)	850 (81.9)	3,613 (79.5)
	Stopped treatment		2,329 (19.6)	1,209 (19.1)	188 (18.1)	932 (20.5)
Reasons for discontinuation	Side effects	Total	633 (57.3)	407 (61.0)	57 (54.3)	169 (50.8)
		Hepatotoxicity	230 (20.8)	151 (22.6)	20 (19.0)	59 (17.7)
		Skin reactions	233 (21.1)	132 (19.8)	18 (17.1)	83 (24.9)
		Platelet abnomality	38 (3.4)	22 (3.3)	1 (1.0)	15 (4.5)
		Gastroenteric trouble	50 (4.5)	41 (6.1)	4 (3.8)	5 (1.5)
		Pain	39 (3.5)	29 (4.3)	8 (7.6)	2 (0.6)
		Others	43 (3.9)	32 (4.8)	6 (5.7)	5 (1.5)
	Resistance		45 (4.1)	19 (2.8)	6 (5.7)	20 (6.0)
	Others^*		427 (38.6)	241 (36.1)	42 (40.0)	144 (43.2)

*Noncooperation, Unidentified, Interruption of one’s self.

No reason for discontinuation of LTBI treatment 1,224 people(3HR 542 people, 4R 83 people, 6-9H 599 people).

Table 8 Analysis of the discontinuation factor for LTBI treatment

Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	2,329 (100.0)
	Male	4,298 (44.8)	1,034 (44.4)	0.696	1.00			-	-	-
	Female	5,286 (55.2)	1,295 (55.6)	1.02	0.93	1.12	-	-	-
Age	Mean±SD	30.82±23.26	35.36±22.34
	≤ 5 years old	1,835 (19.1)	284 (12.2)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	437 (18.8)		1.25	1.07	1.47	1.35	1.15	1.60
	19–35 years old	1,247 (13.0)	436 (18.7)		2.26	1.91	2.67	3.04	2.52	3.66
	36–65 years old	3,811 (39.8)	1,014 (43.5)		1.72	1.49	1.98	2.45	2.06	2.91
	66–75 years old	337 (3.5)	99 (4.3)		1.90	1.47	2.45	2.51	1.89	3.32
	76 ≤ years old	100 (1.0)	59 (2.5)		3.81	2.70	5.38	4.90	3.40	7.07
Comorbidity^*	Chronic lung disease	2,798 (29.2)	596 (25.6)	0.0005	0.83	0.75	0.93	0.90	0.81	1.00
	Diabetes	789 (8.2)	280 (12.0)	<.0001	1.52	1.32	1.76	1.26	1.07	1.47
	Renal failure	46 (0.5)	7 (0.3)	0.2433	0.63	0.28	1.39	-	-	-
	Liver disease	376 (3.9)	104 (4.5)	0.2326	1.15	0.92	1.43	-	-	-
	AIDS	3 (0.0)	1 (0.0)	0.7834	1.37	0.14	13.20	-	-	-
	Cancer	264 (2.8)	62 (2.7)	0.8061	0.97	0.73	1.28	-	-	-
	Rheumatic disease	162 (1.7)	55 (2.4)	0.0298	1.41	1.03	1.92	1.19	0.87	1.63
	Alcohol intoxication	56 (0.6)	16 (0.7)	0.5663	1.18	0.67	2.06	-	-	-
	Use of steroids	3,668 (38.3)	865 (37.1)	0.313	0.95	0.87	1.05	-	-	-
Therapy	6-9H	3,613 (37.7)	932 (40.0)	0.1756	1.00			-	-	-
	3HR	5,121 (53.4)	1,209 (51.9)		0.92	0.83	1.01	0.56	0.50	0.63
	4R	850 (8.9)	188 (8.1)		0.86	0.72	1.02	0.50	0.41	0.60

*Comorbidity: variables from the National Health Insurance Service.

