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. 2021 Oct 15;16(10):e0258809. doi: 10.1371/journal.pone.0258809

Variation of tuberculosis prevalence across diagnostic approaches and geographical areas of Indonesia

Alvera Noviyani 1,2, Tanawin Nopsopon 3, Krit Pongpirul 1,3,4,*
Editor: Frederick Quinn5
PMCID: PMC8519455  PMID: 34653233

Abstract

Background

Tuberculosis (TB) has contributed to a significant disease burden and economic loss worldwide. Given no gold standard for diagnosis, early identification of TB infection has been challenging. This study aimed to comparatively investigate the prevalence of TB across diagnostic approaches (sputum AFB, sputum culture, sputum genetic test, and chest x-ray) and geographical areas of Indonesia.

Methods

Participant demographic variables and TB screening test results were obtained from the Tuberculosis Unit, Health Research and Development Agency, Ministry of Health (HRDA-MoH). The prevalence of pulmonary TB in populations aged 15 years and over was calculated using TB cases as a numerator and populations aged 15 years and over as a denominator. Variations across geographical areas and diagnostic approaches were expressed as prevalence and 95% confidence interval (CI).

Results

A total of 67,944 records were reviewed. Based on bacteriological evidence, the prevalence of TB per 100,000 in Indonesia was 759 (95% CI: 589.7–960.8) with variations across areas: 913 (95% CI 696.7–1,176.7; Sumatra), 593 (95% CI 447.2–770.6; Java-Bali), and 842 (95% CI 634.7–1,091.8; other islands). Also, the prevalence of TB varied across diagnostic approaches: 256.5 (sputum AFB), 545 (sputum culture), 752.2 (chest x-ray), and 894.9 (sputum genetic test). Based on sputum AFB, the TB prevalence varied from 216.6 (95% CI 146.5–286.8; Java-Bali), 259.9 (95% CI 184.2–335.6; other islands) to 307.4 (95% CI 208.3–406.5; Sumatra). Based on sputum culture, the TB prevalence ranged from 487.9 (95% CI 433.6–548.6; Java-Bali), 635.9 (95% CI 564.9–715.1; Sumatra), to 2,129.8 (95% CI 1,664.0–2,735.6; other islands). Based on chest x-ray, the TB prevalence varied from 152.1 (95% CI 147.9–156.3; Java-Bali), 159.2 (95% CI 154.1–164.3; Sumatra), to 864 (95% CI 809–921.4; other islands). Based on sputum genetic test, the TB prevalence ranged from 838.7 (95% CI 748.4–900.8; Java-Bali), 875 (95% CI 775.4–934.2; Sumatra), to 941.2 (95% CI 663.6–992.3; other islands).

Conclusions

The variation of TB prevalence across geographical regions could be confounded by the diagnostic approaches.

Trial registration

This study was approved by the Institutional Review Board of Chulalongkorn University (IRB No. 684/63).

Introduction

Tuberculosis (TB) was one of the top diseases which caused numerous death worldwide [1]. TB was a widespread infectious disease caused by the bacterium Mycobacterium tuberculosis [2, 3], which typically affected the lungs (pulmonary TB) but could also affect other organs (extra-pulmonary TB) [3–5]. TB has continued to remain a hot issue and a major health problem, especially in developing countries [6, 7] which accounted for approximately 95% of TB-related deaths [8]. In 2019, 10.0 million people fell ill with TB, including an estimated 1.2 million children, with approximately 1.4 million TB deaths, including 208 thousand people with HIV/AIDS, which mostly induced by poverty and vulnerability of the community [1, 9]. While the End TB Strategy has been implemented worldwide, declining trends of TB infection and deaths were relatively slow and fell short of the 2020 goal [1]. There were many challenges in efforts to prevent and control global TB. Some of the real challenges faced were significant gaps in funding, lack of access to diagnostic and treatment services, limitations in resources, the emergence, and transmission of multi-drug resistant TB strains in endemic countries, particularly Asian countries [10].

An estimated around 3.6 million people with TB were missed diagnosis by health systems every year, thus did not receive adequate care [11]. Missed diagnosis, particularly on early-stage TB patients who developed mild or no symptoms, led to high numbers of TB infected people arrived at clinics with advanced disease or multi-drug resistant TB (MDR-TB), which was difficult to treat and more likely to cause death [12–14]. In 2019, the largest number of new TB cases occurred in the South-East Asia region, with 44% of global new cases, followed by the African region with 25% of global new cases, and the Western Pacific with 18%. While TB occurred in every part of the world, eight countries comprised two-thirds of global TB incidence which Indonesia ranks second for the incidence of TB in the world after India [1, 9]. The high incidence of TB in Indonesia indicated a high priority for TB prevention and control [15].

Based on the Center for Disease Control and Prevention 2016, Tuberculosis could be found through various testing and diagnosis [16, 17]. TB mycobacteria in the body could be identified with two types of the test: TB skin test (TST) and TB blood tests, while the results only presented that a person has been infected with TB. Other tests, such as a chest x-ray and a sample of sputum, were needed to differentiate whether the person had latent or active TB infection [16].

