ORIGINAL ARTICLE

Bidirectional association between tuberculosis and sarcoidosis

SHENG-HUEI WANG,1 CHI-HSIANG CHUNG,2,3 TSAI-WANG HUANG,4
WEN-CHIUAN TSAI, CHUNG-KAN PENG,1 KUN-LUN HUANG,1,6 WANN-CHERNG PERNG,1 CHIH-FENG CHIAN,1
5

WU-CHIEN CHIEN2,7* AND CHIH-HAO SHEN1*

1
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, National
Defense Medical Center, Taipei, Taiwan; 2Department of Medical Research, Tri-Service General Hospital, National Defense
Medical Center, Taipei, Taiwan; 3Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 4Division of
Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan;
5
Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 6Graduate Institute
of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei, Taiwan; 7School of Public Health, National
Defense Medical Center, Taipei, Taiwan

ABSTRACT
Background and objective: Tuberculosis (TB) and sar-
coidosis are both granulomatous diseases with potential
interassociations. However, much uncertainty remains;
thus, the present study aimed to clarify the association
between these diseases.
Methods: We established two cohorts in this retrospec-
tive longitudinal cohort study using data obtained from
the Taiwan National Health Insurance Database from
2000 to 2015. One cohort, which comprised 31 221
patients with TB and 62 442 age-, sex- and index year-
matched controls, was used to analyse the risk of sar-
coidosis; the other cohort comprised 2442 patients with
sarcoidosis and 9688 controls and was used to assess the
risk of TB. A Cox proportional hazards model adjusted
for potential confounders was used in each cohort.
Results: Patients with TB showed an 8.09-fold higher risk
of developing sarcoidosis than non-TB subjects (95%
CI = 3.66–17.90), whereas patients with sarcoidosis
showed a 1.85-fold higher risk of developing TB than
non-sarcoidosis subjects (95% CI = 1.36–2.50). The TB
subtype analysis revealed the highest risk of developing
sarcoidosis in patients with extrapulmonary TB, and the
highest risk of developing extrapulmonary TB was
observed in patients with sarcoidosis compared with non-
sarcoidosis subjects. Patients with TB showed a higher
risk of developing sarcoidosis throughout the follow-up
period, but patients with sarcoidosis only showed a
higher risk of developing TB within the first year.
Conclusion: TB is a risk factor for developing sarcoido-
sis. The results of this bidirectional cohort study also
highlight the clinical difficulty of diagnosing sarcoidosis
and TB.
Correspondence: Chih-Hao Shen, Division of Pulmonary and
Critical Care Medicine, Department of Internal Medicine, Tri-
Service General Hospital, National Defense Medical Center,
No. 325, Section 2, Cheng-Gong Road, Neihu 114, 11490 Taipei,
Taiwan. Email: potato652@yahoo.com.tw
*C.-H.S. and W.-C.C. contributed equally to this work.
Received 2 May 2018; invited to revise 14 August, 13 October
and 19 November 2018; revised 19 August, 15 October and 3
December 2018; accepted 6 January 2019 (Associate Editor:
Cynthia Chee; Senior Editor: Chris Grainge).
© 2019 Asian Pacific Society of Respirology
S UMM A R Y A T A GL AN C E
This bidirectional cohort study strengthens the evi-
dence that tuberculosis (TB) is a risk factor for sar-
coidosis. Patients with sarcoidosis showed a higher
risk of developing TB within the first year after diag-
nosis of sarcoidosis.
Key words: bidirectional association, granulomatous diseases,
risk factor, sarcoidosis, tuberculosis.
INTRODUCTION
Tuberculosis (TB), an infectious disease caused by
Mycobacteria, is characterized by tubercle bacilli dis-
playing intracellular survival strategies and chronic pul-
monary inflammation. Approximately 10.4 million new
cases of TB and an estimated 1.4 million TB-related
deaths were reported worldwide in 2015; thus, TB has
remained a major global health problem.1 An estimated
one-third of the global population has latent TB infec-
tion (LTBI), which carries a lifelong risk of becoming
active. In Taiwan, the incidences of TB and TB-related
death are 53 and 2.7 cases per 100 000 individuals in
2012, respectively.2 TB is one of the many granuloma-
tous lung diseases.3 Microscopically, the inflammation
produced by TB infection characteristically shows cen-
tral caseous necrosis.4
Sarcoidosis is another granulomatous disease with
multisystem involvement. Pulmonary and mediastinal
involvement of sarcoidosis occurs in more than 90% of
patients.5 The prevalence and incidence of sarcoidosis
ranges from 4.7 to 64 and 1.0 to 35.5 per 100 000 indi-
viduals per year, respectively, and the highest rates
have been observed among African-American and
northern European populations.6 The clinical presenta-
