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. 2020 Sep 10;15(9):e0237931. doi: 10.1371/journal.pone.0237931

Active TB case finding in a high burden setting; comparison of community and facility-based strategies in Lusaka, Zambia

Mary Kagujje 1,*, Lophina Chilukutu 1, Paul Somwe 2, Jacob Mutale 2, Kanema Chiyenu 2, Mwansa Lumpa 2, Winfrida Mwanza 1, Monde Muyoyeta 1
Editor: Frederick Quinn3
PMCID: PMC7482928  PMID: 32911494

Abstract

Introduction

We conducted an implementation science study to increase TB case detection through a combination of interventions at health facility and community levels. We determined the impact of the study in terms of additional cases detected and notification rate and compared the yield of bacteriologically confirmed TB of facility based and community based case finding.

Methodology

Over a period of 18 months, similar case finding activities were conducted at George health facility in Lusaka Zambia and its catchment community, an informal peri-urban settlement. Activities included awareness and demand creation activities, TB screening with digital chest x-ray or symptom screening, sputum evaluation using geneXpert MTB/RIF, TB diagnosis and linkage to treatment.

Results

A total of 18,194 individuals were screened of which 9,846 (54.1%) were screened at the facility and 8,348 (45.9%) were screened in the community. The total number of TB cases diagnosed during the intervention period were 1,026, compared to 759 in the pre-intervention period; an additional 267 TB cases were diagnosed. Of the 563 bacteriologically confirmed TB cases diagnosed under the study, 515/563 (91.5%) and 48/563 (8.5%) were identified at the facility and in the community respectively (P<0.0001). The TB notification rate increased from 246 per 100,000 population pre-intervention to 395 per 100,000 population in the last year of the intervention.

Conclusions

Facility active case finding was more effective in detecting TB cases than community active case finding. Strengthening health systems to appropriately identify and evaluate patients for TB needs to be optimised in high burden settings. At a minimum, provider initiated TB symptom screening with completion of the TB screening and diagnostic cascade should be provided at the health facility in high burden settings. Community screening needs to be systematic and targeted at high risk groups and communities with access barriers.

Introduction

Of the estimated 10 million incident TB cases globally, in 2018, only 7 million were notified [1]. Zambia, a high TB burden country, has an estimated TB treatment coverage of only 58% [1]. The country has an estimated 24,929 missing TB cases [2] and most of these cases are expected to be found in large peri-urban informal settlements of large cities [3]. Based on data from the TB prevalence survey, about 50% of the symptomatic TB cases are missed at the health facility [4]. TB cases are missed at the health facility due to low index of suspicion of TB, failure to complete the TB diagnostic cascade, use of less sensitive diagnostic tools, out of pocket expenditure for patients and weak public private coordination [47].

The undiagnosed and untreated TB cases are key factors contributing to the continued global TB epidemic; perpetuating TB transmission and increased risk for adverse outcomes due to delayed diagnosis [810]. Finding the missing TB cases is thus a global priority for TB control [11] and Active Case finding (ACF) has been identified as one of the key components to achieving this [12].

Much as the term ACF is often used to imply systematic screening and diagnostic evaluation of TB risk groups that happens outside the health facility, it actually constitutes provider initiated screening both inside and outside the health facility [13]. There is evidence on effectiveness of ACF in the community [1419], there is less evidence for the effectiveness of ACF at the health facility [7,20,21] and even less literature comparing the two active case finding strategies [21].

An implementation science study was conducted at a primary health care facility in Lusaka district, Zambia. The objective of the study was to increase TB case detection through a combination of interventions at both the health facility and community level. Additionally, the study assessed and compared the contribution of facility based and community based ACF activities to TB case detection. We report the impact of the study on TB notification in terms of additional cases detected and notification rate and compare the yield of facility based and community based case finding.

Methods

Study setting and study population

This study was undertaken between July 2017 and December 2018 in a TB programmatic setting at George primary health care TB diagnostic facility and its catchment population. George community is an informal, poor, high density peri-urban settlement in Lusaka district in Zambia: Fig 1.

Fig 1. Geographical location of George primary health care centre and community.

Fig 1

Lusaka province with a prevalence of 932/100,000 population, has the second highest burden of TB in Zambia after the Copper belt province [22]. The notification rate of TB in Lusaka district in 2016 (pre intervention period) was 640/100,000 (Lusaka District TB data, unpublished), above the country average of 236/100,000 population [23]. In the same year George health facility had a notification rate of 246/100,000 population. George health facility has an outpatient department (OPD), antiretroviral therapy (ART) clinic, Maternal Child Health (MCH) clinic, a voluntary counselling and testing (VCT) point and TB clinic. The catchment community population was 166,975, 173,130 and 179,360 people in 2016, 2017 and 2018 respectively. Before the study, the clinic had onsite LED microscope with no onsite chest x-ray and geneXpert; a mobile digital x-ray and a geneXpert were installed during the study.