One of the key strategies for tackling TB was an early diagnosis. Unfortunately, sputum testing was only 50% accurate and frequently missed the disease in its early stages [11]. Systematic screening strategy to ensure early and correct diagnosis for all people with TB for instance chest X-ray (CXR) was one of the primary tools for TB screening [18]. There were various methods to diagnose TB disease, although every method had an error and could lead to a missed diagnosis. In detecting tuberculosis, inadequate access to advanced diagnostic tests contributed to suboptimal detection performance [19]. Delay in diagnosis and misdiagnosis led to increased morbidity and mortality in patients and allowed continued TB transmission [19, 20]. In many countries with a high burden of TB, there was geographically substantial heterogeneity in the burden of TB. Besides, decisions about TB funding and policy were usually very decentralized [21]. Thus, data could refer geographically to priority areas as needed.

This research aimed to comparatively investigate the prevalence of TB across diagnostic approaches, including sputum acid-fast bacilli (AFB), sputum culture, sputum genetic test, and chest x-ray, and geographical areas in Indonesia. The area with a high prevalence should be put on the priority list in the TB prevention program.

Materials and methods

Study design

This study analyzed the screening results of Indonesian people using various diagnostic approaches (sputum AFB, sputum culture, sputum genetic test, and chest x-ray) in the data set obtained from the Health Research and Development Agency of the Tuberculosis Unit, Indonesian Ministry of Health (HRDA-MoH). The primary study was carried out using a cross-sectional design which was carried out utilizing interviews, measurements, and chest X-ray examination, and sputum examination for all samples. The sample selection was stratified multi-stage cluster sampling in the public. Training and pilot tests, as well as cleaning, validation, and data analysis, had been completed.

Study setting

The data set represented Indonesia in all of the 34 provinces, which were classified into 3 large islands in Indonesia, Sumatra island, Java-Bali island, and other islands (other islands with a relatively small population which are mostly in the eastern part of Indonesia). Characteristics of the regions are presented in Table 1. Indonesia as the largest archipelagic country in the world had two-thirds of its territory in the form of Indonesian oceans, namely 6.32 million square kilometers, 17,504 islands, and was one of the countries that had the longest coastline in the world after Canada. So, it was necessary to divide the time into 3 zones time in Indonesia, WIB (Western Indonesian Time), WITA (Central Indonesian Time), and WIT (Eastern Indonesian Time). There could be a time difference of up to 8 hours from one island to another. Besides, geographically, Indonesia was located between two continents (Asian Continent and Australian Continent) and two oceans (the Indian Ocean and the Pacific Ocean) which were the most dynamic regions, both economically and politically. This strategic geographical location made Indonesia both superior and highly dependent on the marine [22].

Table 1. Characteristics of the regions in general.

Characteristics Sumatra Java-Bali Others References
Total population 58.56 million 151.59 million 60.05 million [32]
Gender
    Male 29,711,506 76,385,599 30,564,794 [32]
    Female 28,845,705 75,205,663 29,490,650 [32]
Migration rates
    Moving in 7,889,399 15,236,040 6,656,315 [29]
    Moving out 6,669,677 18,329,895 4,585,403 [29]
Noncommunicable diseases
    Hypertention 136,569 384,746 136,886 [29]
    Diabetes mellitus 149,142 415,232 149,412 [29]
    Nutritional Status     by BMI (>18 years)
        Skinny 10466.53 34791.56 12926.95 [29]
        Overweight 17615.35 49730.9 17312.02 [29]
        Obesity 28103.87 82507.31 25844.29 [29]
Infectious diseases
    HIV 6,217 29,689 13,818 [33]
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Study population

Individuals aged 15 years and over who had stayed in the selected cluster for at least one month. Individuals living in military barracks, diplomatic mission houses, hospitals, hotels, dormitories, temporary residences were excluded.

Statistical analysis

Validated and merged data were exported from a Microsoft Access-based database, transformed with SPSS version 22 and Stata software version 15.0. Categorical data were presented with counts and percentages. The prevalence of pulmonary TB in populations aged 15 years and over was calculated using TB cases as a numerator and populations aged 15 years and over as a denominator which is consistent with the WHO’s global tuberculosis guidance [23]. Variations across geographical areas and diagnostic approaches were expressed as prevalence with a 95% confidence interval (CI) using Clopper-Pearson Exact method.

Diagnostics tests

Chest x-ray

After data collection was complete, the chest X-ray image was sent to the central team and submitted to the central reader. Three radiologists, without knowing the results of the field screening (blinded), interpreted the results of the chest X-ray. The classification of the results of the central reading was divided into (1) normal, (2) abnormal lung parenchyma or pleura which consists of TB and non-TB features. The picture of TB consists of seven abnormalities, namely infiltrates nodule consolidation, cavitary lesions, fibrosis, calcification, pleural effusion, and pleural thickening, (3) others. The results of the field chest X-ray reading were used to decide which participants to take sputum from. The results of the central reading were used to decide the case definition.

Sputum AFB

Diagnosis of TB by identifying acid-fast bacilli (AFB) in sputum that is not concentrated (direct smear) with Ziehl-Neelsen (ZN).