tion and radiographical features vary depending on the
stage of sarcoidosis.7 Microscopically, granulomas are
typically non-caseating, coalescent and mainly
Respirology (2019) 24, 467–474
doi: 10.1111/resp.13482
468
distributed along the lymphatics in the bronchovascu-
lar sheath, interlobular septa and subpleural lung
regions.8
Both TB and sarcoidosis are granulomatous diseases
that display clinical and radiological similarities. In
some patients with sarcoidosis, extensive or fibrinoid
necrosis might also be detected in larger spaces,
increasing the difficulty in establishing a differential
diagnosis of TB.9,10 In contrast, current treatments for
sarcoidosis, such as corticosteroids or TNF-α inhibitors,
might significantly increase the incidence of TB after
long-term use.11,12 The association between TB and sar-
coidosis might remain complex and undetermined.
Although the aetiology of sarcoidosis is not well
understood, the involvement of genetic susceptibility,
environmental factors and transmissible infectious has
been hypothesized.13–16 A previous study reported high
Mycobacteria detection rates in countries with a high
sarcoidosis prevalence.17 In a meta-analysis of 31 studies
that used PCR followed by identification of the nucleic
acid sequences specific to Mycobacteria in patients with
sarcoidosis, 231 of the 874 patients were positive for
Mycobacteria.18 However, these studies employed case–
control or cross-sectional designs, preventing the eluci-
dation of the causality between TB and sarcoidosis.
Some conflicting results and uncertainty regarding the
relationship of these two diseases have been noted.19–21
In other studies, the increased detection of sarcoidosis
was associated with a low TB prevalence.22,23
The disparity among these studies might be
explained by the methodological and statistical hetero-
geneity and evidence of publication bias. Therefore, a
longitudinal study evaluating the association between
TB and sarcoidosis is needed. We thus conducted a
bidirectional, nationwide, population-based cohort
study to investigate whether TB increases the risk of
sarcoidosis, and vice versa.
METHODS
Data source
The Taiwanese government launched the Taiwan
National Health Insurance (NHI) programme in 1995
to remove financial barriers to medical care and estab-
lished an insurance claims database called the National
Health Insurance Research Database (NHIRD). Data
from this retrospective cohort study were extracted
from the Longitudinal Health Insurance Database
(LHID), a sub-dataset of the NHIRD containing the
healthcare data of more than 99% of the Taiwanese
population.24 The representativeness of the LHID of the
whole Taiwanese population and the accuracy of the
disease diagnoses in the NHIRD have been vali-
dated.25,26 The personal information in the claims data
was encrypted and anonymized for privacy protection.
This study was approved by the Institutional Review
Board of the Tri-Service General Hospital.
Study population
This study with a retrospective longitudinal design
included two arms (Fig. 1). The diagnoses of TB and
sarcoidosis were coded using the International
© 2019 Asian Pacific Society of Respirology
S-H Wang et al.
Classification of Disease, 9th Revision, Clinical Modifi-
cation (ICD-9-CM). In arm 1, we identified patients
who were newly diagnosed with TB (ICD-9-CM
010-018) between 2000 and 2015. The index date was
the first date of TB diagnosis, once in the inpatient
records or twice in the outpatient records. Patients with
a history of TB or sarcoidosis (ICD-9-CM 135) before
the index date, younger than age 20 years or for whom
data were missing were excluded. The non-TB cohort
was selected from the LHID with the same exclusion
criteria and matched to the TB cohort by sex, age and
index year at a ratio of 2:1. In arm 2, we used a similar
method as in arm 1 to establish the sarcoidosis cohort.
For each patient from the sarcoidosis cohort, four con-
trols from the LHID were randomly selected as the
non-sarcoidosis cohort and were matched by sex, age
and index year.
Outcomes and follow-up
The endpoints of this study were the new development
of sarcoidosis (arm 1) or TB (arm 2). In Taiwan, new
cases of TB must be submitted to the Taiwan Centers
for Disease Control within 7 days, and the final histo-
pathology and TB culture results must also be submit-
ted for document review and medical reimbursement.
Furthermore, TB diagnoses in the LHID were validated
with high accuracy.2 The identification of sarcoidosis in
the present study was based on the ICD coding
extracted from the LHID. The diagnosis of sarcoidosis
was determined by associated specialists based on the