Study procedures

Similar case finding activities were conducted at the health facility and in the community; they included awareness and demand creation activities, TB screening, diagnosis and linkage to treatment.

Awareness and demand creation activities

First, we re-oriented facility health workers and trained community health workers on TB to raise their index of suspicion of the disease. At the health facility, we displayed posters on TB symptoms, community health workers provided daily health talks on TB in all the departments of the clinic and distributed flyers on TB. In the community, we provided door to door sensitization on TB, conducted drama sensitization and displayed posters in places that have/attract large numbers of people and distributed flyers on TB. All these activities had messaging encouraging people to screen for TB.

TB screening and diagnosis

At the health facility, a trained community health worker was stationed at each department to register patient details and refer patients for X-ray screening. In addition, an open access point manned by community health workers was set up to provide fast track TB screening and diagnostic evaluation for clients that were referred by the clinicians and the community health workers and clients presenting directly from the community. In the community, screening and sputum collection points were set up in each mapped zone and identified congregate settings in a rolling fashion with repeated rounds to ensure saturation.

History of the four World Health Organisation (WHO) recommended symptoms for TB screening (cough, fever, night sweats and weight loss) [13] and 2 additional symptoms from the Zambia TB guidelines (chest pain and loss of appetite) [24] was documented for all patients presenting for TB screening. One mobile digital chest x-ray (CXR) from Delft Imaging Systems with Computer Aided Diagnosis (CAD4TB) version 5 was used both for community and facility TB screening. Two WHO recommended algorithms [13], both similar to the standard of care algorithms in Zambia except for duration of symptoms when symptom screening is used [24] were used to evaluate for TB: 1) When CXR was available, all patients were screened with CXR-CAD4TB irrespective of symptoms followed by Xpert for those with abnormal CXR; abnormal CXR was defined as CAD score above 60 and 2) When CXR was not available, individuals with any of the above symptoms, irrespective of duration submitted a sputum sample for Xpert. Additionally, clinicians had the discretion to request for GeneXpert for patients who were symptomatic but with a CAD score below 60.

Each patient was instructed on how to collect a quality sputum sample by a community health worker. All samples were triple packaged before transportation to the laboratory by community health workers on the same day of collection. Samples were rejected by the laboratory if: i) the specimen was leaking out into biohazard bag, ii) the sputum contained many food particles, iii) the volume was less than <0.5mls and if the sputum contained a lot of blood.

HIV status was either self-reported or obtained through opt out HIV testing.

All patients diagnosed with TB that did not return to the screening point for results within 2 days had a home visit carried out by a community health worker to facilitate linkage. Contact tracing was done for TB cases identified during the study per routine service requirements.

Data collection and data management

Data was collected from the study TB screening registers and the existing approved National TB laboratory register, TB treatment register and household contact register. The study TB community and facility screening registers were a modification of the nationally approved presumptive TB register whose additional data elements included history of TB treatment, history of contact to a TB case, duration of cough and CAD score. Data from contact tracing was reported under community screening. Data from the facility and community screening registers was entered into a customized web application operating with a Microsoft SQL Server database backend. Transact SQL queries were used to generate weekly/biweekly reports. Error reports were used to flag data inconsistencies that needed corrective actions to be taken ensuring data integrity. Incremental database backups were made on a daily basis.

Data comparing community and facility case finding was obtained from the screening registers while data on impact of the interventions in terms of additional cases and notification rate was obtained from the facility TB treatment register.

Data analysis

Data was analysed using STATA Statistical Software (Stata Corporation Version 14. College Station, Texas 77845, USA). To show the flow of patients through the diagnostic cascade, 2 flow diagrams were generated for facility and community based case finding and each showed the following steps: individuals screened with presumptive TB, individuals who submitted a sputum sample, individuals with sputum sample evaluated and individuals with sputum evaluated who were diagnosed with bacteriologically confirmed TB(yield). To determine any facility level and community level population characteristic differences among those screened that might account for the differences in case detection, a 2X2 table was constructed and categorical variables were compared using the Chi-squared test and continuous variables using the student t-test.

Additional analysis was done to determine the contribution from the community and facility to the total cases detected; contribution from facility was disaggregated further by entry point to determine which entry point had the highest yield.

To determine the impact of the case finding on TB notifications, additional cases detected were calculated by comparing TB notifications during the intervention period to a corresponding pre-intervention period. The intervention period included notification data from 3rd quarter 2017 to 4th quarter 2018 and the pre- intervention period included notification data from 3rd quarter 2015 to 4th quarter 2016. Additionality was the difference in TB notification between the intervention period and the pre-intervention period and the percentage change was the additional cases divided by the total notifications in the pre-intervention period multiplied by 100 percent. Lastly, changes in notification rates were also determined taking into consideration the catchment population.