Table 9 Analysis of adverse drug reactions to LTBI treatment

Characteristics		Treatment of LTBI		P-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		No side effects	No. (%) Side effects^* No. (%)	P-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	633 (100.0)
	Male	4,298 (44.8)	225 (35.5)	<.0001	1.00			1.00
	Female	5,286 (55.2)	408 (64.5)		1.47	1.25	1.74	1.27	1.07	1.51
Age	Mean±SD	30.82±23.26	43.49±20.45
	≤ 5 years old	1,835 (19.1)	48 (7.6)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	50 (7.9)		0.85	0.57	1.27	0.91	0.61	1.37
	19–35 years old	1,247 (13.0)	100 (15.8)		3.07	2.16	4.36	3.56	2.44	5.21
	36–65 years old	3,811 (39.8)	380 (60.0)		3.81	2.81	5.17	4.38	3.09	6.21
	66–75 years old	337 (3.5)	32 (5.1)		3.63	2.29	5.76	3.82	2.31	6.31
	76 ≤ years old	100 (1.0)	23 (3.6)		8.79	5.14	15.03	9.09	5.12	16.15
Comorbidity^†	Chronic lung disease	2,798 (29.2)	175 (27.6)	0.4062	0.93	0.78	1.11	-	-	-
	Diabetes	789 (8.2)	98 (15.5)	<.0001	2.00	1.60	2.51	1.21	0.94	1.55
	Renal failure	46 (0.5)	5 (0.8)	0.2839	1.69	0.67	4.25	-	-	-
	Liver disease	376 (3.9)	41 (6.5)	0.0017	1.73	1.25	2.41	1.09	0.77	1.53
	AIDS	3 (0.0)	1 (0.2)	0.1187	5.28	0.55	50.75	-	-	-
	Cancer	264 (2.8)	23 (3.6)	0.1949	1.34	0.87	2.07	-	-	-
	Rheumatic disease	162 (1.7)	24 (3.8)	0.0001	2.28	1.47	3.52	1.41	0.90	2.20
	Alcohol intoxication	56 (0.6)	8 (1.3)	0.0358	2.16	1.03	4.53	-	-	-
	Use of steroids	3,668 (38.3)	297 (46.9)	<.0001	1.43	1.22	1.68	1.31	1.11	1.54

*Hepatotoxicity, Skin reactions, Platelet abnormality, Gastroenteric trouble, Pain, Others.

†Comorbidity: variables from the National Health Insurance Service.

Figure 1. Flowchart of the study population according to contact investigations, Latent tuberculosis infection (LTBI) tests, and LTBI treatment

Abstract
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Fig 1.

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Figure 1.Flowchart of the study population according to contact investigations, Latent tuberculosis infection (LTBI) tests, and LTBI treatment

Public Health Weekly Report 2021; 14: 1245-1263

Table 1 The incidence of active tuberculosis by category of close contacts

	Not performed contact investigation (n=321) No. (%)	Subjects for TB screening
		Performed LTBI screening					Not performed LTBI screening (n=45,969) No. (%)
		Positive for LTBI screening			Negative for LTBI screening
		Performed treatment		Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
		Completed (n=9,584) No. (%)	Stopped treatment (n=2,329) No. (%)	Not treated (n=9,258) No. (%)	1 step screening (n=42,640) No. (%)	2 step screening (n=9,453) No. (%)
Total	16 (4.98)	23 (0.24)	16 (0.69)	151 (1.63)	166 (0.39)	11 (0.12)	572 (1.24)
≤ 1 year	15 (4.67)	5 (0.05)	2 (0.09)	82 (0.89)	79 (0.19)	6 (0.06)	199 (0.43)
1-2 years	1 (0.31)	6 (0.06)	8 (0.34)	47 (0.51)	50 (0.12)	1 (0.01)	144 (0.31)
2-3 years	0 (0.00)	4 (0.04)	2 (0.09)	16 (0.17)	19 (0.04)	2 (0.02)	144 (0.31)
> 3years	0 (0.00)	8 (0.08)	4 (0.17)	6 (0.06)	18 (0.04)	2 (0.02)	85 (0.18)

Table 2 Baseline characteristics of close contacts and index patients

Characteristics		Close contacts	Index patients
Characteristics		No. (%)	No. (%)
Total		120,676 (100.0)	58,164 (100.0)
Sex	Male	50,123 (41.5)	35,364 (60.8)
Sex	Female	70,553 (58.5)	22,800 (39.2)
Age	≤ 5 years old	7,664 (6.4)	30 (0.1)
	6–18 years old	16,515 (13.7)	1,616 (2.8)
	19–35 years old	21,874 (18.1)	8,954 (15.4)
	36–65 years old	55,749 (46.2)	23,956 (41.2)
	66–75 years old	11,049 (9.2)	9,953 (17.1)
	76 ≤ years old	7,825 (6.5)	13,655 (23.5)
	Mean±SD	41.98±22.46	57.27±20.28

