tuberculosis research paper thesis in the philippines

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Peer-reviewed

Research Article

High TB burden and low notification rates in the Philippines: The 2016 national TB prevalence survey

Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations Department of Clinical Epidemiology, College of Medicine, University of the Philippines, Manila, Philippines, Division of Infectious Diseases, Department of Medicine, College of Medicine, University of the Philippines–Philippine General Hospital, Manila, Philippines

Roles Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft

Roles Conceptualization, Formal analysis, Methodology, Validation, Writing – original draft, Writing – review & editing

Affiliation Global Tuberculosis Programme, World Health Organization, Geneva, Switzerland

Roles Conceptualization, Formal analysis, Investigation, Methodology, Supervision, Writing – review & editing

Affiliation Department of Clinical Epidemiology, College of Medicine, University of the Philippines, Manila, Philippines

Roles Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – review & editing

Affiliation Institute of Clinical Epidemiology, National Institutes of Health, University of the Philippines, Manila, Philippines

Roles Formal analysis, Investigation, Visualization, Writing – review & editing

Affiliations Foundation for the Advancement of Clinical Epidemiology, Manila, Philippines, Social Innovation in Health Initiative, University of the Philippines, Manila, Philippines

Roles Investigation, Methodology, Writing – review & editing

Affiliation Foundation for the Control of Infectious Diseases, Taft Avenue, Manila, Philippines

Roles Formal analysis, Investigation, Writing – review & editing

Affiliation Division of Infectious Diseases, Department of Medicine, College of Medicine, University of the Philippines–Philippine General Hospital, Manila, Philippines

Affiliations Department of Radiology, University of the Philippines College of Medicine, University of the Philippines, Manila, Philippines, Philippine College of Radiology, Quezon City, Philippines

Roles Formal analysis, Investigation, Methodology, Writing – review & editing

Affiliations Department of Clinical Epidemiology, College of Medicine, University of the Philippines, Manila, Philippines, Institute of Clinical Epidemiology, National Institutes of Health, University of the Philippines, Manila, Philippines

Roles Data curation, Methodology, Validation, Writing – review & editing

Roles Formal analysis, Writing – review & editing

Affiliation Department of Health, National TB Control Program, Manila, Philippines

Roles Funding acquisition, Project administration, Resources, Writing – review & editing

Affiliations Department of Clinical Epidemiology, College of Medicine, University of the Philippines, Manila, Philippines, Foundation for the Advancement of Clinical Epidemiology, Manila, Philippines

Affiliations Division of Infectious Diseases, Department of Medicine, College of Medicine, University of the Philippines–Philippine General Hospital, Manila, Philippines, Foundation for the Control of Infectious Diseases, Taft Avenue, Manila, Philippines

Roles Formal analysis, Investigation, Supervision, Writing – review & editing

Affiliations Department of Clinical Epidemiology, College of Medicine, University of the Philippines, Manila, Philippines, Institute of Health Policy and Development Studies, University of the Philippines, Manila, Philippines

Roles Validation, Writing – review & editing

Affiliations Infectious Diseases Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico di Sant’Orsola, Bologna, Italy, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy

Roles Conceptualization, Funding acquisition, Methodology, Resources, Writing – review & editing

•  [ ... ],

¶ Membership of the Philippine NTPS 2016 Group is provided in the Acknowledgments.

• [ view all ]
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• Mary Ann D. Lansang, 
• Marissa M. Alejandria, 
• Irwin Law, 
• Noel R. Juban, 
• Maria Lourdes E. Amarillo, 
• Olivia T. Sison, 
• Jose Rene B. Cruz, 
• Concepcion F. Ang, 
• Joseph Adrian L. Buensalido, 

• Published: June 4, 2021
• https://doi.org/10.1371/journal.pone.0252240
• Reader Comments

The 3 rd national tuberculosis (TB) survey in the Philippines in 2007 reported a significant decline in the prevalence of TB. Since then, more significant investments for TB control have been made, yet TB burden estimates from routine surveillance data remain relatively stable.

To estimate the prevalence of bacteriologically confirmed pulmonary TB in the Philippines amongst individuals aged ≥15 years in 2016.

In March–December 2016, we conducted a population-based survey with stratified, multi-stage cluster sampling of residents in 106 clusters aged ≥15 years. Survey participants were screened for TB by symptom-based interview and digital chest X-ray. Those with cough ≥2 weeks and/or haemoptysis and/or chest X-ray suggestive of TB were requested to submit 2 sputum specimens for Xpert MTB/RIF, direct sputum smear microscopy using LED fluorescent microscopy, and mycobacterial solid culture (Ogawa method). Bacteriologically confirmed pulmonary TB was defined as MTB culture positive and/or Xpert positive.

There were 46,689 individuals interviewed, and 41,444 (88.8%) consented to a chest X-ray. There were 18,597 (39.8%) eligible for sputum examination and 16,242 (87.3%) submitted at least one specimen. Out of 16,058 sputum-eligible participants, 183 (1.1%) were smear-positive. There were 466 bacteriologically confirmed TB cases: 238 (51.1%) Xpert positive, 69 (14.8%) culture positive, and 159 (34.1%) positive by both Xpert and culture. The estimated TB prevalence per 100,000 population aged ≥15 years was 434 (95% CI: 350−518) for smear-positive TB, and 1,159 (95% CI: 1,016−1,301) for bacteriologically confirmed TB.

This nationally representative survey found that the TB burden in the Philippines in 2016 was higher than estimated from routine TB surveillance data. There was no evidence of a decline in smear and culture positive TB from the 2007 survey despite significant investments in TB control. New strategies for case-finding and patient-centered care must be intensified and expanded.

Citation: Lansang MAD, Alejandria MM, Law I, Juban NR, Amarillo MLE, Sison OT, et al. (2021) High TB burden and low notification rates in the Philippines: The 2016 national TB prevalence survey. PLoS ONE 16(6): e0252240. https://doi.org/10.1371/journal.pone.0252240

Editor: Frederick Quinn, The University of Georgia, UNITED STATES

Received: January 13, 2021; Accepted: May 11, 2021; Published: June 4, 2021

Copyright: © 2021 Lansang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The 2016 NTPS was supported by the Philippines’ Department of Health ( https://doh.gov.ph/ ) through a research grant from the Department of Science and Technology – Philippine Council for Health Research and Development ( http://pchrd.dost.gov.ph/ ), as covered by a Memorandum of Understanding dated 11 December 2015. The Department of Health and the Philippine Council for Health Research and Development were involved in the overall design of the survey and the decision to publish the survey results. Anna Marie Celina Garfin, programme manager of the National TB Control Programme of the Department of Health, is a co-author of the paper.

Competing interests: The authors have declared that no competing interests exist. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated.

Introduction

Globally, tuberculosis (TB) ranked 10th amongst the leading causes of death worldwide and is the leading cause from a single infectious agent with an estimated 1.2 million TB deaths amongst HIV-negative people and 10 million new cases of TB in 2019 [ 1 ]. Globally, the Philippines remains one of the highest TB burden countries and continues to bear the health and socioeconomic consequences of TB. In 2015, TB ranked 4 th amongst the leading causes of mortality in the country and 9 th in terms of disability-adjusted life years [ 2 ]. The estimated incidence of TB was 322 per 100,000, while the estimated number of multi-drug resistant TB cases amongst notified pulmonary TB cases was 15,000 for 2015 [ 3 ].