Ethical issues

Approval to conduct the study was provided by the University of Zambia Biomedical Ethics Research Committee (UNZA BREC) No: 012-05-17 and National Health Research Authority. A waiver of written consent was given by UNZA BREC as the study operations were routine. However, verbal consent was given before participation in the study.

Results

A total of 18,194 individuals were screened for TB under the study; 9,846(54%) were screened at the facility while 8,348(48%) were screened in the community. The characteristics of patients screened for TB in the facility and community are illustrated in Table 1. There were 5,053/9,846(51.3%) males among the individuals screened at the facility and 4,256/8348(51.0%) males among the people screened in the community (P = 0.588). The mean age of individuals screened in the facility was 35.2 (SD 14.2) while in the community it was 31.3 (SD 15.5) (P <0.0001). Among individuals screened at the facility, 4184 /9846 (42.5%) were HIV positive while 718/8348 (8.6%) of those screened in community were HIV positive (P <0.0001). History of previous TB was 1,462/9846(14.8%) at the facility and 474/8348(5.7%) in the community (P <0.0001). Of individuals screened at the facility, 1,864/9846(18.9%) were asymptomatic (had none of the 6 symptoms used for TB screening) while 3,108/8348(37.2%) of those in the community were asymptomatic (P <0.0001).

Table 1. Description and comparison of facility and community patients.

Characteristic Facility 9,846 (%) Community 8,348 (%) P-Value
Male sex 5,053 (51.3) 4,256 (51.0%) 0.588
Mean age (sd) 35.2 (14.2) 31.3 (15.5) <0.0001
HIV positive status 4,183 (42.5) 718 (8.6) <0.0001
Previous TB 1,462 (14.8) 474 (5.7) <0.0001
Symptoms * <0.0001
No symptoms 1,864 (18.9) 3, 108 (37.2)
1 symptom only 2,134 (21.7) 2,261 (27.1)
2 or more symptoms 5,573 (56.7) 2,824 (33.8)
Abnormal CXR 818 (13.8) 229 (4.7) <0.0001

*missing symptoms facility = 275, community = 155

Of the individuals screened at the health facility, 6403/9846(65%) met the definition of presumptive TB, of which 5701/6403 (89%) submitted sputum for evaluation, 3528/5701 (62%) sputum samples were evaluated, and 506/3528(14.3%) had bacteriologically confirmed TB. An additional 220 sputum samples were collected from patients who didn’t meet the definition of presumptive TB. Of these, 9/220(4%) had bacteriologically confirmed TB. The total number of bacteriologically confirmed TB cases at the facility was 515 as illustrated in Fig 2. The overall yield for facility case finding was 515/3748 (13.7%)

Fig 2. Flow diagram of individuals screened at facility level.

Fig 2

Of the individuals screened for TB in the community, 2531/8358(30%) met the definition of presumptive TB, of which 1295/2531 (51%) submitted sputum for evaluation, 1165/1295 (90%) sputum samples were evaluated, and 42/1165(3.6%) had bacteriologically confirmed TB. An additional 404 samples were collected from individuals who didn’t meet the definition of presumptive TB. Of these, 6/404(1%) had bacteriologically confirmed TB. The total number of bacteriologically confirmed TB cases was 48 as illustrated in Fig 3. The overall yield for community case finding was 48/1569 (3.1%)

Fig 3. Flow diagram of individuals screened at community level.

Fig 3

The total number of bacteriologically confirmed TB cases detected was 563. Of these 515/563 (91.5%) were detected at the facility and 48/563 (8.5%) were detected in the community. At the health facility, 49/515(8.7%) TB cases were from ART clinic, 3/515(0.5%) TB cases were from MCH, 232/515(41.2%) TB cases were from OPD, 214/515(38%) TB cases from the fast track, 2/515(0.4%) TB cases were from TB clinic and 9/515(1.6%) TB cases were from VCT: Table 2.

Table 2. TB cases detected by screening entry point.

Area of ACF activity Bacteriologically confirmed TB 563 (%)
Community 48 (8.5)
Overall facility 515 (91.5)
ART 49 (8.7)
MCH 3 (0.5)
OPD 232 (41.2)
Fast track 214(38.0)
TB Clinic 2 (0.4)
VCT 9 (1.6)

A comparison of the TB notifications before the intervention and during the intervention as per the TB treatment register is shown in Table 3.

Table 3. Notifications per quarter.

