Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda.

INTRODUCTION: Catastrophic costs incurred by tuberculosis (TB) patients have received considerable attention, however little is known about costs and pathways to care after a negative TB evaluation.
MATERIALS AND METHODS: We conducted a cross-sectional study of 70 patients with a negative TB evaluation at four community health centres in rural and peri-urban Uganda. Patients were traced 9 months post-evaluation using contact information from TB registers. We collected information on healthcare visits and implemented locally-validated costing questionnaires to assess the financial impact of their symptoms post-evaluation.
RESULTS: Of 70 participants, 57 (81%) were traced and 53 completed the survey. 31/53 (58%) surveyed participants returned to healthcare facilities post-evaluation, making a median of 2 visits each (interquartile range [IQR] 1-3). 11.3% (95%CI 4.3-23.0%) of surveyed patients and 16.1% (95%CI 5.5-33.7%) of those returning to healthcare facilities incurred catastrophic costs (i.e., spent >20% annual household income). Indirect costs related to lost work represented 80% (IQR 32-100%) of total participant costs.
CONCLUSIONS: Patients with TB symptoms who experience financial catastrophe after negative TB evaluation may represent a larger absolute number of patients than those suffering from costs due to TB. They may not be captured by existing definitions of non-TB catastrophic health expenditure.

Introduction

Whilst the incidence and mortality of tuberculosis (TB) are declining globally, they are not declining fast enough to meet the ambitious targets set out in the World Health Organization’s (WHO) END TB strategy [1]. This strategy highlights the need for bold social policies and research in addition to patient-centred care in order to eliminate TB. To this end, there has been increased interest in the diagnostic journey of TB patients and their financial costs as they represent potential opportunities for novel interventions and programmatic development (1,2).

The severe economic implications of a TB diagnosis in lower and middle income countries have been well described [2, 3]. The proportion of patients incurring catastrophic costs (defined as >20% annual household income (AHI)) whilst obtaining a TB diagnosis and treatment serves as a measure of the financial burden of TB. Eliminating catastrophic costs for TB affected households is one of the three key targets in the END TB strategy [1, 4, 5]. However, much less attention has been paid to those who test negative during TB evaluation. These patients represent the vast majority of those embarking upon the TB diagnostic journey. Even in high TB-burden settings such as Uganda, 80–90% of patients with chronic cough will have a negative evaluation for TB [6-8]. Though they likely do not have the disease, persistent symptoms may lead patients to seek alternative diagnoses and therapies even after their negative TB evaluation. It is currently unclear to what extent these patients are at risk of incurring punitive costs in the pursuit of such a solution.

Studies of TB patients suggest that costs due to lost work represent a considerable proportion of their total financial burden [4] leading the END TB strategy to include lost income and non-medical cost in the calculation of ‘catastrophic costs’ in TB patients [9]. By contrast, financial risk in non-TB patients with similar respiratory symptomatology only considers out-of-pocket medical costs, termed by WHO as ‘catastrophic health expenditure’ [10]. It is not known to what extent non-TB patients suffer from non-medical and indirect costs that may not be captured under this current definition.

Previous studies have shown TB-negative individuals are likely to incur catastrophic costs prior to testing when their TB status is unknown [11]. However, to our knowledge, the financial burden accumulated after a negative TB evaluation has not been evaluated. We sought to characterise the number and type of healthcare providers visited by patients after a negative TB evaluation in Uganda and to estimate both the direct and indirect costs they incurred in following these pathways of care.

Materials and methods

Ethics statement

Ethical approval was granted by institutional review boards at the London School of Hygiene and Tropical Medicine (London, UK; MSc Ethics Ref: 15360), Makerere College of Health Sciences (Kampala, Uganda; REC Ref 2016–037) and University of California San Francisco (San Francisco, California, USA; ref:221338 IRB# 15–17296). Written consent was obtained for all in person interviews. Oral consent was taken and recorded for all telephone interviews.