National TB prevalence surveys were conducted in 1981–83, 1997, and 2007 [ 4 – 6 ]. The 2007 survey reported a 31% reduction in bacteriologically positive TB and 27% reduction of smear-positive TB prevalence compared to the 1997 survey, attributed mainly to the implementation, and roll out of the Directly Observed Treatment, Short course (DOTS) program in the late 1990s and early 2000s, complemented by strategic public-private partnerships. The 2007 survey concluded that TB was still a major public health problem in the Philippines, with a prevalence of 2.6 per 1,000 smear-positive TB and 6.6 per 1,000 bacteriologically confirmed TB amongst those aged ≥ 10 years [ 6 ]. Subsequently, the Government of the Philippines developed a strategic framework for TB control, the Philippine Plan of Action to Control Tuberculosis (2010–2016), as part of its health sector agenda. The implementation of the national strategy involved an increased budget for the National TB Control Program (NTP), expansion of NTP priorities from smear-positive TB cases to all forms of TB, engagement of village health workers and communities in case detection and treatment activities, expansion of private sector and public hospital engagement in DOTS programs, and leveraging funding from the Global Fund to Fight AIDS, Tuberculosis and Malaria to expand treatment centers for multidrug-resistant TB (MDR-TB) [ 7 ].

The NTP of the Philippines’ Department of Health (DOH) needed to reassess the TB burden and identify the gaps and challenges whilst shifting the TB target of the Millennium Development Goals −a decline in TB incidence by 2015 − to that of the Sustainable Development Goals − 80 per cent reduction in TB incidence compared to 2015 [ 8 ]. Hence, we conducted the 2016 National TB Prevalence Survey to provide the NTP with accurate and updated information on TB burden as the Philippines segues into its 2017−2022 strategic plan to eliminate TB.

The primary objectives of the survey were to estimate the prevalence of bacteriologically confirmed pulmonary TB (PTB) amongst the population in the Philippines ≥15 years during 2016, and to assess the trends of smear-positive and bacteriologically confirmed PTB prevalence, compared with the results of the 2007 survey.

Study population and methods

Study design, sample size and sampling procedure.

We conducted a population-based, cross-sectional survey from March to December 2016 across 57 provinces from 17 regions of the Philippines. We designed the survey in accordance with the WHO Global Task Force on TB Impact Measurement [ 9 ].

The sample size was calculated using the following assumptions: (1) a maximum 20% reduction in smear-positive TB since 2007, therefore prevalence of smear-positive TB was assumed to be 2.6 per 1,000 individuals aged ≥15 years in 2016; (2) cluster size of 500 individuals eligible to attend the survey; (3) coefficient of between-cluster variation of 0.8 with a corresponding design effect of 1.83; (4) 25% relative precision; and (5) 85% minimum participation rate. The estimated sample size was 51,000 eligible individuals from 102 clusters. Six clusters were added to round off allocations to strata and to account for the cancellation of clusters due to security reasons and/or inaccessible areas, to give a final sample size of 54,000.

Using stratified, multi-stage cluster sampling, 108 clusters were randomly sampled across 4 strata, allocated proportionately to population size as follows: 41 clusters for stratum 1 − National Capital Region, Central Luzon region, and Calabarzon region; 20 for stratum 2 − rest of Luzon island; 21 for stratum 3 − Visayas region; and 26 for stratum 4 − Mindanao region ( Fig 1 ).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

Orange dots–stratum 1 (National Capital Region; blue dots–stratum 2 (rest of Luzon island); green dots–stratum 3 (Visayas region); red dots–stratum 4 (Mindanao region); cross marks (+) − sampled clusters that were dropped.

https://doi.org/10.1371/journal.pone.0252240.g001

Survey procedure

Four survey teams were deployed simultaneously to cover each stratum. Individuals aged ≥15 years old and residing in the cluster for at least 2 weeks before the survey who provided informed consent were interviewed using a structured questionnaire with the following components: (1) TB symptoms screening (cough and duration, sputum production, haemoptysis, fever, weight loss, night sweats); (2) past and/or current TB diagnosis and treatment; (3) health-care seeking behavior of those reporting symptoms; and (4) a history of diabetes mellitus and smoking. After the interview, all participants who consented underwent chest X-ray using a mobile digital machine (MinXray HF 120/60H Powerplus TM ), except for pregnant women, those with physical disabilities that precluded upright chest X-ray, a recent chest X-ray, and, in a few instances, X-ray machine malfunction. A trained physician ( i . e ., field team leader) further interviewed and examined the participants, then interpreted their chest X-rays at the survey site. The digital images were then sent to an off-site radiologist within the day. The off-site radiologists used the following classification, adapted from the WHO TB prevalence survey handbook [ 8 ]: (1) normal chest X-ray; (2) abnormality detected–not TB; (3) pulmonary abnormality detected–not TB; and (4) pulmonary abnormality detected–suspicious for TB.

Eligibility for sputum examination

Participants with screening symptoms of cough ≥2 weeks and/or haemoptysis, and/or radiographic abnormalities suggestive of TB based on the reading of the field team leader were requested to submit 2 sputum specimens: (1) a spot specimen at the survey site, and (2) an early morning specimen collected the next day. Those who did not have a chest X-ray were also instructed to submit sputum, irrespective of screening symptoms. If the volume of the sputum specimens was <3 ml, a third specimen was collected. Participants with discordant readings of their chest X-rays, i.e., normal reading by the field reader and suggestive of TB by the offsite radiologist, were recalled to submit sputum.

Laboratory procedures

The sputum specimens from the field sites were in tightly sealed containers and packaged in insulated ice boxes at 2–8°C with temperature monitor, and transported at least twice a week to the designated six reference laboratories located in the three major island groups of the Philippines. Xpert MTB/RIF version G4 assay (Xpert®) was done on the spot sputum specimens while direct sputum smear microscopy (DSSM) using light emitting diode fluorescence microscope (LED-FM) and mycobacterial culture on Ogawa solid media (one tube) were performed, preferably on the morning specimens, and incubated and observed for growth up to 8 weeks. Tubes with colony growth were sampled, smeared, and stained by Ziehl Neelsen stain, and acid-fast bacilli (AFB) subjected to the MPT64 rapid test for MTB species confirmation. LED-FM readings of sputum smears were reported using the NTP Manual of Procedures scale for AFB microscopy [ 10 ], ranging from 0 (no acid-fast bacilli), scanty, 1+, 2+, and 3+ (>250 AFB in one field on average at 200x magnification or >60 AFB at 400x magnification). Isolates from MTB culture were forwarded to the Research Institute for Tropical Medicine–National TB Reference Laboratory of the Philippine Department of Health for drug sensitivity testing (DST), using the proportion method in 92% and line probe assay in 8% of the isolates.

Survey case definitions

Bacteriologically confirmed TB (BCTB) cases were defined as screen-positive participants with sputum samples positive for MTB on culture and/or Xpert MTB/RIF positive. The Diagnostic and Medical Panel, composed of pulmonologists, infectious disease specialists, a senior radiologist, the laboratory coordinator, one data manager, and the deputy director of the Central Technical Unit, deliberated on the survey classification of all participants with any positive results either on DSSM, Xpert, or culture ( S1 Table ).

Quality management procedures

The quality management unit monitored the field teams and participating laboratories to ensure that survey and laboratory processes adhered to the project standard operating procedures. Senior radiologists at the central level reviewed all chest X-rays of participants with positive laboratory results, all abnormal chest X-rays, and chest X-rays with discordant readings between the field team leader and the off-site radiologist, and a random sample of 5% of normal chest X-rays. External technical assistance was provided by members of the WHO Global Task Force on TB Impact Measurement, the WHO Country Office, and the WHO Regional Office.