Table 3 Baseline characteristics of close contacts

	Characteristics	No. (%)
Relationship	Spouse	35,218 (29.2)
	Brothers and Sisters (siblings)	6,297 (5.2)
	Parents and Children	56,668 (47.0)
	Grandparents and Grandchildren	10,516 (8.7)
	Others (other relatives)	11,977 (9.9)
Years of contact investigation	Not done	322 (0.3)
	2015	31,914 (26.4)
	2016	34,754 (28.8)
	2017	28,336 (23.5)
	2018	25,350 (21.0)
Comorbidity^*	Chronic lung disease	31,187 (25.8)
	Diabetes	12,952 (10.7)
	Renal failure	847 (0.7)
	Liver disease	5,890 (4.9)
	AIDS	24 (0.0)
	Cancer	4,249 (3.5)
	Rheumatic disease	3,260 (2.7)
	Alcohol intoxication	1,063 (0.9)
	Use of steroid	49,746 (41.2)

*Comorbidity: variables form National Health Insurance Service.

Table 4 Baseline characteristics of index patients

	Characteristics	No. (%)
Number of contacts	Mean	2.07
	Standard deviation	1.47
	Minimum	1
	Median	1
	Maximum	100
	First quartile	1
	Third quartile	3
Evidence of symptoms	Yes	41,010 (70.5)
Evidence of symptoms	No	17,154 (29.5)
Symptoms	Sough	29,126 (50.1)
	Sputum	19,950 (34.3)
	Hemoptysis	2,604 (4.5)
	Weight loss	5,320 (9.1)
Cavity on chest PA	Absent	42,845 (73.7)
	Present	13,201 (22.7)
	Missing	2,118 (3.6)
Acid fast bacilli smear result	Positive	22,887 (39.3)
	Negative	33,477 (57.6)
	Others (Undetermined, Not-done, Missing)	1,800 (3.1)

Table 5 Risk factors for the development of tuberculosis

Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics			Incidence of TB cases (No.)	Person-year	Incidence per 1000 person-year	HR	95% CI		aHR	95% CI
Contacts	Status of LTBI	Not performed LTBI screening	572	164,339.53	3.48	1.00			1.00
		Not performed contact investigation	16	1,208.68	13.24	3.89	2.37	6.41	5.94	3.59	9.83
		No LTBI by 1-step	166	116,112.29	1.43	0.39	0.33	0.46	0.42	0.33	0.52
		No LTBI by 2-step	11	27,584.54	0.40	0.11	0.06	0.20	0.16	0.08	0.29
		LTBI with treatment discontinuation	16	6,678.06	2.40	0.66	0.40	1.08	0.57	0.34	0.96
		LTBI with treatment complete	23	26,537.56	0.87	0.24	0.16	0.36	0.25	0.16	0.39
		LTBI without treatment	151	23,327.45	6.47	1.72	1.44	2.07	1.58	1.30	1.93
	Sex	Male	407	151,295.65	2.69	1.00			-	-	-
	Sex	Female	548	214,492.45	2.55	0.95	0.84	1.08	-	-	-
	Age	Under 5	1	24,201.36	0.04	1.00			1.00
		6–18	80	51,868.83	1.54	37.26	5.20	267.19	24.68	3.44	176.81
		19–35	177	67,067.33	2.64	63.56	8.92	452.77	29.02	4.06	207.18
		36–65	384	168,207.33	2.28	54.84	7.72	389.55	14.96	2.09	106.94
		66–75	144	33,050.80	4.36	104.64	14.67	746.38	24.57	3.41	176.91
		Over 76	169	21,392.46	7.90	187.96	26.38	1,339.38	42.67	5.93	307.11
	Relationship to index patients	1st degree^*	878	298,094.68	2.95	1.00			1.00
	Relationship to index patients	2nd degree^†	77	67,693.43	1.14	0.39	0.31	0.49	0.48	0.38	0.61
	Comorbidities	Chronic lung disease	257	93,209.28	2.76	1.08	0.93	1.24	-	-	-
		Diabetes	163	37,399.45	4.36	1.80	1.52	2.13	1.15	0.96	1.38
		Renal failure	17	2,229.59	7.62	2.91	1.80	4.70	1.77	1.09	2.89
		Liver disease	53	17,061.02	3.11	1.19	0.91	1.57	-	-	-
		AIDS	0	71.06	0	0	0	3.02E+104	-	-	-
		Cancer	43	11,828.33	3.64	1.40	1.03	1.90	1.09	0.80	1.48
		Rheumatic disease	32	9,806.36	3.26	1.26	0.89	1.79E+00	-	-	-
		Use of steroids	15	3,145.55	4.77	1.84	1.10	3.06	1.58	0.95	2.63
Index	Cavity	Absence	406	153,859.13	2.64	1.03	0.90	1.17	-	-	-
	Cavity	Presence	547	267,824.49	2.04	1.00			1.00
	Sputum culture	Negative	386	85,194.74	4.53	2.23	1.95	2.54	1.69	1.48	1.94
	Sputum culture	Positive	107	98,735.09	1.08	1.00			1.00
	TB-PCR	Negative	809	245,640.55	3.29	3.03	2.48	3.71	1.74	1.40	2.16
	TB-PCR	Positive	118	107,655.41	1.10	1.00			1.00
	AFB smear	Negative	545	163,612.25	3.33	3.05	2.50	3.72	1.42	1.14	1.76
	AFB smear	Positive	257	203,820.39	1.26	1.00			1.00
	Symptoms	No	676	150,454.44	4.49	3.58	3.10	4.14	2.35	2.00	2.77
	Symptoms	Yes	817	103,754.80	7.87	1.00			1.00