Period Quarter Total notifications
Pre-intervention 2015 Q3 159
2015 Q4 188
2016 Q1 127
2016 Q2 88
2016 Q3 87
2016 Q4 110
Intervention 2017 Q3 182
2017 Q4 137
2018 Q1 177
2018 Q2 178
2018 Q3 194
2018 Q4 158

During the period 18 months before the intervention, 759 TB cases were notified with 272/759(35.8%) of the TB cases being bacteriologically confirmed pulmonary cases, 324/759(42.6%) being clinically diagnosed pulmonary cases and 163/759(21.4%) being extra pulmonary TB cases: Table 4. In the 18 months of the intervention, 1026 TB cases were notified with 598/1026(58.3%) of the TB cases being bacteriologically confirmed pulmonary cases, 361/1026(35.2%) being clinically diagnosed pulmonary cases and 67/1026(6.5%) being extra pulmonary TB cases: Table 4

Table 4. Comparison of before and after notification by type of TB.

Type of TB Notification pre-intervention (Q3 2015-Q4 2016) Notifications during intervention (Q3 2017-Q4-2018) Change (%)
Pulmonary bacteriologically confirmed TB 272 598 326(120%)
Pulmonary clinically diagnosed TB 324 361 37(11%)
Extra pulmonary TB 163 67 -96(-59%)
Total 759 1,026 267 (35%)

The TB notification rate changed from 247 per 100,000 population in 2016, pre-intervention to 310 per 100,000 population in 2017 during which the intervention started in July, to 394 per 100,000 in 2018 during which the intervention span the entire year: Table 5

Table 5. Comparison of before and after notification by type of TB.

Year 2016 2017 2018
Population 166,975 173,130 179,360
Total notifications 412 536 707
Notification rate (per 100,000 population) 246 310 394

Discussion

An additional 267 TB cases were found during the intervention period and there was a significant increase in notification rate; these cannot be credited to a single strategy but rather a combination of strategies including awareness and demand creation activities, increased index of suspicion of TB, increased access to TB screening and diagnostic tools and use of more sensitive screening and diagnostic tools. However, this additionality is also suggestive that TB cases were previously missed, especially at the facility. This is consistent with the findings from the Zambia TB prevalence survey [4] and studies done in other settings [2527] and calls for urgently strengthening health systems so that TB cases who present to the health facility are not missed.

In terms of case finding at facility and community level, the data from Table 1 shows that patients screened in the facility are different from patients screened from the general community; patients from the health facility are more likely to be symptomatic and have risk factors for TB and this is expected. This explains why the yield from facility-based case finding is higher than community based screening. In fact, the facility yield exceed the 10% target recommended in the National TB guidelines on facility case finding [24]. It is interesting to note that screening of patients from OPD gave the highest yield, even higher than ART department that has people at increased risk of TB. This calls for regular screening of patients presenting to OPD for TB and ensuring improved infection control practices in these settings that are often overcrowded. The high yield from fast track could be suggestive that long waiting time at the health facility could be a barrier to TB diagnosis and that fast track services potentially bypass this barrier. Overcrowded, busy facilities should consider using fast track TB services. These should be placed in a visible easy to access part of the clinic and should use the most efficient triage system to minimise waiting times.

Available literature on community TB case finding provides evidence for its effectiveness, however, also shows a low yield from the intervention. In a study done in rural South Africa comparing the yield of facility based screening for TB and contact tracing, which targets a high risk group for TB in the community, facility based screening yielded 11% more cases [21]. Low yield from community-wide TB screening is also seen in a study done in Vietnam where only 94 bacteriologically confirmed TB cases were detected over a 4 year period [17] and a study done in Combodia where 315,872 individuals were screened for TB to identify 783 TB cases [14]. These findings suggest that community activities for TB should be focused on awareness raising and demand creation with referral systems for TB evaluation at facility level for those that need to be evaluated. Community based collection of sputum samples should be limited to hard to reach areas that have limited access to health services.

There were 15 patients that were neither symptomatic for TB nor had abnormal x-ray but were diagnosed for TB. This points to the sensitivity gaps of both symptom screening and chest x-ray screening. There is need to profile these patients so as to provide additional lessons for future TB case finding activities.

There was a significant number of presumptive TB cases who didn’t provide sputum, that is, 11% at the facility and 49% from the community. These could possibly be asymptomatic individuals with abnormal x-ray who couldn’t expectorate sputum at the time. Also, the number of rejected samples was high at 2303/6996(33%) suggesting that the study could have done more in instruction of patients on collection of quality sputum samples. However, these forms of attrition are common in active TB case finding studies. In the community wide screening study in Vietnam, an average of 70% of presumptive TB cases submitted sputum and only about 40% of the sputum samples were evaluated [17]. In another active case finding study in India, only 54% of the presumptive TB cases had their sputum evaluated [28].

This study used evidence based recommendations that are already incorporated into the National TB guidelines and national strategic plans of several high burden countries [2932] so it is easy to replicate in various settings. The weakness of this study is that it had little focus on children, a population vulnerable to TB.