Sputum culture

TB diagnosis uses selective media for the cultivation and isolation of Mycobacterium species. Lowenstein-Jensen (LJ) medium is most widely used for tuberculosis culture in Indonesia.

Sputum genetic test

The Xpert MTB/RIF assay is an automated, cartridge-based nucleic acid amplification test that uses the multi-disease GeneXpert platform.

Ethics committee approval

This study was approved by the Institutional Review Board of Chulalongkorn University (COA No. 1316/2020).

Patient and public involvement

Patients and the public have not been directly involved in the design, conduct, or reporting of this study. However, we believe that our study would provide additional information for patients who lived in or would travel to relatively high TB incidence areas and for the public to have a more accessible real-world experience.

Results

Demographic characteristics of the participants

Indonesia consisted of 17,491 islands in 34 provinces, including the Special Capital Region Jakarta. The province consisted of districts (district) and municipality (city); the city was further divided into districts, which were then divided into administrative villages [24], the following was the presentation of population distribution that was eligible as participants according to demographic characteristics (Table 2). There were six groups of participants according to the age years (15–24 years old, 25–34 years old, 35–44 years old, 45–54 years old, 55–64 years old, and 65 years old and over). The region classification of the study was divided into three big islands in Indonesia: Sumatra island, Java-Bali island, and other islands (other islands with a relatively small population which are mostly in the eastern part of Indonesia) with urban and rural as an area classification.

Table 2. Distribution of eligible populations and participants according to demographic characteristics.

Characteristics Eligible Participants Non-participants
n (%) n (%) n (%)
Total 76,576 67,944 8,632
Age group (years) *
    15–24 16,982 (22.2) 14,505 (21.3) 2,477 (28.7)
    25–34 17,760 (23.2) 15,192 (22.4) 2,568 (29.7)
    35–44 16,107 (21.0) 14,386 (21.2) 1,721 (19.9)
    45–54 12,677 (16.6) 11,643 (17.1) 1,034 (12.0)
    55–64 7,410 (9.7) 6,870 (10.1) 540 (6.3)
    65 or more 5,640 (7.4) 5,348 (7.9) 292 (3.4)
Gender
    Male 36,759 (48.0) 31,632 (46.6) 5,127 (59.4)
    Female 39,817 (52.0) 36,312 (53.4) 3,505 (40.6)
Area Classification
    Urban 37,865 (49.4) 31,871 (46.9) 5,994 (69.4)
    Rural 38,711 (50.6) 36,073 (53.1) 2,638 (30.6)
Region *
    Sumatra 22,700 (29.6) 19,739 (29.1) 2,961 (34.3)
    Java-Bali 31,049 (40.5) 28,150 (41.4) 2,899 (33.6)
    Other 22,827 (29.8) 20,055 (29.5) 2,772 (32.1)
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Data were presented in counts and percentages.

*Total percentage was not equal to 100% due to rounding.

Tuberculosis prevalence

The prevalence of tuberculosis was 759.1 (95% CI: 589.7–960.8) per 100,000 population aged 15 years and over with an increasing trend of TB prevalence with aging. The TB prevalence was higher in the 65+ age group than other groups with 1,581.7 (95% CI: 1,122.7–2,153.7) per 100,000 population (Table 3). Tuberculosis prevalence in Indonesia was higher in urban areas than in rural areas, and the Sumatra region had the highest TB prevalence with 913.1 (95% CI: 696.7–1,176.7) per 100,000 population.

Table 3. Estimated TB prevalence per 100,000 population aged 15 years and over according to demographic characteristics and diagnostic approach.

Characteristics Observed Chest x-ray Sputum AFB Sputum Culture Sputum Genetic Test
Prevalence 95% CI Prevalence 95% CI Prevalence 95% CI Prevalence 95% CI Prevalence 95% CI
Total 759.1 589.7–960.8 725.2 718.1–732.2 256.5 210.1–302.9 545.0 509.5–583.0 894.9 848.7–928.2
Age group (years)
    15–24 360.8 254.3–494.7 783.8 741.2–828.7 137.5 77.3–197.8 414.5 330.7–518.3 851.8 659.6–944.6
    25–34 753.4 561.8–995.0 109.1 104.3–114.2 239.9 155.5–324.4 561.4 477.0–659.7 893.6 766.1–955.6
    35–44 713.8 527.4–941.0 142.9 137.3–148.7 265.1 170.7–359.4 584.7 503.8–677.5 933.3 809.7–978.7
    45–54 835.5 608.9–1,108.3 205.7 198.5–213.2 271.5 166.3–376.7 479.7 408.9–561.8 891.3 761.4–954.6
    55–64 1,029.5 734.1–1,398.5 284.7 274.2–295.5 318.6 174.1–463.1 529.6 446.5–627.2 909.1 748.6–971.1
    65 or more 1,581.7 1,122.7–2,153.7 373.7 360.9–386.8 527.6 292.0–763.2 678.9 583.6–788.6 875.0 729.5–947.8
Gender
    Male 1,082.7 872.8–1,337.3 200.8 196.4–205.3 392.5 314.5–470.5 607.9 558.6–661.2 896.9 839.9–935.2
    Female 460.6 353.6–590.8 133.5 130.1–137.1 131.0 87.6–174.4 463.0 414.2–517.3 890.4 794.4–944.7
Area Classification
    Urban 845.8 678.2–1,047.7 150.1 146.2–154.0 282.2 219.6–344.7 736.6 673.8–804.7 912.0 847.3–950.8
    Rural 674.2 511.9–873.6 177.9 174.0–181.9 231.4 163.3–299.5 408.8 369.0–452.7 876.1 800.7–925.6
Region
    Sumatra 913.1 696.7–1,176.7 159.2 154.1–164.3 307.4 208.3–406.5 635.9 564.9–715.1 875.0 775.4–934.2
    Java-Bali 593.1 447.2–770.6 152.1 147.9–156.3 216.6 146.5–286.8 487.9 433.6–548.6 838.7 748.4–900.8
    Other 842.1 634.7–1,091.8 864.0 809.0–921.4 259.9 184.2–335.6 2,129.8 1,664.0–2,735.6 941.2 663.6–992.3
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Data were presented in counts and percentages.