Study setting

This exploratory cross-sectional study was carried out in four geographically-distinct areas of Uganda, two peri-urban and two rural, all within 150km of Kampala. Study sites were selected from those participating in XPEL TB trial, a cluster randomized trial to evaluate the effectiveness and implementation of onsite GeneXpert testing at community health centres [12]. One community-level TB microscopy centre was selected at random per a priori-defined area from those participating in the trial. Each of these centres uses sputum smear microscopy as the primary method of diagnosis for TB, tests more than 150 patients a year and refers sputum samples to a district or regional facility for Xpert MTB/Rif testing as part of the Uganda national TB program Xpert referral network.

Participants

Potential participants were identified from TB laboratory registers routinely kept at the four centres. Adult patients (≥18 years) who could consent and had a negative TB test result at these centres in quarter three and four of 2017 were eligible for inclusion. Individuals with a positive TB test result or who started treatment for TB within 2 weeks of their original evaluation were excluded. A convenience sample of 70 eligible individuals was taken. Preference was shown for individuals with recorded mobile telephone information, but in all other respects sampling was random. Participants were traced approximately 9 months after their negative test (Fig 1). Once traced, participants were given information about the study purpose and procedures and then asked to provide informed consent. If contacted by telephone, participants were read a standardised information and consent script and asked to consent over the phone–this was recorded as an audio data file.

Fig 1

Participant tracing procedure.

NOK = next of kin; VHT = village health team.

Surveys

All traced participants found to be alive were surveyed in participants’ local languages. Participants found to have died had the approximate date and reported cause of death recorded. Information was collected for up to ten healthcare facility visits made after a participant’s negative TB evaluation. This included the number and type of facility and time taken to visit. Cost data was collected for the post-evaluation period using locally-validated questionnaires adapted from the WHO patient costs survey for TB [9]. The adapted tool is presented in the Supplementary information. Costs incurred prior to and during TB evaluation were not evaluated. Participants were asked to estimate the cost of each component part of their visit (e.g., travel expenses, medication) including the value of any lost income. Total direct (out-of-pocket costs, split into medical e.g., medication, and non-medical e.g., transport) and indirect (lost income) costs were calculated. Total indirect costs per participant were calculated by taking a fraction of reported annual personal income based on the reported number of days of work lost due to symptoms post-TB evaluation. Dissavings were defined as the sum of reported borrowing, selling of assets and taking-out of loans. Cost data were collected in Ugandan Shillings (USh) and reported in both United States Dollars ($) and as a proportion of pre-morbid annual household income. During the data collection period the median nominal exchange rate was 3,680USh to $1USD; this was used calculate and report results in USD.

Data analysis

Patient characteristics, costs and healthcare-seeking behaviours were described using proportions with 95% confidence intervals for dichotomous outcomes and medians with inter-quartile ranges for non-parametric continuous outcomes. Wilcoxon Rank Sum tests were used to assess statistical differences in time and cost data between dichotomous variables. Univariate and multivariable sub-analyses were conducted using logistic and linear regression for binary and continuous dependent variables respectively. All data were analysed in STATA (version 15, StataCorp USA).

Ethical approval was granted by institutional review boards at the London School of Hygiene and Tropical Medicine (London, UK), Makerere College of Health Sciences (Kampala, Uganda) and University of California San Francisco (San Francisco, California, USA).

Results

Tracing was successful in 57/70 individuals (81%). Four traced individuals had died. Of the remaining 53, all consented to being surveyed. Surveys were administered a median of 10 months following negative TB evaluation (range 8–14 months). The 13 untraced individuals were younger than the 57 traced participants (mean difference -14.5 years 95%CI -23.3 - -5.7). No other statistically significant difference was found between these groups.

The 53 surveyed participants had a median age of 40 (IQR 32–51), 28 (53%) were female (Table 1). Thirty-three were traced by phone (62%). Median AHI (mAHI) was $1,174 (IQR $489–$3,261). Eighty-seven percent (n = 46) visited another healthcare facility before presenting for TB evaluation, making a median of 3 visits (IQR 2–5) pre-evaluation.

Table 1

Characteristics of surveyed participants.