Conclusions

Overall, active case finding increases TB case detection. In this high burden TB setting, facility based active case finding was significantly more effective than community based active case finding. Strengthening health systems to appropriately identify and evaluate patients for TB needs to be optimised in high burden settings with low TB case detection rates. At a minimum, provider initiated TB symptom screening with completion of the TB screening and diagnostic cascade should be provided at the health facility in high burden settings. In addition, health care workers should be equipped with skills to diagnose TB.

Much as the yield of community screening low, community screening has its role in TB case finding as it not only reaches populations that are disproportionately affected by access barriers but is also an avenue to facilitate behavioral change on early health seeking behavior among patients with presumptive TB. For its yield to improve, general community screening should be discouraged and instead systematic and targeted screening provided to those at highest risk including contacts and people living in TB hotspots and those living in communities with access barriers to health facilities.

Supporting information

S1 Data. Facility vs community case finding published data

(XLS)

Acknowledgments

CIDRZ Staff: Tumeyo Phiri is acknowledged for his role in processing sputum samples collected under the study; Joel Bwalya is acknowledged for his role in data entry; Kella Siame, Priscilla Chisenga and Mercy Mwale are acknowledged for their role in data collection, the community and facility health workers at George clinic are acknowledged for their active participation in the project.

Ministry of Health staff: Bridget Banda, Martha Tembo, Njobvu Nkumbwizya, Bridget Nchimunya, Charity Mumba, Abigail Chinkondya, Mercy Chansa, Wilfred Njeleka are acknowledged for working closely with the project staff.

Data Availability

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

Funding Statement

Initials: MM Grant Number: STBP/TBREACH/GSA/W5-26 Funder: The Stop TB Partnership's TB REACH initiative with funding from the government of Canada URL: http://www.stoptb.org/global/awards/tbreach/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Frederick Quinn

21 May 2020

PONE-D-20-06815

Active TB case finding in a high burden setting; comparison of community and facility-based strategies in Lusaka, Zambia

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Reviewers' comments:

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Comments to the Author

1. 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: Partly

Reviewer #3: Yes

**********

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

Reviewer #1: N/A

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #2: Yes

Reviewer #3: Yes

**********

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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: Active case finding for tuberculosis (TB) is recommended by the World Health Organization as an approach to find particularly in high-burden settings, that why that manuscript is so relevant for the control of TB in development world.

Line 107 - History of cough, fever, night sweats, weight loss, chest pain and loss of appetite was documented for all patients presenting for TB screening;

The authors should clarify if all the TB symptoms screening were used based WHO's recommended.

The authors should explain how the diagnostic testing followed the standard of care for TB diagnosis in Lusaka. How were all sputum samples dropped off in study clinics and transported to the laboratory or clinic that have a facility like Xpert MTB/RIF testing.

In data analysis, the authors should be expanded and clarified to ensure that readers understand exactly what the researchers studied. Alternatively, they could include another statistical method as Poisson regression to fit the different variables. So that, the tables will be easier to understand.

Reviewer #2: I congrautulate the authors on conducting this piece of work. Indeed any extra-case detected is a couple of leaves saved from

exposure. The authors have carried out an implementation study whose objective appears to be, demonstrating the utility of

internvensions to improve active case finding at the facility and community. However i find it rather difficult to make out

what the actual intervention is, in other words there is need for clarity on what it is that is being done.

On first reading the study appears to have used a massive sample size but actually the samples that end up being tested to

confirm TB are only about 15-16%, this is because, the data has been filtered through a number of steps and it make it hard to figure out what the denominator is, surely the denominator ought to be with samples tested and the conclusions restricted to tested samples.

The extrapolation would be acceptable if the samples that get tested were randomly selected but this is not the case here. So the interpretation here my be somewhat misleading.

Abstract

The abstract is well written but the results reporting could benefit from clarifying the denominators

of each of the proportions reported and these out to be restricted to the samples tested. Only then will

it be possible to assess if the conclusions are appropriate for the results.

Introduction

Line 51, the authors state that 24,929 cases are missed in Zambia, this predominantly occurs in

In peri urban setting and that 50% missed at facilities. Can they expand on why 50% are missed at

facilities, is it a methodological?, awareness?, capacity problem? Ultimately this is what

the study aims to narrow ....as a gap!!

The introduction in general lacks the context within which the study is set, how do i evaluate the

intervention, who has used this interventions in the way you have designed it?, what does WHO recommend,

Zambia's TB incidence is ~ 208 per 100,000 persons per year, So, comparatively how is this approach expected to improve ACF relative to where it has been implemented?... will you approach improve time to identification, cost of extra case identified, or raw numbers of identified?... what is your measure of improvement.. With such a triangulation of information, one could fully understand what you are doing, how it compares elsewhere in terms of benefits and the anticipated improvements in ACF at detection level and cost involved...