AFB, Acid-fast bacilli; CI, confidence interval; TB, tuberculosis.

Diagnostic approach variation

Chest x-ray

Among participants who were screened positive, 43,6% had no symptoms of cough 14 days or more or blood cough (Table 4). There were 11,202 participants with abnormal Chest X-ray results from 15,446 total participants. Tuberculosis prevalence according to Chest X-ray examination was 725.2 (95% CI: 718.1–732.2) per 100,000 population. The prevalence of TB with positive Chest x-ray was higher at the age 15–24 years with 783.8 (95% CI: 741.2–828.7) per 100,000 population. The prevalence across the demographic region of chest x-ray examination results in Indonesia was higher in males with 200.8 (95% CI: 196.4–205.3) per 100,000 population than the female with 133.5 (95% CI: 130.1–137.1) per 100,000 population. The prevalence was higher in the other regions in Indonesia with 864 (95% CI 809.0–921.4) per 100,000 population than in Sumatra and Java-Bali and higher in rural areas.

Table 4. Distribution of screened participants.
Coughing ≥14 days or coughing up blood Chest x-ray n %
Yes Normal 3,844 24.9
Yes Abnormal 4,459 28.9
Yes No chest x-ray 249 1.6
No Abnormal 6,743 43.6
No Normal or No chest x-ray 151 1.0
Total 15,446 100.0
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Data were presented in counts and percentages.

Sputum AFB

Tuberculosis prevalence according to sputum AFB examination was 256.5 (95% CI: 210.1–302.9) per 100,000 population. The highest TB prevalence is at 65 years and over the group, while the lowest prevalence is at 15–24 years group with 527.6 (95% CI: 292.0–763.2) and 137.5 (95% CI:77.3–197.8) per 100,000 population, respectively. The prevalence of TB with a positive sputum AFB was higher in the male than the female with 392.5 (95% CI: 314.5–470.5) compared with 131.0 (95% CI: 87.6–174.4) per 100,000 population, respectively. The prevalence increased with age, the highest prevalence was 527.6 (95% CI: 292.0–763.2) per 100,000 population in the 65-year-and-over group. The finding showed that urban areas had a higher TB prevalence than rural areas. Referring to the division of regions, Sumatra island had the highest prevalence estimate by sputum AFB examination with a prevalence of 307.4 (95% CI: 208.3–406.5) per 100,000 population than in other regions.

Sputum culture

Sputum culture examination was taken from spot sputum and morning sputum of participants, of 106 participants with contaminated sputum culture results, 95 (89.6%) had spot sputum results and from 47 participants with contaminated spot sputum culture, 37 (78.7%) had results on sputum morning. Among negative culture results, there were 41 with MTB (Mycobacterium tuberculosis) positive and 104 with NTM (Non-Tuberculosis Mycobacterium) from morning culture and there were 39 with a positive spot culture of MTB (Mycobacterium tuberculosis), and 59 with NTM (Non-Tuberculosis Mycobacterium) in negative culture results (Table 5). Tuberculosis prevalence according to culture examination was 545.0 (95% CI: 509.5–583.0) per 100,000 population while culture-negative tuberculosis prevalence was 945.5 (95% CI: 941.7–949.0) per 100,000 population.

Table 5. Compliance with sputum culture examination results (spot and morning sputum).
Culture Morning sputum
Negative MTB NTM Contamination N/A Total
Spot sputum Negative 3,772 41 104 87 170 4,174
MTB 39 89 0 3 2 133
NTM 59 0 14 5 1 79
Contamination 34 2 1 8 2 47
N/A 85 1 3 3 13 105
Total 3,989 133 122 106 188 4,538
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MTB, Mycobacterium tuberculosis; N/A, not available; NTM, non-tuberculosis mycobacterium.

According to the demographic region, the prevalence of TB with positive culture was higher in the other regions in Indonesia with 2,129.8 (95% CI: 1,664.0–2,735.6) per 100,000 population than Sumatra and Java-Bali region. The prevalence was higher in male than female participants, with 607.9 (95% CI: 558.6–661.2) and 463.0 (95% CI: 414.2–517.3) per 100,000 population, respectively. The prevalence of TB with culture examination was higher in urban areas than in rural areas. The prevalence of TB with positive culture examination was higher at the age of 65 years and over with 678.9 (95% CI: 583.6–788.6) per 100,000 population.