*1st degree: Spouse / Brothers and Sisters (siblings) / Parents and Children.

†2nd degree: Grandparents and Grandchildren / Others (other relatives).

Table 6 The risk of tuberculosis according to screening and treatment of latent tuberculosis infection in household contacts

Characteristics			No.	person-year	Incidence per 1000 PY	Hazard Ratio I	Hazard Ratio II (adjusted)
Screening		Performed	939	364,579.43	2.58	1.00	1.00
Screening		Not performed	16	1,208.68	13.24	5.38 (3.28-8.83)	7.40 (4.49-12.19)
Result of LTBI screening		Negative	177	143,696.83	1.23	1.00	1.00
Result of LTBI screening		Positive	190	56,543.07	3.36	2.71 (2.21-3.33)	2.28 (1.85-2.82)
Treatment of LTBI	case 1	treated	39	33,215.62	1.17	1.00	1.00
	case 1	Not treated	151	23,327.45	6.47	5.42 (3.81-7.71)	5.46 (3.76-7.92)
	case 2	Treatment complete	23	26,537.56	0.87	1.00	1.00
		Stopped treatment	16	6,678.06	2.40	2.78 (1.47-5.25)	2.47 (1.30-4.68)
		Not treated	151	23,327.45	6.47	7.34 (4.73-11.38)	7.29 (4.61-11.51)

Table 7 Completion and discontinuation of LTBI treatment for each type of drug treatment

Characteristics			Treatment of LTBI	3HR	4R	6-9H
Treatment	Total		11,913	6,330	1,038	4,545
	completed Treatment		9,584 (80.4)	5,121 (80.9)	850 (81.9)	3,613 (79.5)
	Stopped treatment		2,329 (19.6)	1,209 (19.1)	188 (18.1)	932 (20.5)
Reasons for discontinuation	Side effects	Total	633 (57.3)	407 (61.0)	57 (54.3)	169 (50.8)
		Hepatotoxicity	230 (20.8)	151 (22.6)	20 (19.0)	59 (17.7)
		Skin reactions	233 (21.1)	132 (19.8)	18 (17.1)	83 (24.9)
		Platelet abnomality	38 (3.4)	22 (3.3)	1 (1.0)	15 (4.5)
		Gastroenteric trouble	50 (4.5)	41 (6.1)	4 (3.8)	5 (1.5)
		Pain	39 (3.5)	29 (4.3)	8 (7.6)	2 (0.6)
		Others	43 (3.9)	32 (4.8)	6 (5.7)	5 (1.5)
	Resistance		45 (4.1)	19 (2.8)	6 (5.7)	20 (6.0)
	Others^*		427 (38.6)	241 (36.1)	42 (40.0)	144 (43.2)

*Noncooperation, Unidentified, Interruption of one’s self.

No reason for discontinuation of LTBI treatment 1,224 people(3HR 542 people, 4R 83 people, 6-9H 599 people).