clinical manifestations, radiological imaging and histo-
pathology. In addition, other granulomatous diseases,
such as TB, should be excluded clinically. The Taiwan
NHI randomly sampled claims from hospitals and
reviewed medical records rigorously for maintaining
the accuracy of ICD coding. The follow-up period was
defined as the time interval from the index date to the
diagnosis of sarcoidosis (arm 1) or TB (arm 2),
31 December 2015, or withdrawal from the NHI pro-
gramme, whichever occurred first.
Demographic variables and co-morbidities
The demographic variables in this study included gen-
der, age and urbanization level. Variables that were
identified as possible risk factors for or comorbidities
of TB or sarcoidosis were investigated, including diabe-
tes mellitus (DM; ICD-9-CM 250), hypertension (ICD-
9-CM 401-405), hyperlipidaemia (ICD-9-CM 272),
ischaemic heart disease (IHD; ICD-9-CM 401-414),
congestive heart failure (CHF; ICD-9-CM 428), cancer
(ICD-9-CM 140-208), chronic obstructive pulmonary
disease (COPD; ICD-9-CM 490-491, 495-496), stroke
(ICD-9-CM 430-438), chronic kidney disease (CKD;
ICD-9-CM 585) and human immunodeficiency virus
(HIV) infection (ICD-9-CM 042, 043, 044, V08).
Statistical analysis
Data from patients in these two arms were compared
using the chi-square test for categorical variables and
Student’s t-test for continuous variables. We used the
Kaplan–Meier method to analyse the cumulative
Respirology (2019) 24, 467–474
Relationship between TB and sarcoidosis
Figure 1 Flow chart showing the selection of the study subjects. TB, tuberculosis.
incidence of sarcoidosis in arm 1 and TB in arm 2. The
incidence rate ratios (IRR) of sarcoidosis (arm 1) and
TB (arm 2) were analysed using a Poisson regression
model. The adjusted hazard ratios (HR) for the risk of
sarcoidosis (arm 1) and TB (arm 2) were assessed with
Cox proportional hazards regression analyses. All statis-
tical analyses were performed using SAS 9.4 software
(SPSS, Inc., Chicago, IL, USA). A two-tailed P-value of
<0.05 was considered statistically significant.
RESULTS
Arm 1: TB and the risk of sarcoidosis
After matching for gender, age and index year, we identi-
fied 31 221 patients in the TB cohort and 62 442 patients
in the non-TB cohort (Fig. 1). Patients in the TB cohort
had a higher prevalence of DM, cancer, COPD and HIV,
and a lower prevalence of hypertension, hyperlipidae-
mia, IHD, CHF, stroke and CKD than the non-TB cohort
(Table 1). The mean follow-up periods in the TB and
non-TB cohorts were 9.52 and 10.04 years, respectively.
The mean period before sarcoidosis development was
6.13 and 8.83 years in the TB and non-TB cohorts,
respectively (Table S1A, Supplementary Information).
According to the multivariate Cox proportional hazard
analysis, the TB cohort showed a significantly higher risk
of sarcoidosis than the non-TB cohort (adjusted HR =
8.09, 95% CI = 3.66–17.90). The IRR of sarcoidosis was
14.77-fold higher in the TB cohort than in the non-TB
cohort (95% CI = 14.03–15.51) (Table 2). In Figure 2A,
Respirology (2019) 24, 467–474
469
patients in the TB cohort exhibited a higher cumulative
incidence of sarcoidosis than patients in the non-TB
cohort by the end of the follow-up period (log-rank test;
P < 0.001). After stratification (Table S2A, Supplementary
Information), all patients in the TB cohort showed a sig-
nificantly higher adjusted HR than patients in the non-
TB cohort, with the exception of patients in the CKD and
level 4 urbanization subgroups.
We classified the TB cohort into pulmonary TB, extra-
pulmonary TB and miliary TB subgroups, according to
the ICD-9-CM codes. The pulmonary and extrapulmon-
ary TB subgroups had higher adjusted HR (2.19 and 8.88,
respectively) for developing sarcoidosis than the non-TB
cohort (Table 3A). In Table 4, the TB cohort had a higher
incidence of sarcoidosis development in all period sub-
groups. Higher adjusted HR were observed for the follow-
up periods of 1–5 and >5 years in the TB cohort than in
the non-TB cohort (2.60 and 7.98, respectively).
Arm 2: Sarcoidosis and the risk of TB
After matching, we identified 2442 patients in the sar-
coidosis cohort and 9688 patients in the non-
sarcoidosis cohort (Fig. 1). In Table 1, the sarcoidosis
cohort had a higher prevalence of cancer and HIV and
a lower prevalence of DM, hypertension, hyperlipidae-
mia, IHD, CHF, COPD, stroke and CKD than the non-
sarcoidosis cohort. The mean follow-up periods in the
sarcoidosis and non-sarcoidosis cohorts were 7.46 and
8.26 years, respectively. The mean period before TB
development was 1.48 years in the sarcoidosis
© 2019 Asian Pacific Society of Respirology
470 S-H Wang et al.