Sputum genetic test

Sputum genetic test result indicated 213 M. tuberculosis (MTB) detected, which 184 MTB were not resistant to rifampicin (rifampicin susceptible), 19 MTB were resistant to rifampicin, and 10 MTB were indeterminate (Table 6). TB prevalence according to Xpert TB examination was 894.9 (95% CI: 948.7–928.2) while Xpert TB-negative tuberculosis prevalence was 924.0 (95% CI: 614.0–1,367.0) per 100,000 population. The prevalence of TB with positive sputum genetic test was higher in the other regions of Indonesia following by Sumatra and Java-Bali region with 941.2 (95% CI: 663.6–992.3), 875.0 (95% CI: 775.4–934.2), and 838.7 (95%CI: 748.4–900.8) per 100,000 population respectively. The prevalence of TB with positive sputum genetic test examination was higher at the age of 35–44 years with 933.3 (95% CI: 809.7–978.7) per 100,000 population. Prevalence in males and females was slightly different and higher in urban areas.

Table 6. The results of the sputum genetic test.
Examination results Xpert MTB
Positive 213
    RIF Sensitive 184
    RIF Resistance 19
    RIF Indeterminate 10
Negative 407
Not detected 22
Error/invalid 4
Total 646
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MTB, Mycobacterium tuberculosis; RIF, rifampicin.

Discussion

The prevalence of TB in the Indonesian population aged 15 years and over was 759 per 100,000; the highest TB prevalence was in the old age group (55 years and over); with a significant variation of TB prevalence across geographical areas and diagnostic approaches. The prevalence of TB was higher in the male group (prevalence of positive TB sputum AFB 393 per 100,000 and TB with bacteriological confirmation 1,082 per 100,000) than female (prevalence of positive TB sputum AFB 131 per 100,000 and TB with bacteriological confirmation 461 per 100,000). This result is consistent with other countries that show a higher prevalence in males than females [25–28]. This is probably because a male is more exposed to TB risk factors such as smoking. Indonesia’s basic health research data shows that the smoking behavior of the Indonesian population aged 15 years and over, amounted to 33.8% in 2018. Men who smoke every day or smoke occasionally are 47.3%, while women are only 1, 2% [29]. Tuberculosis prevalence in Indonesia was higher in urban areas than rural areas, and the Sumatra region had the highest prevalence of TB with 913 (95% CI: 696.7–1,176.7). This could occur because there was more access to health services in the islands of Sumatra and Java but was slightly different for island areas in central and eastern Indonesia. This happened because the two islands were still underdeveloped areas.

The survey participation rate (88.7%) indicates that the survey results can be generalized. These results are not much different from other countries, such as Cambodia 89.2% [27], Myanmar 92.6% [28], and the Philippines 76% [26]. The participation was higher amongst women (53.4%) than men (46.6%) and amongst those in rural areas (53.1%) than in the urban areas (46.9%). According to the tuberculosis prevalence of the Philippines which has similar island patterns with Indonesia, the Philippines has similar results as a participation rate was higher amongst women and rural areas, and TB prevalence was higher in the old age group [26].

The prevalence of TB with positive chest x-ray was higher at the age of 15–24 years, higher in males than females, and higher in rural areas. The proportion of participants aged 65 years and over who underwent chest x-ray was lower than younger ages. Most of the reason was that they were unable to visit the study sites because of illness, disability, or unable to walk. The proportion of female participants who underwent chest x-rays was lower than the male because some pregnant women did not have chest x-rays. The TB prevalence was higher in the other regions in Indonesia than in Sumatra and Java-Bali. Apart from the possibility that the participants in these areas were more frequently exposed to TB germs and TB risk factors, this might be because the area was still underdeveloped so that lack of education could be one of the determining factors.

As symptom-based case finding was not optimal, the passive TB case detection that has been carried out so far might also have contributed to the delay in TB diagnosis and treatment. The limitations of case finding or symptom detection tools and access to health services needed to be improved. Total 26.1% of participants who went to health personnel showed positive screening symptoms. TB cases obtained from positive screening were 245 (57.5%). Among participants who were screened positive, 44% had no symptoms of cough 14 days or more or coughing up blood. Tuberculosis prevalence according to chest x-ray examination is 725.2 per 100,000 population. The use of chest x-ray increased the number of asymptomatic TB cases by 181 (73.9% of symptomatic cases). If the chest x-ray were not used in screening, this study would have lost 42.5% of cases. This meant that the use of chest x-rays could improve case findings. Intensive case finding needed to be supported by all levels of society, including communities and community organizations that cared about TB.