Data management and analysis

Survey teams captured data via tablet computers. Barcodes were used to identify survey participants, including their sputum specimens and laboratory results, stored in a non-relational database management system. Data entry and data checking programmes were developed using Epi Info TM versions 3.5.4 and 7.1 [ 11 ]. The central data management unit cleaned, validated, and merged all electronic databases from the field teams, reference laboratories, off-site radiologists, and central radiologists.

STATA® version 14 was used for data analysis (StataCorp, Texas, USA). We used the best-practice analytical methods recommended by the WHO Global Task Force on prevalence surveys to estimate TB prevalence to account for cluster sampling, non-participation, and missing data [ 9 , 12 ]. Three logistic regression models were conducted: (1) cluster-level analysis, (2) individual-level analysis, and (3) estimation with inverse probability weighting and with multiple value imputation. Only model 3 is presented in this article. To determine possible risk factors for TB, multiple logistic regression analysis with inverse probability weight and backward elimination strategy was done.

As an approximate indicator of case detection [ 13 ], we also estimated the prevalence to case notification ratios (P:N) by comparing the age- and sex-specific BCTB prevalence rates to TB case notification rates for smear-positive PTB for the same age groups and sex as reported in the national TB registry for 2016. Lastly, we compared estimated prevalence rates for smear-positive and culture-positive TB in the 2007 and 2016 national TB prevalence surveys (NTPS). Recognizing that there were fundamental differences between the two surveys in the sampling design, age groups covered, screening procedures, chest X-ray imaging interpretation, diagnostic tests used, and TB case definition, we restricted our comparison of the two surveys to the following common parameters: age eligibility, screening outcomes defined by chest X-ray only, and PTB cases defined by Ogawa culture only. This allowed estimations of adjusted prevalence rates for 2007 and 2016 for culture-positive TB cases as well as smear-positive/culture-positive TB.

Ethics statement

On January 19, 2016, the National Ethics Committee approved the survey protocol, standard operating procedures, data collection forms, and consent forms in English and four Philippine languages. The study was done in accordance with the National Ethical Guidelines for Health and Health Related Research and the Data Privacy Act of 2012. The written informed consent forms were supplemented with an individually administered video information using a tablet computer, outlining the survey procedures as well as the risks and benefits of participation. Minors (below 18 years) provided written assent, but their parent or guardian also provided written informed consent. A two-item quiz was administered to document competence and comprehension of the participants.

The city/municipal health officer and the NTP coordinator per cluster were informed of participants who were classified as TB cases in their respective areas via password-protected email communications. Clinical recommendations on management for each TB case including the x-ray and laboratory results were also provided to the health officers by the Diagnostic and Medical Panel.

Survey participants

There were 89,663 individuals enumerated in106 clusters of the 108 original clusters in the sampling frame. Two clusters were eventually dropped–one due to safety issues in a conflict-affected area and the other due to an inability to do household enumeration and community mobilization due to restrictions imposed by the village officers. Compared with the 2010 Philippine census, the age and sex distributions of the population in the clusters were similar in the survey-eligible population, except for slightly higher proportions (1.5–1.6%) in the age groups aged ≥55 years in the 2016 NTPS enumeration, for which we did not make population-adjusted estimates. Of the total enumerated, 28,197 (31.4%) were not eligible to participate due to age or residence criteria. Of those eligible to participate, 46,689 (76.0%) attended the survey, resulting in an average of 440 participants per cluster (range: 149–572). Participation was significantly higher amongst women (82.2%) than men (69.5%); individuals aged ≥65 years (90.1%) than those aged ≤25 years (70.0%); and amongst those in rural clusters (80.2%) than in the urban clusters (71.5%) (all P <0.001) ( Fig 2 ).

(1) CXR: Chest X-ray; FTF: Field tracking form; DSSM: Direct sputum smear microscopy. (2) One sputum: no laboratory result (error on two Xpert runs; no DSSM and MTB culture).

https://doi.org/10.1371/journal.pone.0252240.g002

Amongst participants, 46,689 (100%) were screened for symptoms and 41,444 (88.8%) underwent chest X-ray. There were 18,597 (39.8%) who were assessed as eligible for sputum collection, out of whom 10,702 (57.5%) had chest X-ray abnormalities suggestive of TB alone; while 1,457 (7.8%) had screening symptoms alone and 1,358 (7.3%) were positive on both chest X-ray and screening symptoms. Another 5,080 (27.3%) who did not report symptoms refused or were unable to undergo chest X-ray ( Fig 2 ).

Laboratory results

Of the 18,597 eligible for sputum specimen collection, 16,242 (87.3%) submitted at least one sputum sample, while 15,547 (83.6%) submitted two samples. Laboratory results were available for 16,241 (99.9%) samples. A total of 16,058 (98.9%) had a valid DSSM, out of which 183 (1.1%) were smear-positive. There were 16,200 (99.7%) with valid Xpert results, out of which 397 (2.4%) were Xpert-positive. Valid culture results were available for 15,776 (97.1%), out of which 232 (1.5%) were MTB-positive ( Fig 2 ). Of the 232 MTB-positive samples, there were 4 weakly positive samples (≤9 colonies) that were both smear-negative and Xpert-negative.

Survey TB cases

There were 466 bacteriologically confirmed pulmonary TB cases, only 173 (37.1%) of whom were smear-positive. Based on the survey case definition using Xpert and/or MTB culture, 238 (51.1%) were Xpert-positive only, 69 (14.8%) were culture-positive only, and 159 (34.1%) were both Xpert and culture-positive ( Fig 3 ).

Green bars − culture-positive and Xpert-positive; orange bars − culture-negative and Xpert-positive; blue bars − culture-positive and Xpert negative. BCTB: bacteriologically confirmed TB.

https://doi.org/10.1371/journal.pone.0252240.g003

Regarding the extent of TB recurrence among the 466 survey TB cases, 77 (16.5%) reported previous TB treatment at some point in the past five years and 30 (6.4%) stated they were on treatment at the time of the survey. Thus, 359 (77%) were considered new cases. Amongst the 238 survey TB cases who were positive by Xpert alone, 71 (29.8%) had current or previous history of TB treatment, compared to 36 out of 228 (15.8%) who were positive by culture alone or Xpert with culture. Rifampicin resistance was detected in 29 (7.3%) of the 397 Xpert-positive cases, with a significantly higher proportion seen among those with previous TB treatment (15 out of 81, 18.5%) compared to the treatment-naive cases (14 out of 385, 3.6%). Three of the 29 rifampicin-resistant specimens detected by Xpert were rifampicin-susceptible by DST. Overall, rifampicin resistance was 5.7% by DST (13 isolates). Out of 229 available MTB isolates, resistance to one or more anti-TB drugs were as follows: isoniazid alone − 5.7% (13 isolates); streptomycin alone − 3.0% (7 isolates); isoniazid and streptomycin– 2.6% (6 isolates); rifampicin and isoniazid (MDR-TB), with or without other first-line or second-line drugs −3.9% (9 isolates).

Only 150 (32.1%) of the BCTB cases reported screening symptoms, with symptoms being more frequent among smear-positive TB cases (88 out of 173, 50.9%) compared to smear-negative TB cases. On the other hand, the frequency of screening symptoms among the sputum-eligible participants who were non-cases was much lower (2,537 out of 15,775, 16.1%).