Study setting and study population

There is limited information about the study site and population. For example one can not make out

the geographic distribution of the population used in your study, this is critical information as

the prevalence of TB by such sub-locations is likely to be known, it helps one evaluate the appropriateness of the

communities to include and the depth of the followup all of which determine how the scarce resources are apportioned.

Data collection and data management

What is the data availability policy to enhance the provenance of this?

Data analysis

The authors have not explained the statistical methods used, so it makes it hard to understand what analysis was done.

In my opinion there has been limited statistical input to the work

with the samples size used, a number of approaches could have been used to robustly analyse the data

The authors use the work Impact on case finding?, how is impact defined, raw numbers, proportion, cost per sample found?,

lives potentially save frome exposure

I see tables cited in materials and methods, to me this would mean results are being reported in MM

Results

It is shame, with this amount of data, alot of statistical analysis to properly unpick these characteristics

There samples are selected through a number of non-random selection criteria which makes extrapolations difficult

We need to be sure of the denominators used. From your selection procedure, you screened ~ 50%/50% the community and hospital

and the positive cases 91.5% and 8.5%, could you give an idea of what it costs to identify these (0.08*8,348).... actually the denominator should be the

the samples tested. Actually it appears the prevalence is 14.3% among tested at the facility and 3.6 in the community

What is the utility of p-values on line 187, in this case?? are you detecting more than you would expect?

I suspect the best use of this would be to establish that the ACF with and without any in intervention was significantly different

i.e. Q3 2016, Q3 2017... that is hwre the statistical differences would carry more weight!!

On line 194 you introduce, incidence at national level, is this published or is it data that comes from the your database. How can

that be independently verified, or is this peer reviewed data

It would be better if table 4 showed temporal gain rather than a compounded cumulative change

Discussion

I am unsure what the proportions represent, (in reference to the query raised on the denominator),

it makes it rather hard to follow the discussion

Reviewer #3: The very important topic needs only a punctual review to be published. the conclusions could be further elaborated to guide health systems in Africa.the objectives must be clear, the methodology described and the discussion of results must be aligned with the results presented

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: Osvaldo Frederico Inlamea

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files to be viewed.]

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Attachment

Submitted filename: PONE-D-20-06815.pdf

PLoS One. 2020 Sep 10;15(9):e0237931. doi: 10.1371/journal.pone.0237931.r002

Author response to Decision Letter 0


5 Jul 2020

Reviewer 1:

Comment 1: Line 107-History of cough, fever, night sweats, weight loss, chest pain and loss of appetite was documented for all patients presenting for TB screening;The authors should clarify if all the TB symptoms screening were used based WHO's recommended

Response 1: We have clarified that cough, fever, weight loss and night sweats are the WHO recommended symptoms for TB screening and that loss of appetite and chest pain are recommended by the Zambia TB guidelines.See methods section, line 127-130, Page 7

Comment 2: The authors should explain how the diagnostic testing followed the standard of care for TB diagnosis in Lusaka. How were all sputum samples dropped off in study clinics and transported to the laboratory or clinic that have a facility like Xpert MTB/RIF testing

Response 2: We have clarified that our algorithms are similar to the standard of care in Zambia. See methods section, line 132-134, page 7. The project installed a geneXpert instrument at the study site, George clinic. All the samples, both from the community and the facility, were transported to the laboratory for geneXpert MTB/RIF testing on the same day of collection by community health workers. This has been clarified in the methods section, line 103, page 6 and line 142-143, page 7.

Comment 3:In data analysis, the authors should be expanded and clarified to ensure that readers understand exactly what the researchers studied. Alternatively, they could include another statistical method as Poisson regression to fit the different variables. So that, the tables will be easier to understand

Response 3: Thank you for the feedback. We have made various changes to the data analysis section to make it more clear. See methods section, line 168-189, page 8-9. Additionally, Poisson regression would not be suitable statistics to run on the data as this was a prospective cross sectional study.

Reviewer 2:

Comment 1:The abstract is well written but the results reporting could benefit from clarifying the denominators of each of the proportions reported and these out to be restricted to the samples tested. Only then will it be possible to assess if the conclusions are appropriate for the results

Response 1: The denominators have been added to the parts where they were missing. See abstract section, line 41 page 2

Comment 2:Line 51, the authors state that 24,929 cases are missed in Zambia, this predominantly occurs In peri urban setting and that 50% missed at facilities. Can they expand on why 50% are missed at facilities, is it a methodological?, awareness?, capacity problem? Ultimately this is whatthe study aims to narrow ....as a gap!!