The prevalence of TB with a positive smear was higher in males than females. The prevalence increased with age, urban areas were higher than rural areas, and Sumatra was higher than in other regions. The higher prevalence in urban areas was different from other studies in China which indicated an association of TB prevalence and rural residence [30]. Generally, in urban areas, the participation rate was relatively low although the TB prevalence in urban areas was not lower than in rural areas, the low participation rate could estimate the interval from urban prevalence to be wide. The high prevalence of TB in the island of Sumatra could be caused by the density and many cities and districts on the island, which resulted in more people being directly exposed to TB germs and TB sufferers. This could also be caused by the limited geographical location of other island areas, making it difficult to send samples. The accuracy of TB diagnosis was reduced when only a microscopic examination is used. Contamination in morning sputum (3%) was higher than spot sputum (1.1%). This difference was suspected because when removing the sputum spots, the participants were accompanied by laboratory staff, while the issuance of morning sputum in their respective homes was unaccompanied. The results showed that most of the pulmonary TB cases were associated with sputum specimens which are like cases in Saudi Arabia [31].

The limitations of this study are the lack of genomic sequencing and the availability of negative culture results. Other additional accurate examinations were needed to enhance the quality of the microscopic examination. Sputum genetic test examination was proven to reduce false-positive results. Since this study was conducted in a community, further research to see this trend in routine health services is needed to update the TB diagnostic algorithm. Tuberculosis prevalence according to sputum AFB examination, culture examination, and sputum genetic test examination was 256.5, 545, and 894.9 per 100,000 population, respectively.

The prevalence of TB with positive culture was higher in males than females who lived in urban areas. The prevalence was higher in the other regions in Indonesia than in Sumatra and Java-Bali because the central and eastern regions of Indonesia were still remote and underdeveloped areas, so there might be many TB risk factors and the lack of availability of access to health services that affect the handling and prevention of TB in these areas. The high number of non-TB positive smears showed that a more accurate but simple method of diagnosis such as a sputum genetic test was needed to reduce false-positive rates and unnecessary treatment. The prevalence of TB with positive sputum genetic test was higher in males than the female with a slight difference, and higher in urban areas. The prevalence was higher in the other regions in Indonesia than in Sumatra and Java-Bali. Epidemiological studies show that the prevalence of TB is decreasing by about 4% per year, indicating that incidence decreased by about 2.4% per year. Thus, several factors are likely to contribute to the reduction in TB incidence in Indonesia; for example, rapid improvements in the economy and other related social and economic factors.

Conclusion

TB prevalence varies across geographical areas of Indonesia and could be confounded by the diagnostic approaches. The prevalence of pulmonary TB in Indonesia with bacteriological confirmation was 759.0 per 100,000 population aged 15 years and over with higher prevalence in urban areas and the Sumatra region had the highest prevalence. TB prevalence was 725.2 with chest x-ray, 256.5 with sputum AFB, 545.0 with sputum culture, and 894.9 per 100,000 population with sputum genetic test examination. Indonesia is a vast country. It is undeniable that the spread of TB varies in each geographic area. Adding potential human resources need to be considered, as educational background can be part of understanding tuberculosis, and limited transportation facilities caused by the location between islands which are quite far from each other. Furthermore, a limited number of health workers, health facilities, and medical equipment could be a significant problem for Indonesia.

Acknowledgments

The authors would like to thank the Ministry of Health of the Republic of Indonesia for providing and allowing the authors to use the data. Thanks to reviewers for constructive and positive comments.

Data Availability

The data in this study has legal or ethical restriction as there is a written statement between the researcher and the Indonesian Ministry of Health on sharing a de-identified data set because the data contains potentially sensitive information, and the data are owned by a third-party organization (Indonesian Ministry of Health). Requests for data must submit formally to the Head of the Health Research and Development Agency, the Indonesian Ministry of Health. The data can be requested or accessed through Health Research and Development Agency, Indonesian Ministry of Health (layanan.data@litbang.kemkes.go.id).

Funding Statement

AN received the ASEAN Scholarship 2019 from Chulalongkorn University.

References

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Decision Letter 0

Frederick Quinn

30 Jul 2021

PONE-D-21-15288

Variation of tuberculosis prevalence across diagnostic approaches and geographical areas of Indonesia.

PLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors analyzed 67,944 records and report the prevalence of TB in different areas of Indonesia comparing sputum AFB, sputum culture, sputum genetic test, and chest radiograph. The authors use only the prevalence and the confidence interval to compare the different groups. The study reports the classification of three large islands in Indonesia: the island of Sumatra, the island of Java-Bali, and other islands (eastern part of Indonesia) with a classification of urban and rural areas.

Although the title is attractive, they do not conduct any geographic study.

The authors did not discuss the prevalence of TB in other developing countries, which would contribute to the conceptualization of TB at the global level.

Although they conclude that diagnostic approaches confuse tuberculosis, they do not mention full genomic sequencing as an alternative.

Then it would be convenient to modify the discussion by including data from other countries.

Reviewer #2: This is an interesting study represents an analysis of Variation of TB prevalence across diagnostic approaches and 5 geographical areas of Indonesia

This article could be published in the Journal PLOS ONE after a major revision. I have some comments on it:

Introduction: In line 53 “MTb” name must be in italics; review of the rest of the document.

Methodology: The methodology does not describe the diagnostic tests used and the quality standards used to validate the results. Explain more about the methods used.