Table 1 Characteristics of arms 1 and 2

Arm 1 Arm 2

TB Non-TB Sarcoidosis Non-sarcoidosis

Characteristic No. % No. % P-value No. % No. % P-value

No. 31 221 33.3 62 442 66.7 2422 20.0 9688 80.0

Gender 0.999 0.999
Female 9001 28.8 18 002 28.8 1375 56.8 5500 56.8
Male 22 220 71.2 44 440 71.2 1047 43.2 4188 43.2
Age (years) 67.75  17.33 62.64  17.41 0.391 49.39  19.59 49.93  16.18 0.139
20–44 5438 17.4 10 876 17.4 0.999 905 37.4 3620 37.4 0.999
45–69 11 292 36.2 22 584 36.2 1303 53.8 5212 53.8
≥70 14 491 46.4 28 928 46.4 214 8.8 856 8.8
Co-morbidities
DM 8156 26.1 15 114 24.2 <0.001 374 15.4 1990 20.5 <0.001
Hypertension 9478 30.4 25 247 40.4 <0.001 482 19.9 2887 29.8 <0.001
Hyperlipidaemia 1078 3.5 4806 7.7 <0.001 93 3.8 718 7.4 <0.001
IHD 5040 16.1 16 973 27.2 <0.001 135 5.6 1777 18.3 <0.001
CHF 3091 9.9 8108 13.0 <0.001 90 3.7 744 7.7 <0.001
Cancer 8802 28.2 12 513 20.0 <0.001 363 15.0 1386 14.3 0.206
COPD 9497 30.4 14 623 23.4 <0.001 201 8.3 1082 11.2 <0.001
Stroke 4676 15.0 14 926 23.9 <0.001 88 3.6 1392 14.4 <0.001
CKD 1068 3.4 5850 9.4 <0.001 55 2.3 500 5.2 <0.001
HIV 180 0.6 2 0 <0.001 6 0.3 0 0.0 —
Urbanization level <0.001 <0.001
Level 1 (highest) 8960 28.7 19 811 31.7 850 35.1 3374 34.8
Level 2 13 733 44.0 27 964 44.8 1376 56.8 4051 41.8
Level 3 2565 8.2 4861 7.8 80 3.3 827 8.5
Level 4 (lowest) 5963 19.1 9806 15.7 116 4.8 1436 14.8

CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus;
HIV, human immunodeficiency virus; IHD, ischaemic heart disease; TB, tuberculosis.