Response 2: We have included the various reasons why TB cases are missed. See introduction section, line 59-62, page 4

Comment 3:The introduction in general lacks the context within which the study is set, how do i evaluate the intervention, who has used this interventions in the way you have designed it?, what does WHO recommend. Zambia's TB incidence is ~ 208 per 100,000 persons per year, So, comparatively how is this approach expected to improve ACF relative to where it has been implemented?... will you approach improve time to identification, cost of extra case identified, or raw numbers of identified?... what is your measure of improvement. With such a triangulation of information, one could fully understand what you are doing, how it compares elsewhere in terms of benefits and the anticipated improvements in ACF at detection level and cost involved...

Response 3: The context of the study is provided under methodology section, line 87- 103, page 5-6. We have clarified that our algorithms are WHO recommended and are similar to the standard of care Zambia. See methods section, line 132-134, page 7. Our approach did not measure time to identification but rather measured increase in TB case detection by using a quasi-experimental approach, before and after comparison. The overall case finding approach was measured in terms additional cases detected and change in TB notification rate. This was been clarified in the introduction section, line 81-83, page 5. Facility case finding and community case finding are being compared in terms of yield of bacteriologically confirmed TB diagnosis. See introduction section, line 81-83, page 5. Yield has been defined as bacteriologically confirmed TB cases detected among those who submitted sputum. See methods section line 172-173, page 9. The comment about TB incidence in Zambia is noted. In the methods section, under study setting and study population sub section, we have included the notification rates for Lusaka district as well as the pre- intervention notification for George health facility to better contextualise the ACF relation to notification rate. methodology section, line 94- 98, page 5. We have noted the comment of the cost of each additional case found. The costing aspect of this study will be reported in separate manuscript.

Comment 4:There is limited information about the study site and population. For example one can not make out the geographic distribution of the population used in your study, this is critical information as the prevalence of TB by such sub-locations is likely to be known, it helps one evaluate the appropriateness of the communities to include and the depth of the followup all of which determine how the scarce resources are apportioned

Response 4: Geographical distribution and location of the population has been included. See methods section, line 87-92, page 5

Comment 5:What is the data availability policy to enhance the provenance of this?

Response 5: The data has been shared under additional information

Comment 6: The authors have not explained the statistical methods used, so it makes it hard to understand what analysis was done. In my opinion there has been limited statistical input to the work with the samples size used, a number of approaches could have been used to robustly analyse the data. The authors use the work Impact on case finding?, how is impact defined, raw numbers, proportion, cost per sample found?,lives potentially save from exposure

Response 6: We have made various changes to the data analysis section in order to make it more clear. See methods section, line 168-189, page 8-9. The overall case finding approach was measured in terms additional cases detected and change in TB notification rate. This was been clarified in the introduction section, 81-83, page 5. Facility case finding and community case finding are being compared in terms of yield. See introduction section 82-83, page 5. Yield has been defined as bacteriologically confirmed TB cases detected among those who submitted sputum. See methods section line 172-173, page 9.

Comment 7:I see tables cited in materials and methods, to me this would mean results are being reported in MM

Response 7: The citations have been removed

Comment 8: It is shame, with this amount of data, alot of statistical analysis to properly unpick these characteristics. There samples are selected through a number of non-random selection criteria which makes extrapolations difficult, We need to be sure of the denominators used. From your selection procedure, you screened ~ 50%/50% the community and hospital and the positive cases 91.5% and 8.5%, could you give an idea of what it costs to identify these (0.08*8,348).... actually the denominator should be the the samples tested. Actually it appears the prevalence is 14.3% among tested at the facility and 3.6 in the community

Comment 8: The analysis of data follows the TB diagnostic cascade. At each level of the cascade, the denominator changes. This is reflected in the flow diagram and has been clarified under the methods section, line 169-173, page 8-9. We have added denominators to the figures in the results section, line 199-249, page 10-12. Information on cost will be provided in a different manuscript

Indeed, the yield is dependent on the samples tested. The overall yield for facility and community case finding case finding were 13.7% and 3.1% respectively. This is shown in the results section, Line 2116, page 11 and line 226 page 11 respectively

Comment 9:What is the utility of p-values on line 187, in this case?? are you detecting more than you would expect?I suspect the best use of this would be to establish that the ACF with and without any in intervention was significantly different i.e. Q3 2016, Q3 2017... that is hwre the statistical differences would carry more weight!!

Response 9: The p-values were originally intended to show that there was a statistically significant difference between the yield for community and facility case finding. To improve the flow of the results section, the content on line 185-187 which include the p-values has since been deleted and the yields put under the respective sections.thanks for the suggestion on use of p-values to show effect of ACF, however, we want to focus this data on the trend in TB notifications

Comment 10:On line 194 you introduce, incidence at national level, is this published or is it data that comes from the your database. How can that be independently verified, or is this peer reviewed data

Response 10: The notification rate is for the facility. We have provided data on George notifications and the population in 2016, 2017 and 2018 so that it is possible to verify the notification rate. A clear table on this is provided in results section, line 255, page 13

Comment 11: It would be better if table 4 showed temporal gain rather than a compounded cumulative change

Response 11: We don’t understand what the reviewer is suggesting. We would like further explanation on this for us to adequately respond.