Among BCTB cases with screening symptoms, cough of ≥2 weeks duration was the most frequently reported symptom among the BCTB cases (n = 117, 25.1%), followed by both cough of ≥2 weeks and haemoptysis (n = 22, 4.7%), while haemoptysis alone was present in only 5 cases (1.1%). The proportion of BCTB cases reporting cough of ≥2 weeks was significantly higher than among non-cases (P<0.001) ( Table 1 ).

https://doi.org/10.1371/journal.pone.0252240.t001

With regard to chest X-ray screening, 409 out of 438 (93.4%) BCTB cases who underwent chest imaging had radiologic findings suggestive of TB, a yield higher than symptom screening. Notably, two-thirds of cases with X-ray findings were asymptomatic, and these X-ray findings tended to be extensive. Bilateral lung involvement was seen in 275 (67.2%) cases. Ground glass or reticular densities were found in 396 (90.4%) cases–with or without cavities, nodularities, or calcifications. Another 6 had only cavity formation and no other findings.

Prevalence of TB

The weighted and adjusted prevalence of bacteriologically confirmed pulmonary TB was 1,159 per 100,000 population aged ≥15 years (95% CI: 1,016–1,301) and 434 (95% CI: 350–518) per 100,000 population for smear-positive pulmonary TB. The estimated prevalence rate for culture-positive pulmonary TB was 587 per 100,000 (95% CI: 488 −687). Men were 2.5 times more likely to have pulmonary TB compared to women. The estimated prevalence increased with age, peaking at 45–54 years (1,714 per 100,000 [95% CI: 1,364–2,064]) ( Table 2 ).

https://doi.org/10.1371/journal.pone.0252240.t002

Within the age group 15 − 24 years, the weighted prevalence rates for smear-positive TB and BCTB in the 15–19 year old population were 151 per 100,000 (95% CI: 48–254) and 613 (95% CI: 403–822), respectively, suggesting a significant TB burden even among adolescents. There was no significant difference in the estimated prevalence rates among the four geographic strata, but the highest prevalence rate of BCTB was seen in Stratum 1 (1,358 per 100,000 [95% CI: 1,103–1,612]), which has the highest population density in the country at 20,785 persons per square kilometer [ 14 ] and includes large settlements of urban slum dwellings.

The estimated prevalence-to-notification (P:N) ratio across all age groups was 3.1, and was higher in men than women. The highest ratio of 4.2 was found in the age group 15–24 years but consistently high throughout ( Table 3 ).

https://doi.org/10.1371/journal.pone.0252240.t003

In the restricted analysis on common survey parameters for 2007 and 2016, the estimated adjusted prevalence rates for culture-positive TB in the adult population were: 463 per 100,000 (95% range: 333−592) and 512 per 100,000 (95% range: 420−603), respectively. For smear-positive culture-positive TB, the estimated adjusted prevalence rates were: 193 per 100,000 (95% range: 117−269) and 286 per 100,000 (95% range: 223−349) for the 2007 and 2016 surveys, respectively.

Health-care seeking behaviour of symptomatic participants

Of the 46,689 survey participants, only 2,815 (6.0%) reported having screening symptoms. Of these, only 534 (19.0%) consulted a healthcare worker, with more women (271/1,162, 23.3%) seeking care compared to men (263/1,653, 15.9%) (p<0.001). The proportion of participants aged ≥65 years seeking care was significantly higher (164/591, 27.7%, p<0.001) compared to other age groups. No statistically significant difference was seen in the proportion seeking care between the urban (225/1,272, 17.7%) and rural areas (309/1,543, 20%). Amongst those who sought formal care, there were twice more who went to public facilities (359, 12.8%) compared to private providers (166, 5.9%); while only a few went to traditional healers (10, 0.4%). The rest of the participants either did not take any action (1,143, 40.6%) or self-medicated (1,130, 40.1%). Amongst 1,653 men and 1,162 women with screening symptoms, more women (502, 43.2%) self-medicated compared to men (628, 38.0%) (p = 0.005), while more men (759, 45.9%) than women (384, 33.0%) (p<0.001) did not take action. Out of 2,273 survey participants who provided ≥1 reason/s for non-consultation, perceived triviality of symptoms (937, 41.2%), access issues like cost of travel and distance to the health facility (875, 38.5%), and concern about missing school or work (169, 7.4%) were the main reasons for not seeking formal health care.

Fig 4 shows the risk factors independently associated with BCTB on multivariable analysis. Age groups ≥45 years were at risk for BCTB, with those ≥65 years old having 2.8 times higher risk. Other factors significantly associated with TB were: previous TB treatment, self-report of diabetes mellitus, and residing in an urban setting. Smoking and sex were analyzed as interacting variables, showing that men with more than five pack-years smoking history were 3.5 times more at risk (aOR = 3.5, 95% CI: 1.9−6.3) while women smokers had twice risk than non-smokers. Surrogate indicators for lower socioeconomic status, such as recipients of the Philippine government’s conditional cash transfer program for the poorest of the poor (called Pantawid Pamilyang Pilipino Program , or 4Ps) and absence of health insurance coverage, were 1.6–1.8 times more likely to have TB. Related surrogate indicators, which were analyzed as interacting variables, showed that households without a refrigerator had 1.7 times the risk of TB, irrespective of household size.

a Adjusted odds ratios (aOR) were estimated using survey logistic regression with stratified cluster design and adjusted for inverse probability weights. 4Ps: Pantawid Pamilyang Pilipino Program , a cash transfer program for the poor.

https://doi.org/10.1371/journal.pone.0252240.g004

The estimated burden of bacteriologically confirmed pulmonary TB in the Philippines in 2016 was 1,159 per 100,000 adult population, indicating an unacceptably high number of people who are not diagnosed with or reported to have TB. This estimate, when projected to all ages and all forms of TB, translates to approximately 1 million Filipinos with TB. In contrast, in 2016, the NTP notified only 330,000 TB cases [ 15 ] − not all of which were bacteriologically confirmed − equivalent to an estimated P:N ratio of 3.1 in 2016. In addition, only half of survey participants who claimed to be on TB treatment at the time of the survey were found in the national TB registry. Those reported to the TB registry were mostly treated by the public sector, underscoring the low engagement of private providers in TB case notification. At the time of the survey, the implementing rules and regulations for mandatory notification of TB to the national TB registry, as provided by the Comprehensive TB Elimination Plan Act (Republic Act 10767), had not yet been fully developed. Other reasons for under-reporting in the country’s TB registry are: insufficient systematic TB screening and case detection, particularly among high-risk groups; limited contact tracing efforts; inadequate engagement with community-based organizations, non-governmental organizations, and the private sector including private hospitals and workplace initiatives; under-utilization of Xpert MTB/RIF services; lack of human resources and time to encode TB cases into the Integrated TB Information System of the country; lack of computer hardware and/or internet connectivity, which deter or delay reporting; and pervasive service access issues such as geographical and financial barriers and inappropriate health-seeking behaviour [ 16 ].

The high prevalence of TB in the Philippines is multifactorial. Globally, the key social determinants of TB epidemiology are global social inequalities, population mobility, and rapid urbanisation and population growth [ 17 ]. Although poverty rates in the Philippines have slightly declined through the years − poverty incidence of 21.6% in 2015 compared to 25.8% in 2014 − marked inequities persist, e . g ., poverty incidence rates in 2015 of 40.8% for farmers and 36.9% for fishermen [ 18 ]. Rapid urbanisation has been associated with a rise in slum housing, with 43.5% of the population living in slum dwellings in 2016 compared to 38.3% in 2014 [ 19 ]. The higher prevalence rates seen in the urban National Capital Region (stratum 1 in this survey) and in survey clusters located in urban slums suggest that crowded living conditions fuel TB transmission.