Table 8 Analysis of the discontinuation factor for LTBI treatment

Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		LTBI with treatment completion No. (%)	LTBI with treatment discontinuation No. (%)	p-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	2,329 (100.0)
	Male	4,298 (44.8)	1,034 (44.4)	0.696	1.00			-	-	-
	Female	5,286 (55.2)	1,295 (55.6)	1.02	0.93	1.12	-	-	-
Age	Mean±SD	30.82±23.26	35.36±22.34
	≤ 5 years old	1,835 (19.1)	284 (12.2)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	437 (18.8)		1.25	1.07	1.47	1.35	1.15	1.60
	19–35 years old	1,247 (13.0)	436 (18.7)		2.26	1.91	2.67	3.04	2.52	3.66
	36–65 years old	3,811 (39.8)	1,014 (43.5)		1.72	1.49	1.98	2.45	2.06	2.91
	66–75 years old	337 (3.5)	99 (4.3)		1.90	1.47	2.45	2.51	1.89	3.32
	76 ≤ years old	100 (1.0)	59 (2.5)		3.81	2.70	5.38	4.90	3.40	7.07
Comorbidity^*	Chronic lung disease	2,798 (29.2)	596 (25.6)	0.0005	0.83	0.75	0.93	0.90	0.81	1.00
	Diabetes	789 (8.2)	280 (12.0)	<.0001	1.52	1.32	1.76	1.26	1.07	1.47
	Renal failure	46 (0.5)	7 (0.3)	0.2433	0.63	0.28	1.39	-	-	-
	Liver disease	376 (3.9)	104 (4.5)	0.2326	1.15	0.92	1.43	-	-	-
	AIDS	3 (0.0)	1 (0.0)	0.7834	1.37	0.14	13.20	-	-	-
	Cancer	264 (2.8)	62 (2.7)	0.8061	0.97	0.73	1.28	-	-	-
	Rheumatic disease	162 (1.7)	55 (2.4)	0.0298	1.41	1.03	1.92	1.19	0.87	1.63
	Alcohol intoxication	56 (0.6)	16 (0.7)	0.5663	1.18	0.67	2.06	-	-	-
	Use of steroids	3,668 (38.3)	865 (37.1)	0.313	0.95	0.87	1.05	-	-	-
Therapy	6-9H	3,613 (37.7)	932 (40.0)	0.1756	1.00			-	-	-
	3HR	5,121 (53.4)	1,209 (51.9)		0.92	0.83	1.01	0.56	0.50	0.63
	4R	850 (8.9)	188 (8.1)		0.86	0.72	1.02	0.50	0.41	0.60

*Comorbidity: variables from the National Health Insurance Service.

Table 9 Analysis of adverse drug reactions to LTBI treatment

Characteristics		Treatment of LTBI		P-value	Hazard Ratio I			Hazard Ratio II (adjusted)
Characteristics		No side effects	No. (%) Side effects^* No. (%)	P-value	HR	95% CI		aHR	95% CI
Sex	Total	9,584 (100.0)	633 (100.0)
	Male	4,298 (44.8)	225 (35.5)	<.0001	1.00			1.00
	Female	5,286 (55.2)	408 (64.5)		1.47	1.25	1.74	1.27	1.07	1.51
Age	Mean±SD	30.82±23.26	43.49±20.45
	≤ 5 years old	1,835 (19.1)	48 (7.6)	<.0001	1.00			1.00
	6–18 years old	2,254 (23.5)	50 (7.9)		0.85	0.57	1.27	0.91	0.61	1.37
	19–35 years old	1,247 (13.0)	100 (15.8)		3.07	2.16	4.36	3.56	2.44	5.21
	36–65 years old	3,811 (39.8)	380 (60.0)		3.81	2.81	5.17	4.38	3.09	6.21
	66–75 years old	337 (3.5)	32 (5.1)		3.63	2.29	5.76	3.82	2.31	6.31
	76 ≤ years old	100 (1.0)	23 (3.6)		8.79	5.14	15.03	9.09	5.12	16.15
Comorbidity^†	Chronic lung disease	2,798 (29.2)	175 (27.6)	0.4062	0.93	0.78	1.11	-	-	-
	Diabetes	789 (8.2)	98 (15.5)	<.0001	2.00	1.60	2.51	1.21	0.94	1.55
	Renal failure	46 (0.5)	5 (0.8)	0.2839	1.69	0.67	4.25	-	-	-
	Liver disease	376 (3.9)	41 (6.5)	0.0017	1.73	1.25	2.41	1.09	0.77	1.53
	AIDS	3 (0.0)	1 (0.2)	0.1187	5.28	0.55	50.75	-	-	-
	Cancer	264 (2.8)	23 (3.6)	0.1949	1.34	0.87	2.07	-	-	-
	Rheumatic disease	162 (1.7)	24 (3.8)	0.0001	2.28	1.47	3.52	1.41	0.90	2.20
	Alcohol intoxication	56 (0.6)	8 (1.3)	0.0358	2.16	1.03	4.53	-	-	-
	Use of steroids	3,668 (38.3)	297 (46.9)	<.0001	1.43	1.22	1.68	1.31	1.11	1.54

*Hepatotoxicity, Skin reactions, Platelet abnormality, Gastroenteric trouble, Pain, Others.

†Comorbidity: variables from the National Health Insurance Service.

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