Results: The authors must show the risk factors of the patients (HIV, DM, malnutrition, immigration, etc.) and their association with the results in the diagnostic tests, in a table.

• What is the proportion of negative bk and positive culture in the different geographical areas? And how much is the culture, contributing to the timely diagnosis in these cases?.

• How do the authors explain that the prevalence of the positive culture is higher in the eastern region of Indonesia, compared to the results of the Chest X-ray and sputum AFB methods where the positive results are higher for others regions?.

• The authors could include data on the prevalence of migration-related TB cases, do you have any data on tuberculosis in migrants that you can include?.

• In your study you didn’t differentiate between active and latent TB, or the observed results include both?.

The discussion part is very short, need to discuss more issues of “person’ place, and time”.

In the conclusion, could the authors explain from their point of view, some reasons for the spread of TB in the different geographical areas of Indonesia and their strategies or suggestions to improve early detection?.

• The article has some mistakes in English language and have to be corrected.

**********

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Reviewer #1: No

Reviewer #2: Yes: Armando Martínez-Guarneros

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PLoS One. 2021 Oct 15;16(10):e0258809. doi: 10.1371/journal.pone.0258809.r002

Author response to Decision Letter 0

22 Sep 2021

Dear Editor,

We thank you and the reviewers for the comments and suggestions. Please find our point-by-point responses below.

Editor: Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

Response: Thank you for your time and consideration. The manuscript was revised to meet PLOS ONE’s publication criteria as well as the style requirements.

Editor: 2. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Response: Thank you very much. We have updated the grant information both in ‘Funding Information’ and ‘Financial Disclosure’ sections.

Editor: 3. Thank you for stating the following in the Acknowledgments/ Funding Section of your manuscript: “ASEAN Scholarships 2019 by Chulalongkorn University.” We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: “AN received the ASEAN Scholarship 2019 from Chulalongkorn University.”

Response: Thank you so much for your direction. We are sorry for the confusion and thank you very much for pointing that out. We removed the funding information from the Acknowledgment Section and other areas of the manuscript accordingly. The Funding Statement is correct and can be presented as it currently reads.

Editor: 4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: The data in this study has legal or ethical restriction as there is a written statement between the researcher and the Indonesian Ministry of Health on sharing a de-identified data set because the data contains potentially sensitive information, and the data are owned by a third-party organization (Indonesian Ministry of Health). Requests for data must submit formally to the Head of the Health Research and Development Agency, the Indonesian Ministry of Health. The data can be requested or accessed through Health Research and Development Agency, Indonesian Ministry of Health (layanan.data@litbang.kemkes.go.id).

Editor: 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section.

Response: Thank you for your explanation. Ethics statement has been modified in which only written in Methods section. All ethics statement written in other section other than as suggested section is deleted.

Reviewer #1: The authors analysed 67,944 records and report the prevalence of TB in different areas of Indonesia comparing sputum AFB, sputum culture, sputum genetic test, and chest radiograph. The authors use only the prevalence and the confidence interval to compare the different groups. The study reports the classification of three large islands in Indonesia: the island of Sumatra, the island of Java-Bali, and other islands (eastern part of Indonesia) with a classification of urban and rural areas.

Response: Thank you for your time in reviewing the manuscript.

Reviewer #1: Although the title is attractive, they do not conduct any geographic study.

Response: Thank you for the advice so we already changed the term to regional variation to minimize confusion.

Reviewer #1: The authors did not discuss the prevalence of TB in other developing countries, which would contribute to the conceptualization of TB at the global level.

Response: Thank you very much for improving the generalizability of our work. The discussion about contribution to the conceptualization of TB at the global level by using TB prevalence in developing countries is provided in the Discussion section as advised (Line 213-220, 225-231). As this study can be beneficial for other developing countries that has a wide geographics boundaries especially the country that has many islands, we specifically included the Philippines as one of the reference countries, because the Philippines has the similar island patterns with Indonesia.

Reviewer #1: Although they conclude that diagnostic approaches confuse tuberculosis, they do not mention full genomic sequencing as an alternative.

Response: Thank you very much for pointing that out. We have addressed this suggestion as a study limitation in the Discussion section.

Reviewer #1: Then it would be convenient to modify the discussion by including data from other countries.

Response: Thank you for your suggestion. The data from other countries added as suggested.

Reviewer #2: This is an interesting study represents an analysis of Variation of TB prevalence across diagnostic approaches and 5 geographical areas of Indonesia. This article could be published in the Journal PLOS ONE after a major revision. I have some comments on it.

Response: Thank you very much for your time in reviewing the manuscript. We are pleased to know that our study is interesting, and your comments are very constructive and useful to develop it.

Reviewer #2: Introduction: In line 53 “MTb” name must be in italics; review of the rest of the document.

Response: The term Mycobacterium tuberculosis in the manuscript was italicized.

Reviewer #2: Methodology: The methodology does not describe the diagnostic tests used and the quality standards used to validate the results. Explain more about the methods used.

Response: Thank you very much for the comment. We did not collect the detail specification of each diagnostic test at each institution; however, the description of each diagnostic test was expanded by using information provided by the Indonesian Ministry of Health.