On the demand side of health care, the healthcare seeking behaviour of symptomatic individuals remained low. Self-medication remains a prevalent practice in the country, with 43.4% reporting this action in the 2007 survey and 40.1% in the 2016 survey. However, there was a higher proportion of survey participants who took no action for symptoms suggestive of TB in the 2016 survey (41%, vs. 25% in 2007), while the proportion consulting a healthcare provider decreased (19% in 2016 vs. 32% in 2007) [ 20 ]. In both surveys, the prevailing reasons for non-consultation were perceived triviality of symptoms, costs for travel to health facilities, and missed work or school days, suggesting the need for improving social and behavior change communications and patient-centered care to address access issues, including significant out-of-pocket issues related to TB care in the country.

On the supply side, reliance on passive case detection using poorly sensitive diagnostic tools such as light microscopy likely contributed to delayed or missed case detection and treatment. Using a combination of a new rapid highly sensitive and specific molecular test (Xpert MTB/RIF), an improved DSSM with LED fluorescent microscopy, digital chest X-rays and traditional symptom screening, the survey detected more than the expected number of TB cases. Screening for TB using symptoms of cough and haemoptysis alone would have missed two-thirds of bacteriologically confirmed cases. Chest X-ray screening detected almost all PTB cases, with the number needed to screen to detect one TB case at 100. Using DSSM alone for diagnosis missed two-thirds of bacteriologically confirmed cases. Although culture remains the reference standard for TB diagnosis, Xpert MTB/RIF detected 1.7 times more TB cases than culture under field survey conditions. This suggests that a combination of community-based active case detection and intensive case finding among high-risk groups (e.g., particularly male smokers, those with diabetes mellitus, the elderly, poor households, and urban dwellers) and healthcare settings such as hospitals and private clinics with chest X-ray, screening for TB symptoms, and fairly rapid molecular diagnostic tests such as Xpert MTB/RIF could significantly ramp up case finding and treatment. These expanded case-finding and treatment efforts should be coupled with mandatory notification of TB cases, patient-centered treatment and support, and contact tracing.

Overall, the 2016 NTPS survey provided nationally representative, precise, and reliable estimates of the prevalence of TB in the country. Multiple layers of external monitoring by the WHO team, a steering committee led by the NTP that regularly monitored survey operations, and internal quality management procedures of the project team ensured that the survey was conducted according to internationally accepted standards. On the other hand, amongst the limitations of the survey were the 76% participation rate (vs. the target of 85%) as well as the relatively low rates of chest X-ray participation (88%) and sputum submission (87%). The lower-than-expected participation rate was due to a number of factors: the campaign period in the run-up to the local elections in May 2016, work or school priorities of the eligible population, several tropical cyclones, and immunization campaigns prioritized by the Department of Health. To address some of the challenges, we extended survey hours to the evenings and weekends and/or surveys days in several clusters. Moreover, missing data were accounted for in the estimation of prevalence through multiple imputation analysis.

Despite the lower-than-expected sputum submission rate, the high volume of sputum specimens submitted to only six reference laboratories led to heavy workloads in the laboratories. The paucibacillary nature of specimens, logistics and cold storage during specimen transportation, and laboratory workload may have impacted on culture performance, but laboratory performance quality indicators suggest overall acceptable performance (4.1% contamination rate and 89.0%% culture-positive among smear-positive samples).

The addition of Xpert MTB/RIF to the 2016 NTPS strengthened the detection of prevalent TB cases. However, it should be noted that there were 238 BCTB cases who were positive by Xpert alone. After the survey was completed, a 2017 study of the accuracy of Xpert MTB/RIF showed that its specificity was lower at 92.7% (95% CI: 82.4−98.0%) for those who reported TB in the past two or less years [ 21 ]. Given that 71 (29.8%) of the 238 reported a history of TB of ≤5 years, it is possible that there was some over-diagnosis of TB, with 35 (49.3%) of the 71 having a ‘very low’ Xpert semi-quantitative result. On the other hand, amongst the 222 of the 238 who also had a chest X-ray, the vast majority (204, 91.9%) had findings highly suggestive of TB as confirmed by the Diagnostic and Medical Panel.

Lastly, another limitation was the exclusion of HIV serostatus in the survey. In 2015, during survey protocol preparation, the reported incidence rate of TB/HIV was 4.3 per 100,000 [ 3 ]. At this level, the sample size and sampling requirements as well as the logistics of HIV pre-test counseling and testing exceeded the available funds and scope of the 2016 NTPS.

Conclusion and recommendations

The 2016 nationally representative survey showed that TB remains a significant health burden in the Philippines with no evidence of decline in smear and culture positive TB compared to the 2007 survey. Reasons for the high TB burden are multifactorial, hence eliminating TB must be a national and multi-sectoral priority.

In alignment with the latest WHO guidance [ 22 ], systematic screening of subpopulations with structural risk factors using Xpert MTB/RIF should be prioritized specifically amongst men, older age groups, the poor and urban dwellers, those previously treated for TB, smokers, and those with diabetes mellitus. Engagement with communities, non-governmental organizations, and the private establishments and work places, will be critical in ramping up active and intensive case finding efforts. While TB culture remains the reference standard for diagnosis and is required for drug susceptibility testing, the rapid turnaround of results and accuracy of Xpert MTB/RIF can potentially decrease pre-treatment loss to follow-up, allow timely initiation of treatment, almost triple the TB cases detected compared to DSSM, and identify MDR-TB cases early. To ramp up case finding and treatment, laboratory capacity for Xpert testing should be expanded and decentralized and the supply chain management system should be strengthened to ensure a steady supply of Xpert cartridges and anti-TB drugs.

Addressing behavioural barriers to healthcare-seeking is central to finding undiagnosed people with TB, through improved social and behavior change interventions and patient-centered care. Innovations and implementation research are needed to strengthen behavior change technology and to support access to care strategies. Social and financial risk protection should also be priorities as the Philippine government moves towards implementation of the Universal Health Care Law.

Low notification rates of TB cases by private providers may be addressed by developing user-friendly applications for reporting to the national registry, creating social contracts with the private sector and/or civil society groups for upscaling case detection and care services, and exploring approaches to overcome barriers such as stigma and lack of confidence in the public sector. Overall, eliminating TB will require comprehensive and sustained poverty alleviation efforts and multi-sectoral partnership at the national and local levels.

Supporting information

S1 table. case definition algorithm used by the diagnostic and medical panel..

https://doi.org/10.1371/journal.pone.0252240.s001

Acknowledgments

The following members of the Philippine NTPS 2016 Group are authors of this report: Mary Ann D. Lansang, Marissa M. Alejandria, Irwin Law, Noel R. Juban, Maria Lourdes E. Amarillo, Olivia T. Sison, Jose Rene B. Cruz, Concepcion F. Ang, Joseph Adrian L. Buensalido, Johanna Patricia A. Cañal, Nina T. Castillo-Carandang, Cynthia P. Cordero, Donna Mae G. Gaviola, Mary Ann J. Ladia, Hilton Y. Lam, Jacinto Blas V. Mantaring III, Myrna T. Mendoza, Maria Sonia S. Salamat, Marina Tadolini, Anna Marie Celina G. Garfin.