Patient characteristics		Number/median
		(percentage/IQR)
Age (years)		40 (32–51)
Sex	Male	25 (47)
	Female	28 (53)
HIV status	Positive	27 (51)
	Negative	24 (45)
	Unknown	2 (4)
Living Environment	Rural	29 (55)
	Urban-/Peri-urban	24 (45)
Mobile phone ownership	Yes	35 (66)
	No	18 (34)
Tracing method	Mobile phone	33 (62)
	Address	20 (38)
Test type used in the initial negative TB evaluation	Smear Microscopy	47 (89)
	Xpert MTB/Rif	6 (11)
Awareness of negative TB test result	Aware	38 (72)
	Not aware	15 (28)

Total number of surveyed participants = 53

Most participants were evaluated for TB with smear microscopy (n = 47, 89%); the remainder were evaluated with Xpert MTB/Rif. Twenty-eight percent were not aware of the result of their evaluation. Six participants (11.3%; 95%CI 4–23%) reported being diagnosed with TB more than 2 weeks after their negative index evaluation and had subsequently been started on anti-tuberculous therapy.

Pathways to care

Symptoms persisted for a median of 4 weeks post-evaluation (IQR 3–13) in surveyed individuals (n = 53), causing a median loss of 7 days of work (IQR 1–30). Twenty-two participants made no further visit to any health facility post-evaluation. The remaining 31 participants (58%) made a total of 83 visits to healthcare post-evaluation, a median of 2 visits each (IQR 1–3) (Fig 2). Fig 3 shows a flowchart detailing pathways to care.

Fig 2

The distribution of healthcare facility visits made by study participants after TB evaluation.

Fig 3

Patient pathways to care after TB evaluation.

Flowchart showing patient pathways to care after TB evaluation. To the right of each facility visit, coloured boxes represent the types of facilities participants visited (see Key). Numbers within the boxes represent the number of participants visiting that type of facility. Blank boxes indicate that facility type was not visited. If a participant visited a further facility, their next visit is recorded at the next step of the flow chart. If a participant did not visit a further facility, they exit the flow chart to the left of their current facility visit. CHW = Community Health Worker.

Participants spent a median of 20 minutes travelling (IQR 10–60) and 2 hours visiting (IQR 1.25–5) per facility visit. The most commonly visited facilities were private clinics or hospitals, constituting 36% of all visits made. Local pharmacies (22%) and level III or IV government health centres (23%) were also commonly visited.

Costs of healthcare seeking behaviour post-evaluation

Participants (n = 53) incurred a median of $16.46 total costs post-TB evaluation (IQR $7.07-$93.33). Direct and indirect costs represented 20% (IQR 0–68%) and 80% (IQR 32–100%) of total costs respectively. Participants lost a median of $13.17 in indirect costs (IQR $1.05-$65.84). For those who accessed healthcare post-evaluation (n = 31), direct costs were a median of $8.97 (IQR $3.40-$30.57). Out-of-pocket medical costs represented 68% (IQR 59–86%) of total direct costs.

The median cost of a facility visit was $10.19 (IQR $4.35-$28.53) (Table 2). Of the 83 visits made, medical costs occurred in 62 visits and non-medical costs in 72 visits. Purchase of medicines was the most frequent medical cost, occurring in 56 (67%) visits. In 38 visits these costs represented the only medical cost. Radiology was the most expensive type of medical cost with a median cost of $6.79. However, it was only accessed in 6 of 83 (7%) visits. Travel costs were the most common type of non-medical direct cost, incurred in 64 of 83 (77%) visits. Food costs were incurred in 32/83 visits and represented a median of 33% (IQR 24–68%) of non-medical costs when they occurred. The fraction of total direct participant expenditure represented by different cost categories is presented in Fig 4.

Table 2

Participant costs per facility visit.