Reviewer #2: Results: The authors must show the risk factors of the patients (HIV, DM, malnutrition, immigration, etc.) and their association with the results in the diagnostic tests, in a table.

Response: Thank you for pointing out, unfortunately we did not have individual-level data on comorbidities. Nevertheless, we added one more table that shows the cases of a relevant comorbidities across regions in Indonesia based on a publish literature (Table 1).

Reviewer #2: What is the proportion of negative and positive culture in the different geographical areas? And how much is the culture, contributing to the timely diagnosis in these cases?.

Response: Thank you very much for pointing that out. We have addressed this suggestion as a study limitation in the Discussion section.

Reviewer #2: How do the authors explain that the prevalence of the positive culture is higher in the eastern region of Indonesia, compared to the results of the Chest X-ray and sputum AFB methods where the positive results are higher for others regions?.

Response: Thank you for the comments. In the eastern region of Indonesia, there are more sub-regions than other regions that are still underdeveloped and undeveloped; the education level is relatively low and the number of uneducated people in understanding tuberculosis is high. That effect sputum smear test might not be done properly and correctly at home. In addition to that, limited number of health workers who can assist in performing repeated sputum smear sampling and lack of medical facilities such as a TB detection device in the form of an up-to-date chest x-ray machine can affect the test results. Another possible interpretation of a negative smear test result is that the number of Mycobacterium tuberculosis bacteria is too small so that it cannot be detected through a microscope and further tests are needed by performing a microscopic examination of sputum or culture.

Reviewer #2: The authors could include data on the prevalence of migration-related TB cases, do you have any data on tuberculosis in migrants that you can include?.

Response: Thank you for the advice. We are sorry that our dataset does not include migrants or migration-related TB cases so we could not calculate the prevalence of migration-related TB. However, we added the Indonesian migrant data based on other literatures.

Reviewer #2: In your study you didn’t differentiate between active and latent TB, or the observed results include both?.

Response: In our study, the observed results included both active and latent TB.

Reviewer #2: The discussion part is very short, need to discuss more issues of “person’ place, and time”.

Response: Thank you so much for your comments, in fact your points above already help us expand the discussion be much more comprehensive and we are very thankful for that. We also added some more discussion on the time.

Reviewer #2: In the conclusion, could the authors explain from their point of view, some reasons for the spread of TB in the different geographical areas of Indonesia and their strategies or suggestions to improve early detection?.

Response: Additional point of view about reason for regional distribution of TB and strategies to improve early TB detection was provided in the Conclusion section. Education equality, rural and underdeveloped areas, low number of health worker, lack of health facilities and medical equipment were the major determinants for TB distribution along regional areas in Indonesia. We suggested several strategies to enhance TB initial detection: the government need to allocate extra budget for adding medical equipment which distributed evenly across geographical areas and allow public access to standardize laboratories especially for chest X-rays. Chest X-rays play a significant role to detect TB symptoms and was considered as the gold standard for initial TB confirmation in Indonesia.

Reviewer #2: The article has some mistakes in English language and have to be corrected.

Response: Thank you very much. We did a proof-reading service prior to resubmit the manuscript to review and enhance in English language.

We hope that our responses are satisfactory. Should there be anything that might improve our work, please kindly inform us. Thank you very much for your kind consideration.

Best Regards,

Assoc. Prof. Dr. Krit Pongpirul, MD, MPH, PhD.

On behalf of the authors

Attachment

Submitted filename: Response to Reviewer TB 2 KP clean.docx

Click here for additional data file. (22.2KB, docx)

Decision Letter 1

Frederick Quinn

6 Oct 2021

Variation of tuberculosis prevalence across diagnostic approaches and geographical areas of Indonesia.

PONE-D-21-15288R1

Dear Dr. Pongpirul,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Frederick Quinn

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have addressed all observations made to the original manuscript. There are no more observations to the article. Hopefully, the study will have a good impact on the area.

Reviewer #2: The comments were satisfactorily resolved by the authors, so I consider that the study entitled "Variation of tuberculosis prevalence across diagnostic approaches and geographical areas of Indonesia" could be accepted for publication by the PLOSONE Journal. Yours sincerely PhD. Armando Martinez-Guarneros.

**********

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Reviewer #1: No

Reviewer #2: Yes: José Armando Martinez-Guarneros

Acceptance letter

Frederick Quinn

8 Oct 2021

PONE-D-21-15288R1

Variation of tuberculosis prevalence across diagnostic approaches and geographical areas of Indonesia.

Dear Dr. Pongpirul:

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Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Frederick Quinn

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Response to Reviewer TB 2 KP clean.docx

    Click here for additional data file. (22.2KB, docx)

    Data Availability Statement

    The data in this study has legal or ethical restriction as there is a written statement between the researcher and the Indonesian Ministry of Health on sharing a de-identified data set because the data contains potentially sensitive information, and the data are owned by a third-party organization (Indonesian Ministry of Health). Requests for data must submit formally to the Head of the Health Research and Development Agency, the Indonesian Ministry of Health. The data can be requested or accessed through Health Research and Development Agency, Indonesian Ministry of Health (layanan.data@litbang.kemkes.go.id).

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