We gratefully acknowledge the overall project management support provided by the Foundation for the Advancement of Clinical Epidemiology, Inc; the dedicated and efficient conduct of the survey by all survey team members; the participation of the Foundation for the Control of Infectious Diseases and the Philippine College of Radiology in key workstreams of the survey; the overall supervision and guidance of the NTPS Steering Committee and the Technical Working Group; and the expert contributions of the Diagnostic and Medical Panel members. We also express our gratitude to the Philippines’ Department of Health for the overall coordination, the survey joint secretariat of the Department of Health and the Philippine Council for Health Research and Development, the local government units for graciously facilitating the logistics of the survey, and the University of the Philippines Manila for administrative support. Special thanks are due to members of the WHO Global Task Force on Impact Measurement, the WHO Country Office, and the WHO Western Pacific Regional Office for providing expert technical assistance.

This paper is dedicated to the memory of Dr. Thelma Tupasi † — project leader of the Philippine 1997 and 2007 national TB prevalence surveys, staunch TB advocate and leader in the Philippines and internationally, and trailblazer in person-centered MDR-TB care.

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Tuberculosis among children, adolescents and young adults in the Philippines: a surveillance report

Affiliations.

• 1 Centre for International Child Health, University of Melbourne, Department of Paediatrics and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia.
• 2 School of Population and Global Health, University of Melbourne, Melbourne, Australia.
• 3 WHO Country Office for the Philippines, Manila, Philippines.
• 4 Victorian Tuberculosis Program, Melbourne Health, Melbourne, Australia.
• 5 Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia.
• 6 Centre for Adolescent Health, Royal Children's Hospital, Melbourne, Australia.
• 7 Murdoch Children's Research Institute, Melbourne, Australia.
• 8 Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
• 9 International Union Against Tuberculosis and Lung Disease, Paris, France.
• PMID: 30766743
• PMCID: PMC6356044
• DOI: 10.5365/wpsar.2017.8.4.011

The Philippines, a country with a young population, is currently experiencing an intense and persistent tuberculosis epidemic. We analysed patient-based national surveillance data to investigate the epidemiology of reported tuberculosis among children (aged 0-9 years), adolescents (aged 10-19 years) and young adults (aged 20-24 years) to better understand the burden of disease and treatment outcomes in these age groups. Descriptive analyses were performed to assess age-related patterns in notifications and treatment outcomes. Data quality was assessed against international benchmarks at the national and regional levels. Overall, 27.3% of tuberculosis notifications for the Philippines in 2015 pertained to children, adolescents and young adults aged 0-24 years. Treatment outcomes were generally favourable, with 81% of patients being cured or completing treatment. The data quality assessment revealed substantial regional variation in some indicators and suggested potential underdetection of tuberculosis in children aged 0-4 years. Children, adolescents and young adults in the Philippines constitute a substantial proportion of patients in the national tuberculosis surveillance data set. Long-term progress against tuberculosis in the Philippines relies on improving the control of tuberculosis in these key age groups.

• Age Distribution
• Child, Preschool
• Infant, Newborn
• Outcome Assessment, Health Care
• Philippines / epidemiology
• Population Surveillance
• Tuberculosis / epidemiology*
• Young Adult

Grants and funding

• 001/WHO_/World Health Organization/International

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Research Questions and Priorities for Tuberculosis: A Survey of Published Systematic Reviews and Meta-Analyses

Ioana nicolau.

1 McGill University, Montreal, Quebec, Canada

Daphne Ling

2 Emory University, Atlanta, Georgia, United States of America

Christian Lienhardt

3 Stop TB Partnership, World Health Organization, Geneva, Switzerland

Madhukar Pai

Conceived and designed the experiments: IN CL MP. Performed the experiments: IN DL LT. Analyzed the data: IN CL MP. Wrote the paper: IN MP.

Systematic reviews are increasingly informing policies in tuberculosis (TB) care and control. They may also be a source of questions for future research. As part of the process of developing the International Roadmap for TB Research, we did a systematic review of published systematic reviews on TB, to identify research priorities that are most frequently suggested in reviews.

Methodology/Principal Findings

We searched EMBASE, MEDLINE, Web of Science, and the Cochrane Library for systematic reviews and meta-analyses on any aspect of TB published between 2005 and 2010. One reviewer extracted data and a second reviewer independently extracted data from a random subset of included studies. In total, 137 systematic reviews, with 141 research questions, were included in this review. We used the UK Health Research Classification System (HRCS) to help us classify the research questions and priorities. The three most common research topics were in the area of detection, screening and diagnosis of TB (32.6%), development and evaluation of treatments and therapeutic interventions (23.4%), and TB aetiology and risk factors (19.9%). The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests and drug-resistant TB tests and immunological tests. Other important topics of future research were genetic susceptibility linked to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics.

Conclusions

Systematic reviews are a good source of key research priorities. Findings from our survey have informed the development of the International Roadmap for TB Research by the TB Research Movement.

Introduction

Tuberculosis (TB) continues to pose a major threat to global health [1] , and research is a key component of the Global Plan to Stop TB2011-2015 [2] . Research is particularly critical for developing new tools and approaches needed for eliminating TB by 2050 [3] . Recognizing this, the Stop TB Partnership and the World Health Organization's (WHO) Stop TB Department have launched the TB Research Movement, with the aim of boosting TB research and accelerating progress in TB control towards international targets [4] . One of the main outputs of the TB Research Movement in 2011 was the publication of the International Roadmap for Tuberculosis Research [5] in October of 2011. This roadmap outlines all priority areas for investment in TB research and is intended to promote coordination and harmonization of scientific work on TB. Research priorities are identified in the areas of epidemiology; fundamental research; R&D of new diagnostics, drugs and vaccines; and operational and public health research. The ultimate goal is to reach all populations, including people with TB/HIV co-infection or MDR-TB and children, with new and better methods of prevention, diagnosis and treatment [5] .

The process for developing this roadmap has been recently described by Lienhardt and colleagues [4] . Briefly, the research roadmap was developed through a priority ranking exercise conducted by a multidisciplinary group of 50 research experts, a multidisciplinary Delphi consultation, a series of systematic reviews and an open web-based survey [4] .Among the systematic reviews that were commissioned, one was focused on all the TB research agendas that have been published from 1998 to 2010 [6] . As a next step, we were commissioned to review all the published systematic reviews and meta-analyses on TB (in all areas, including drugs, vaccines, diagnostics), to assess what research priorities have been identified in these reviews. The objectives of our systematic review were as follows: (1) to identify all systematic reviews and meta-analyses pertaining to any aspect of tuberculosis from 2005 to 2010, and (2) to assess, compile and rank the research priorities that were identified.

MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for systematic reviews and meta-analyses on TB. The search strategy was developed in consultation with a medical librarian. The search was limited to systematic reviews and meta-analyses published between January 1, 2005 and July 1, 2010, in order to focus on contemporary TB literature and identify research priorities of greatest relevance to current TB control.

The search strategy included the following keywords and MeSH terms: [‘tuberculosis’ (explode) OR ‘ Mycobacterium tuberculosis ’(explode) OR ‘tuberculosis’.ti,ab. OR ‘tuberculos*’.tw] AND [‘meta analysis’ (explode) OR ‘meta analyses’.ti,ab OR ‘meta-analyses’.ti,ab OR ‘meta-analysis’.ti,ab OR ‘metanalys*’.ti,ab OR ‘systematic review’.tw]. The search was not limited to English and the last search was performed on August 18, 2010.