cohort and 5.78 years in the non-sarcoidosis cohort
(Table S1B, Supplementary Information).
According to the Cox proportional hazards analysis,
the adjusted HR for the risk of TB was 1.85-fold higher in
the sarcoidosis cohort than in the non-sarcoidosis cohort
(95% CI = 1.36–2.50; Table 2). The sarcoidosis cohort
had a significantly higher cumulative incidence of TB
than the non-sarcoidosis cohort at the end of the follow-
up period (Fig. 2B). After stratification, the sarcoidosis
cohort showed significantly higher adjusted HR than the
non-sarcoidosis cohort, with the exception of the male
gender, age > 70 years, DM, hypertension, IHD, CHF,
non-cancer, COPD, stroke, CKD and level 4 urbanization
subgroups (Table S2B, Supplementary Information).
The sarcoidosis cohort showed a higher risk of
developing pulmonary (adjusted HR = 1.08, 95%
CI = 1.02–1.64) and extrapulmonary TB (adjusted HR =
6.60, 95% CI = 3.58–11.22) than the non-sarcoidosis
cohort (Table 3B). In Table 4, the sarcoidosis cohort
had a higher TB incidence rate and adjusted HR for
developing TB in the follow-up periods of <6 and
6–12 months than the non-sarcoidosis cohort, but not
in the follow-up period of more than 1 year.
DISCUSSION
To the best of our knowledge, this report represents
the first nationwide cohort study to address the
bidirectional relationship between TB and sarcoidosis.
Patients with TB had an 8.08-fold higher risk of devel-
oping sarcoidosis than the non-TB patients; the risk
was significant throughout the follow-up period. In
contrast, patients with sarcoidosis had a 1.85-fold
higher risk of developing TB than non-sarcoidosis
patients, but the risk was only significant within the
1-year follow-up period.
Although patients in the TB and non-TB cohorts
showed varying prevalences of co-morbidities and
urbanization levels on the index day (Table 1), TB
remained an independent risk factor for sarcoidosis in
the adjusted Cox regression analysis (Table 2). In
Table S2A (Supplementary Information), patients in the
TB cohort had a higher incidence of sarcoidosis than
patients in the non-TB cohort in most of the subgroup
analyses of sex, age, co-morbidity and urbanization
level. A previous review article including epidemiologi-
cal and molecular studies identified TB as a trigger for
inciting immune responses that lead to sarcoidosis,
particularly in countries with a high TB burden.21 Our
longitudinal study strengthened the evidence showing
that TB independently increased the risk of sarcoidosis.
Patients with TB had an increased risk of developing
sarcoidosis throughout the follow-up period (Table 4).
TB is likely to manifest as progressive disease, while sar-
coidosis post-TB is likely to happen more slowly, long
after the TB has been treated. In the majority of patients
with active TB, the active state of the disease was due to

© 2019 Asian Pacific Society of Respirology Respirology (2019) 24, 467–474

Relationship between TB and sarcoidosis 471

Table 2 Factors for sarcoidosis (arm 1) or TB (arm 2) determined by the Cox regression

Arm 1 Arm 2
† †
Characteristic aHR (95% CI) P-value aHR (95% CI) P-value

TB (arm 1)/sarcoidosis (arm 2) 8.09 (3.66–17.90) <0.001 1.85 (1.36–2.50) <0.001

Male 0.77 (0.45–1.31) 0.331 2.26 (1.74–2.92) <0.001
Age (years)
20–44 Reference Reference
45–69 0.55 (0.23–1.28) 0.163 1.03 (0.70–1.51) 0.878
≥70 0.83 (0.67–1.88) 0.655 1.21 (0.80–1.84) 0.374
Co-morbidities
DM 1.22 (0.70–2.15) 0.482 1.08 (0.82–1.44) 0.578
Hypertension 0.55 (0.30–0.98) 0.044 0.92 (0.69–1.23) 0.575
Hyperlipidaemia 0.80 (0.28–2.23) 0.673 0.74 (0.47–1.15) 0.182
IHD 1.04 (0.57–1.89) 0.899 0.75 (0.55–1.04) 0.084
CHF 1.35 (0.66–2.73) 0.411 1.51 (1.05–2.16) 0.027
Cancer 1.51 (0.90–2.52) 0.119 2.71 (2.09–3.52) <0.001
COPD 1.05 (0.61–1.82) 0.849 2.73 (2.07–3.60) <0.001
Stroke 0.61 (0.29–1.28) 0.191 1.37 (1.00–1.87) 0.048
CKD 1.38 (0.49–3.91) 0.543 1.38 (0.91–2.10) 0.113
HIV 0 0.977 — —
Urbanization level
Level 1 (highest) 1.04 (0.54–2.01) 0.912 1.00 (0.69–1.47) 0.994
Level 2 0.79 (0.43–1.49) 0.468 1.12 (0.78–1.59) 0.545
Level 3 0.31 (0.07–1.37) 0.123 0.49 (0.24–1.01) 0.052
Level 4 (lowest) Reference Reference
†
All variables were included in the multivariate Cox analysis.
aHR, adjusted hazard ratio; CHF, congestive heart failure; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary dis-
ease; DM, diabetes mellitus; HIV, human immunodeficiency virus; IHD, ischaemic heart disease; TB, tuberculosis.