Comment 12: I am unsure what the proportions represent, (in reference to the query raised on the denominator),it makes it rather hard to follow the discussion

Response 12: Thank you. We have added denominators to the proportions in the discussion section, line 301 page 15

Reviewer 3

Comment 1:The very important topic needs only a punctual review to be published. the conclusions could be further elaborated to guide health systems in Africa.the objectives must be clear, the methodology described and the discussion of results must be aligned with the results presented

Response 1:Thank you so much.We have made some few changes to the conclusion, see conclusion section line 313- 227, Page 15-16. We have clarified the objectives, see introduction section, line 78-83, Page 5. Various changes have been made to the methods and discussion section, please see respective sections. Methods section, line 86-189, page 5-9 and discussion section, line 258-310, page 13-15

PONE-D-20-06815 Reviewer

Comment 1: Please make it clear what the aim of the study is and how it can be measurable. both in the abstract and in the text

Response 1: This has been clarified. See abstract section, line 25-29, page 2 and introduction section, line 78-83, page 5

Comment 2: Describe the community, is it around urban area? Urban or rural? where are the health facilities located serving the population? What population do these health facilities serve? is it differentiated in terms of knowledge level, socio-economic status?

Response 2: This has been clarified under methods section, line 87-92, page 5

Comment 3: Were there differences in the time of sputum collection and sample reception? Those patients were informed about how to collect sputum correctly?

Response 3: We have clarified that samples were received in the laboratory on the same day that they were collected. See methods section, line 142-143, page 7. All patients were instructed on how to collect sputum samples. See methods section, line 142-143, page 7

Comment 4: Please Clarify what are the criteria for rejection of sputum (sputum not evaluated 2,173

Response 4: Samples were rejected by the laboratory if: i) the specimen was leaking out into biohazard bag, ii) the sputum contained many food particles, iii) the volume was less than <0.5mls and if the sputum contained a lot of blood. See methods section, line 143-145, page 7

Comment 5: Explain in the discussion probable cause of low MTB detection in the sputum (only 506).

Response 5: The 506 cases were detected from 3528 presumptive TB cases giving a yield of 14.3%. This was higher than the 10% target provided in the Zambia National TB guidelines. See discussion section, line 274-275, page 14

Comment 6: In line 107 until 109 you describe different symptoms for TB including duration of cough but in table 1. You describe statistics of cough and symptoms, please clarify if you include or no the cough with other symptoms.

Response 6: Cough is included in the other symptoms. Cough has now been removed since it is included in the other symptoms

Comment 7: Was the information from line 107 to 109 used to describe typical characteristics of TB?

Response 7: We have clarified that cough, fever, weight loss and night sweats are the WHO recommended symptoms for TB screening and that loss of appetite and chest pain are recommended by the Zambia TB guidelines. See methods section, line 127-130, Page 7

Comment 8: improve the methodology and results in the abstract. so you can answer first the objective of the study.

A total of 18,194 individuals were screened through the facility 9,846 (54.1%) and 8,348 (45.9%) were screened through the community. 9,309 (51.2%) were male.....

Response 8:Both methodology and results section have been revised. See abstract section, line 31-44, page 2

Attachment

Submitted filename: RESPONSE TO REVIEWERS.docx

Decision Letter 1

Frederick Quinn

6 Aug 2020

Active TB case finding in a high burden setting; comparison of community and facility-based strategies in Lusaka, Zambia

PONE-D-20-06815R1

Dear Dr.Kagujje,

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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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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: (No Response)

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: I Don't Know

**********

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 clarified the doubts in the first review.Targeting should be applied in TB interventions to improve yield and use resources more efficiently in Lusaka, Zambia.A screening tool should be provided for vulnerable populations to guide health workers to identify presumptive cases.

The authors used a representative number of individuals to screen TB in the community. Data improvement for TB, specifically synchronizing laboratory and TB registers, is another timely recommendation, especially in the current context of TB in Lusaka.

Reviewer #2: The paper is reporting findings from an implementation study, while i think a more robust statistical analysis could be done, i accept that the authors statement that they have another paper in preparation that would capture that. Therefore this would be considered a descriptive paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Adrian Muwonge

Acceptance letter

Frederick Quinn

19 Aug 2020

PONE-D-20-06815R1

Active TB case finding in a high burden setting; comparison of community and facility-based strategies in Lusaka, Zambia

Dear Dr. Kagujje:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

    S1 Data. Facility vs community case finding published data

    (XLS)

    Attachment

    Submitted filename: PONE-D-20-06815.pdf

    Attachment

    Submitted filename: RESPONSE TO REVIEWERS.docx

    Data Availability Statement

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


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