Studies were included if they focused on any aspect of tuberculosis. We included systematic reviews and meta-analyses published in English, French, Spanish, and Italian. The languages included were based on the skill set of our research team. We included systematic review and meta-analyses that had focused on tuberculosis or on a tuberculosis related topic (e.g. BCG), in the title or abstract. We considered a study to be a systematic review or meta-analysis if the authors identified the study as such, or if the title or abstract contained the words “systematic review” or “meta-analysis”. Moreover, studies were regarded as systematic reviews if the authors reported a systematic, explicit approach to identify, select, and synthesize the available evidence.

The first screening of the titles and abstracts obtained following the electronic search was done by one reviewer (IN). Subsequently, the same reviewer (IN) screened the full text articles, determined the eligibility, and decided on the final inclusion of studies in the systematic review. Further, a second reviewer (MP) independently searched, screened and identified studies for the inclusion in the review.

Data abstraction

We developed a data extraction form which was pilot-tested by two reviewers (IN and DL). The reviewers independently piloted the forms until there were no major disagreements in the data extraction process. One reviewer (IN) extracted the data from all the included studies and the second reviewer (DL) extracted data in duplicate for a random subset of 15% of the total number of included articles. Additionally, a third reviewer (LT) independently extracted data for all included studies on the study characteristics section of the data extraction form. Disagreements between the three reviewers were resolved by consensus.

Study characteristics

We extracted data from the text or online supplement of each included systematic review or meta-analysis. Information was collected on two main points: i) the main focus of the systematic review, and ii) questions and priorities identified for future research. The UK Health Research Classification System (HRCS) [7] , developed by the UK Clinical Research Collaboration for the classification and analysis of all types of health research, was used to determine the focus of the included studies as well as the focus of the research questions/priorities. In particular, the HRCS Research Activity Codes [7] were used to assign a category for the main focus of the studies and the research questions/priorities.

The main focus of each included systematic review was determined by extracting keywords from the title and abstract and matching them with the criteria developed by the HRCS. The Codes were divided into eight major categories: (1) Underpinning research; (2) Aetiology; (3) Prevention of disease and conditions, and promotion of well-being; (4) Detection, screening and diagnosis; (5) Development of treatments and therapeutic interventions; (6) Evaluation of treatments and therapeutic interventions; (7) Management of diseases and conditions; and (8) Health and social care services research (see Table 1 for full description). These research categories were used in Tables 2 and ​ and3, 3 , to provide an overarching framework for grouping TB research.

In the HRCS, each of the eight major categories is further subdivided into five to nine subcategories with definitions for the type of research that belonged to that subcategory. For instance, “(1)Underpinning research” includes five subcategories: (1.1)studies of normal biological development and functioning, including gene, gene products, biological pathways, molecular and cellular structures, and development and characterization of model systems; (1.2) studies that do not address health directly but cover issues such as psychological and socioeconomic processes, individual or group characteristics and behaviours, and social and cultural beliefs; (1.3) research in chemical and physical sciences that may lead to the future development of diagnostic tools or treatments; (1.4) studies that target the development of novel methodologies and measurements including the development of statistical methods, and the development of mapping methodologies; and (1.5)research involving the development and/or distribution of resources for use by the research community, and infrastructure to support research networks. Using the main categories and the subdivisions within each category, we mapped the corresponding TB research areas found in the literature search (refer to Tables 1 and ​ and2 2 ).

Quantitative data synthesis

Study characteristics were summarized using descriptive statistics. Measures such as total count, frequency, and proportion, were used to summarize data. Data analyses were performed using STATA Version 11.0.

There were a total of 973 records identified through the electronic database search ( Figure 1 ). The first screening of titles and abstracts was done on 680 records. Following the first screening process, 528 records were excluded. The reasons for exclusion are listed in Figure 1 . The full text screening of articles was performed on 152 records. Overall, there were 137 systematic reviews included in our analysis [8] – [144] .

Characteristics of included TB systematic reviews

The 137 reviews were published in 61 different journals. The majority of reviews (39.4%) were published in journals with impact factors of five or less, and only six (4.3%) reviews were published in journals with a high impact factor (>15). However, a large proportion of the reviews (38.6%) were published in journals that did not have an impact factor. In addition, approximately 24% of the main authors were from the United States and 41% were from four other countries (China, UK, Canada, and Italy). The remaining 34.1% of authors were from 26 different countries.

Out of the 137 reviews, 131 (95.6%) self identified as a systematic review or meta-analysis, which means that they used the term “systematic review” or “meta-analysis” in the title or abstract. Approximately 91% (124) of all reviews were not Cochrane reviews. Among the 13 Cochrane reviews, 9 of them focused on “evaluation of treatments and therapeutic interventions”.

Half of the reviews (67 [48.9%]) reported having a funding source, whereas only 15 reviews (11.0%) reported not being funded and 55 reviews (40.1%) did not report funding status. Most of the reviews (109 [79.6%]) included less than 50 studies in their review and within those reviews, the majority had between 1,000 and 10,000 participants (34/109[31.2%]).

Focus of TB systematic reviews

The main focus of each review was determined using the HRCS as described in the Methods section. The classification categories were subdivided into major tuberculosis research areas as described in Table 2 . The three most common review categories, in decreasing order, were “Detection, screening and diagnosis” with 46/141(32.6%) systematic reviews, “Development and evaluation of treatments and therapeutic interventions” with 33/141(23.4%) systematic reviews and “Aetiology” with 28/141(19.9%) systematic reviews.

Within the category of “Detection, screening and diagnosis”, 17/46 (37%) of the reviews focused on bacteriological diagnostics for active TB, such as improving processing methods of sputum smear microscopy, and assessing the use of nucleic acid amplification tests (NAATs). The two other most common TB research aims were bacteriological diagnostics for MDR-TB (9/46[20%]) and immunological diagnostics (9/46[20%]). More specifically, bacteriological diagnostics for MDR-TB included tests such as line-probe assays, bacteriophage based assays, and colorimetric redox assays. Immunological diagnostics were focused mainly on testing and evaluating interferon-gamma release assays (IGRAs).

In the category “Development and evaluation of treatments and therapeutic interventions”, 10/33 (30%) studies focused on drug resistant tuberculosis treatment, 9/33 (27.3%) studies on evaluating different regimen combinations for tuberculosis treatment, and 6/33(18.2%) on treatment of latent tuberculosis infection (LTBI).

In the category “Aetiology”, 11/28 (39.3%) systematic reviews focused on biological/genetic risk factors such as genetic susceptibility and gene targets,11/28 (39.3%) studies targeted surveillance and distribution of TB/HIV co-infection, MDRTB and HIV, and diabetes and TB, and 5/28(17.9%) focused on travel risk for LTBI and nosocomial TB exposure.

Research priorities

Out of 137 reviews, 103 (75%) identified at least one research question or a research priority. Of these, 48 (46.6%) identified only one research priority, 33 (32.0%) two research priorities, 7 (6.8%) three, 7 (6.8%) four, and 8 (7.8%) five research priorities. None of the reviews identified more than five research priorities.

Table 3 shows the summary of research priorities by category, subdivision, and TB-specific research priority. The three major categories of research priorities/questions were “Detection, screening and diagnosis” responsible for 50/191 (26.2%) of all the identified research priorities, “Aetiology” with 42/191 (22.0%), and “Evaluation of treatments and therapeutic interventions” with 37/191 (19.4%).