LTBI reactivation. Chronic inflammation involving CD4+ retains tubercle bacilli during LTBI.27 Most patients with
and CD8+ T cells, Th17 cells, TNF-α and interferon- TB completed treatment within 1 year, and we propose
gamma (IFN-γ) develops when the immune system that the effects of TB on the development of sarcoidosis

Figure 2 Kaplan–Meier analysis of the cumulative incidence of (A) sarcoidosis (arm 1, log-rank P < 0.001) and (B) tuberculosis (TB;
arm 2, log-rank P < 0.001). , With; , without.

Respirology (2019) 24, 467–474 © 2019 Asian Pacific Society of Respirology

472 S-H Wang et al.

Table 3 (A) Incidence rates and aHR for sarcoidosis in arm 1 stratified by TB type. (B) Comparison of the incidence
rates and aHR for TB subgroups in arm 2

(A)

Subgroup Event Rate IRR (95% CI) aHR (95% CI)† P-value

Non-TB 8 0.01 1.00 (reference) 1.00 (reference) —

Pulmonary TB 40 0.16 12.60 (11.85–13.40) 2.19 (1.22–3.95) <0.001
Extrapulmonary TB 16 0.36 28.52 (27.68–29.38) 8.88 (2.10–17.15) <0.001
Miliary TB 0 0 0 0 0.824

(B)

Sarcoidosis cohort Non-sarcoidosis cohort

TB subgroup Event Rate Event Rate IRR (95% CI) aHR (95% CI)† P-value

Pulmonary TB 40 103.44 151 102.03 1.01 (1.00–1.80) 1.08 (1.02–1.64) 0.028

Extrapulmonary TB 31 1.75 33 0.42 4.17 (1.28–9.66) 6.60 (3.58–11.22) <0.001
Miliary TB 3 684.93 3 592.89 1.16 (0.85–3.57) 3.00 (0.55–16.48) 0.207
†
HR were adjusted for all covariates listed in Table 1.
aHR, adjusted HR; HR, hazard ratio; IRR, incidence rate ratio; Rate, incidence rate (per 1000 person-years); TB, tuberculosis.

might involve chronic inflammation and autoimmunity.
Although the pathophysiological association between TB
and sarcoidosis remains elusive, some hypotheses and
evidence have been presented.
First, mycobacterial deoxyribonucleic acid was iden-
tified in 30–50% of sarcoid samples.17,18 High lipid and
glycolipoprotein contents in the cell membrane render
Mycobacterium tuberculosis as a poorly degradable
antigen in macrophage phagosomes, and the subse-
quent microbial-induced host response promotes the
aggregation of inflammatory cells, leading to a nidus
for sarcoid tissue formation.6 This hypothesis is sup-
ported by the research findings that undegradable
mycobacterial antigens may trigger antigen-specific
CD4+ and CD8+ T-cell responses in sites of sarcoid
granulomas.28,29 Second, the similarity of the host B-cell
and T-cell immune responses towards mycobacterial
antigens, such as superoxide dismutase, heat-shock
proteins, mycolyl transferase (e.g. Ag85A) and catalase
peroxidase (e.g. katG), in patients with sarcoidosis and
TB suggests that TB plays a crucial role in the patho-
genesis of sarcoidosis.30–34
In the subgroup analysis presented in Table 3A,
patients with extrapulmonary TB had a higher risk of
developing sarcoidosis than patients with pulmonary
TB (arm 1). In Table 3B, patients with sarcoidosis also
had a higher risk of developing extrapulmonary TB
than pulmonary TB (arm 2). These findings highlight
the difficulty of differentiating sarcoidosis and extrapul-
monary TB in the clinic. The radiological findings of
patients with pulmonary TB differ from patients with
sarcoidosis. In contrast, the differentiation of extrapul-
monary TB and sarcoidosis might only be possible
using specimens from the lesion for histopathological
examination and culture of M. tuberculosis. Because
the culture of M. tuberculosis may require months to
diagnose TB, the initial diagnosis might change several
months later. In Table 4, both TB and sarcoidosis
cohorts showed a higher risk of endpoint development
within 1 year, which might strengthen the hypothesis
that the short risk period for developing TB in sarcoid-
osis patients may be associated with misdiagnosis. In
addition, studies investigating the rare coexistence of
both diseases might be warranted in the future.35,36