	Total cost per facility visit (IQR)	Direct cost per facility visit (IQR)	Direct medical costs per facility visit (IQR)	Direct non-medical costs per facility visit (IQR)	Indirect cost per facility visit (IQR)
Median cost	10.19	6.79	4.35	1.36	2.72
($ USD)	(4.35–28.53)	(2.58–16.30)	(0–11.41)	(0.54–4.07)	(0–13.59)
Median cost as a percentage of mAHI (%)	0.9%	0.6%	0.4%	0.1%	0.2%
	(0.4–2.4)	(0.2–1.4)	(0–1.0)	(0.04–0.3)	(0–1.2)

Costs per facility visit in absolute terms and as a percentage of median annual household income; n = 83. USD = United States Dollar, mAHI = median annual household income, IQR = interquartile range.

Fig 4

Distribution of direct costs during facility visits by study participants.

Direct costs incurred in 83 facility visits by the 31 study participants who returned to healthcare after TB evaluation. Slices represent the percentage of overall direct costs incurred by study participants by cost category (percentages labelled). The number of visits in which the specified cost category was accessed is also shown on the slices in brackets. The inner legend shows the median and inter-quartile range (in brackets) spent in that cost category, when accessed.

In total, 11% (95%CI 4.3–23.0%) of study participants spent >20% of AHI post-TB evaluation, incurring catastrophic costs. This amounted to 16.1% (95%CI 5.5–33.7%) of the 31 patients who accessed healthcare post-evaluation. Total financial losses were not significantly greater in those who attended healthcare post-evaluation, although they trended towards being so (median $40.61 [attended] vs $13.64 [did not attend]; p = 0.09). All participants suffering catastrophic costs experienced symptoms for more than 6 weeks post-evaluation.

Of surveyed individuals (n = 53), 66% (95%CI 51.7–78.5%) suffered dissavings post-evaluation. They incurred a median loss of $32.61 (IQR $10.87-$206.52), equivalent to 1.8% of AHI. Borrowing money was the most common form of dissaving (21/53) whilst selling assets incurred the largest median loss ($70.65, IQR $21.74-$353.26). Dissavings were significantly more common amongst participants who attended care post-evaluation (p = 0.04). However, the magnitude of dissaving did not vary between those who attended care post-evaluation and those who did not (p = 0.6). Catastrophic costs trended towards being more common in those that incurred dissavings (p = 0.07).

Discussion

Patients with chronic cough whose evaluation for TB is negative, although considered to be ‘completed’ from the perspective of National TB Programmes, remain patients with ongoing symptoms sufficiently troubling as to prompt further healthcare-seeking. More than 10% of individuals experienced financial catastrophe after negative TB evaluation without even considering costs incurred prior to or during TB evaluation. In TB patients these pre-diagnostic costs represent 48–53% of total expenditure [4]. Spending of this magnitude is sufficiently prevalent to warrant the attention of primary healthcare programs.

Despite a negative evaluation for TB, many individuals continue to search for diagnostic and therapeutic solutions. Although a significant minority did not visit any further facility, more than half did so, some many times over. These results are consistent with the likely range of aetiologies of chronic cough in this setting [13]. The sickest and hardest to diagnose patients may repeatedly access care without resolution, whilst those with self-limiting infectious illnesses require little, if any, further medical attention. However, a lack of accurate diagnostic data means this interpretation warrants further study. Visits to the private sector predominated, contributing 61% of all post-evaluation healthcare episodes. This is consistent with other studies of pathways to care in high-TB burden settings [14, 15].

Many participants experienced significant financial burden from their symptoms post-evaluation, and 11% financial catastrophe. Although this study did not include pre-evaluation costs, the authors and others have previously documented the potential for these costs to be financially catastrophic [4, 11]. Our study shows that for some, these costs do not stop after a negative test for TB. Taken together, the proportion of individuals with non-tuberculous chronic cough experiencing financial catastrophe during their diagnostic journey is likely higher than reported here. TB-negative individuals represent the majority of patients undergoing evaluation for TB. At a community level they could constitute as large a total financial burden as those with the disease. This cost burden likely reflects not only unwell and difficult-to-diagnose individuals who repeatedly access care but also the high indirect cost of seeking healthcare in this environment relative to income. The high burden of indirect costs in this study mirrors those found to occur in TB-affected households, which are characterised by lost income, inability to work and job loss [4, 16–19]. The fact that 28% of participants did not return to receive the results of their TB test is further suggestion that accessing healthcare in this environment is prohibitively expensive for some. The cost of accessing healthcare in lower- and middle-income countries is known to be financially challenging for many and often leads to dissaving and other coping strategies not traditionally assessed in financial risk protection research [20].