In the most common category, “Detection, screening and diagnosis”, the top research priority was the evaluation of bacteriological TB diagnostic tests in 14/50 (28.0%) reviews. Other frequently cited TB research priorities were: evaluation of immunological TB diagnostic tests (6/50 [12.0%]); discovery and development of new TB diagnostic tests (5/50 [10.2%]); and development of new bacteriological MDR-TB diagnostics (5/50 [10.2%]). Two priorities had almost equal importance and were highly prevalent in TB literature. The main priority in that category was to investigate the detection, screening and diagnosis of drug-resistant TB and MDR-TB. Studies called for the need to develop studies that detect resistance from smear positive specimens, determine the accuracy of colorimetric methods, line-probe assays, phage-based assays for rapid screening and nitrate reductase assay (NRA), and find the clinical usefulness of rapid diagnosis of rifampicin-resistant TB. Another frequency priority was to address unresolved research questions on interferon-gamma release assays (IGRAs), discover new antigens with immunodiagnostic potential, and test IGRAs in various populations and settings to establish test reproducibility. Evaluating sputum processing methods and smear microscopy, assessing nucleic acid amplification tests (NAATs), and evaluating tests for extrapulmonary TB (e.g. adenosine deaminase for pleural TB) were commonly cited priorities.

Within the “Aetiology” category, the main TB research priorities were: development of new research methods; better study designs or statistical tools for studying drug resistant TB, MDR-TB, links between HIV and MDR-TB; comparison of diagnostic tests (17/42 [40.5%]); identification of biological and genetic risk factors (15/42 [35.7%]); and evaluation of the role of risk factors such as tobacco and air pollutants (7/42 [16.7%]). The most frequent priority was to examine gene and gene products in relation to TB disease and susceptibility to disease. Key genes such as vitamin D receptor polymorphisms, IL10 gene, and drug-metabolizing enzyme (DME) gene polymorphisms were commonly mentioned for future research. The second most frequent research priority on TB/HIV included recommendations to conduct studies investigating XDR-TB and HIV co-infection, identifying a comprehensive definition of IRIS (immune reconstitution inflammatory syndrome), and investigating sputum processing methods with direct smears in settings with high and low HIV prevalence.

The category “Evaluation of treatments and therapeutic interventions” was the third most frequent. It focused on TB/HIV drug treatments (12/37 [32.4%]), drug-resistant TB treatments (11/37 [29.7%]), new TB drugs and active tuberculosis regimens (8/37[21.6%]). Implementing studies that evaluate new treatments and therapeutic interventions for drug-resistant TB, MDR-TB, and XDR-TB, was a prominent research priority. Such studies would need to examine methods to improve treatment outcomes for patients with XDR TB such as using later-generation fluoroquinolones, discovering methods to tailor treatment regimens for various forms of TB drug resistance, and investigating the use of quality-controlled laboratory testing for all first and second-line drugs that define XDR-TB. Another frequently cited priority was designing trials to evaluate the optimal duration of TB treatment, the influence of level of immunosuppression on effectiveness of TB drugs, and the combination of anti-TB chemoprophylaxis with antiretroviral therapy.

Systematic reviews and meta-analyses are widely acknowledged as a key component of the policy and guideline development process [145] . A large number of systematic reviews have been published in the area of TB diagnostics [146] , and these are increasingly being used for developing guidelines [147] . To this end, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool has increasingly been adopted by policy makers and guideline developers to provide an explicit, comprehensive and transparent process for moving from evidence to recommendations [145] .

Systematic reviews often conclude by making suggestions for the direction of future research, and thus could be a good source for identifying the most important questions for TB research. Our survey collected descriptive information from all eligible systematic reviews and meta-analyses that were subsequently used to generate a list of research priorities in TB which were used for developing the International Roadmap for Tuberculosis Research [5] .

Our systematic search showed that a fairly high number of systematic reviews were published on TB during the period of 2005 to 2010. The findings of our review need to be interpreted along with a recent systematic review by Rylance and colleagues [6] on 33 articles with research agendas on TB. These authors found that the top priority areas for research were new TB drug development (28 articles), diagnosis and diagnostic tests (27), epidemiology (20), health services research (16), basic research (13), and vaccine development and use (13).

In our review of 137 TB systematic reviews, the top three categories for the focus of the research priorities/questions were “Detection, screening and diagnosis” “Aetiology” and “Evaluation of treatments and therapeutic interventions.” TB diagnosis and treatment were among the most important research priorities in both reviews. One possible reason of why TB diagnosis research ranked high on our list could be that our review focused on years 2005 to 2010, a period when major advances have been made in TB diagnostics, especially with IGRAs becoming a very popular subject of research [148] . Also, this time period saw the introduction of several WHO policies on TB diagnostics. Further, the emphasis on new tools in the Global Plan to Stop TB 2006–2015 [149] , along with the creation of product development partnerships such as the Foundation for Innovative New Diagnostics (FIND), AERAS, and Global Alliance for TB Drug Development, may have inspired research on new diagnostics and drugs.

The research priorities determined were mainly focused on the discovery and evaluation of bacteriological TB tests, drug-resistant TB tests and immunological tests, with special focus on IGRA tests. Also, tests for extra-pulmonary TB came up as a frequently cited priority in the Detection of TB category. Other important topics of future research were genetic susceptibility to TB and disease determinants attributed to HIV/TB. Evaluation of drug treatments for TB, drug-resistant TB and HIV/TB were also frequently proposed research topics. Many articles cited the need for improved and tailored treatment methods for MDR-TB and XDR-TB.

Although several systematic reviews identified areas for further research, the questions themselves were often framed in a generic way, rather than in a highly focused manner with specific recommendation for action. Future TB systematic reviews will need to be more focused, and propose highly specific, answerable questions that are amenable to well-designed research studies.

Our study has several limitations. Due to the poor overall quality of reporting of the systematic reviews, the findings may not be representative of the general output from the TB research community [150] . The inclusion of eligible studies was limited by the fact that we only reviewed articles in three other languages besides English. We were also unable to search ‘grey’ literature, contact authors, or hand search journals. The review also did not include any unpublished literature. Due to its overarching and generic nature, the Health Research Classification System categories were at times non-specific and difficult to match with specific areas of TB research. Furthermore, it was difficult to classify research priorities into narrow subdivisions since some research priorities could qualify for more than one subdivision. By categorizing research priorities into larger, predefined categories, we lost detailed information on individual research priorities. To remedy this, we condensed each priority and extracted the topic words from it. The topic words were then grouped together to form the summary of repeated priorities/questions and calculate the frequency.

There has been a lot of recent attention and focus on childhood TB, but because our search was last performed in 2010, our analysis may have missed research priorities in this important area.

In summary, our systematic review of published systematic reviews on TB helped identify several key priorities for future TB research. This exercise was useful to describe the landscape of TB research and the overarching TB research themes arising from systematic reviews and meta-analyses conducted over the last 5 years. Their scope is, however, limited, since systematic reviews themselves are influenced by current hot topics or new technologies. They are nevertheless useful in indicating research priorities on areas that receive high attention, either due to recent scientific developments or increasing questions surrounding advancement of knowledge in these very areas. They bring useful additional arguments and information to the broader, deeper and more rigorously conducted process of international research agenda development.

Funding Statement

This work was supported in part by the Stop TB Partnership and World Health Organization. Dr Christian Lienhardt from the Stop TB Partnership and WHO provided input in study design and interpretation and revised the manuscript for intellectual content. Additional funding was provided by the European-Developing Countries Clinical Trials Programme (EDCTP; TB-NEAT grant). EDCTP had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.