Table 4 Incidence rates and aHR for sarcoidosis/TB stratified by follow-up year

Event Rate Event Rate IRR aHR P-value

Arm 1 TB cohort Non-TB cohort

<6 months 5 0.35 0 0 — — —
6 months–1 year 3 0.21 0 0 — — —
1–5 years 23 0.16 4 0.01 11.93 (9.92–13.93) 2.60 (1.03–3.72) <0.001
>5 years 25 0.21 4 0.02 13.50 (11.50–15.50) 7.98 (5.47–11.97) <0.001
Arm 2 Sarcoidosis cohort Non-sarcoidosis cohort
<6 months 50 44.72 27 5.79 7.73 (6.34–8.11) 7.80 (6.01–8.97) <0.001
6 months–1 year 7 6.92 15 3.62 1.92 (1.04–2.09) 2.20 (1.49–4.85) 0.007
1–5 years 8 0.85 77 2.12 0.40 (0.08–1.42) 0.87 (0.21–1.68) 0.356
>5 years 9 1.38 92 2.63 0.52 (0.19–1.06) 0.90 (0.31–2.02) 0.227

HR were adjusted for all covariates listed in Table 1.

aHR, adjusted HR; HR, hazard ratio; IRR, incidence rate ratio; Rate, incidence rate (per 1000 person-years); TB, tuberculosis.

© 2019 Asian Pacific Society of Respirology Respirology (2019) 24, 467–474

Relationship between TB and sarcoidosis
This study has some limitations. First, we were
unable to analyse TB severity in the subgroups for
associated data unavailable from the NHIRD. Second,
the disease identifications were based on the ICD-
9-CM, and misclassification by physicians is possible.
Although other diseases in the NHIRD have been exter-
nally validated, these data may not be as precise or
rigid as data from the randomized controlled trials.2,37,38
Third, unpreventable biases remain in retrospective
cohort studies despite cautious adjustments for poten-
tial confounders. Nevertheless, our findings derived
from a nationwide cohort study with a large sample
size and 15-year follow-up period contribute new infor-
mation regarding the relationship between TB and
sarcoidosis.
In conclusion, patients with TB showed an 8.08-fold
higher risk of developing sarcoidosis than the general
population. TB patients developing sarcoidosis is likely
to happen more slowly, long after the TB has been
treated. This bidirectional cohort also highlights the
clinical difficulty of diagnosing sarcoidosis and TB in a
short risk period. We recommend that physicians mon-
itor the development of sarcoidosis when caring for
patients with TB.
Acknowledgements
This study was performed in part using data from the NHIRD,
which is managed and provided by the National Health Research
Institutes, Taiwan. The conclusions and interpretations in this
article do not represent the views of the Department of Health,
the Bureau of the NHI or the National Health Research Institutes.
This work was supported by grants from Teh-Tzer Study Group
for Human Medical Research Foundation (B1061066).
Abbreviations: aHR, adjusted HR; CHF, congestive heart
failure; CKD, chronic kidney disease; DM, diabetes mellitus; HR,
hazard ratio; ICD-9-CM, International Classification of Disease,
9th Revision, Clinical Modification; IHD, ischaemic heart disease;
IRR, incidence rate ratio; LHID, Longitudinal Health Insurance
Database; LTBI, latent TB infection; NHI, National Health
Insurance; NHIRD, National Health Insurance Research
Database; PCR, polymerase chain reaction; TB, tuberculosis;
TNF-α, tumour necrosis factor-alpha.
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Supplementary Information
Additional supplementary information can be accessed via
the html version of this article at the publisher’s website.
Table S1 (A) Years to sarcoidosis in arm 1. (B) Years to
tuberculosis in arm 2.
Table S2 (A) Subgroup analysis and comparison of the
incidence rates and adjusted HR in arm 1. (B) Subgroup
analysis and comparison of the incidence rates and adjusted
HR in arm 2.
Table S3 Immunosuppressive treatment of sarcoidosis
patients in arm 2 (n = 2422).
Respirology (2019) 24, 467–474