There were several limitations to this study. Firstly, the methodology predisposes costing information to recall bias. Steps were taken to mitigate this by making survey questions as unambiguous as possible. Nevertheless, cost findings need to be interpreted with a degree of caution. Second, the study’s cross-sectional design does not allow for definitive conclusions to be drawn on causality between observed associations. Last, this study did not include costs incurred prior to evaluation, which limits the extent to which firm conclusions can be drawn regarding the total cost incurred by participants during their illness. Despite these limitations, this study focuses on a patient group that has been comparatively neglected by international health research and presents important insights into the financial implications of their health issues. The generalisability of our findings could be seen as a limitation as we purposefully did not institute complex sampling procedures to make our subjects completely representative of the population they are derived from. However, the aim of the study was to describe the situation in these areas of Uganda in order to illustrate issues that could be widespread, rather than to derive specific generalisable conclusions. Of note, rates of phone ownership in study participants are consistent with those of the general population in Uganda [21, 22].

The move towards universal health coverage (UHC), advocated by the WHO as a possible solution to catastrophic health expenditure, may help patients surmount the financial barriers to medical costs for non-TB illnesses. However, UHC-related interventions by themselves will likely not be sufficient to mitigate financial catastrophe for patients as medical costs are only one driver of total patient cost [4, 18, 23]. Parallel social protection initiatives to prevent or reduce non-medical and indirect costs are likely to be essential as these costs make up a significant proportion of patient expenditure. These initiatives have been proven to mitigate such costs in TB patients [24]. Furthermore, under the current definition of catastrophic health expenditure advocated by the WHO, these non-medical and indirect costs are excluded when assessing the financial stress on non-TB patients [10]. A definition of financial catastrophe that accounts for the important financial burdens that non-direct medical costs and indirect costs create would support identification of affected patients and allow health programs to better select and target interventions.

Conclusions

Far from avoiding the catastrophic costs incurred by many of their TB-positive counterparts, some individuals continue to experience financial catastrophe after negative TB evaluation. They may represent a larger economic burden at a community level than those suffering from similar costs due to TB and may not be captured by existing definitions of non-TB catastrophic health expenditure. A prospective longitudinal study with recruitment at the point of TB evaluation would allow more accurate cost estimation, capture of final diagnoses and allow exploration of alternative definitions of financial catastrophe and their relationship to outcomes. Furthermore, such a study could be designed to prospectively compare the costs after both a positive and negative TB evaluation from the same population. Meanwhile, more attention needs to be paid to encouraging TB-negative patients to return to the clinic that tested them to coordinate further investigative efforts.

Multivariable logistic regression of factors associated with increased odds of attending healthcare facilities after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis. All variables found to be associated with accessing healthcare post-evaluation with a significance level of p≤0.1 in the univariate analysis were included in the multivariable analysis along with age and sex. A longer duration of symptoms after TB evaluation was associated with increased odds of attending healthcare facilities post-evaluation. Subjects living in rural settings and those with HIV infection had lower odds. Four or more healthcare attendances prior to TB evaluation trended towards association with increased odds of attendance post-evaluation but was non-significant.

(PDF)

Click here for additional data file.

Univariate logistic regression analysis comparing the unadjusted odds of attending healthcare facilities by study participants after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). OR = odds ratio; TB = tuberculosis; NTLP = National Tuberculosis and Leprosy Program. Variables that demonstrated an association with a significance level of p≤0.1 were taken through to multivariable analysis along with age and sex.

(PDF)

Click here for additional data file.

Univariate linear regression analysis comparing the unadjusted total cost incurred by participants after negative TB evaluation.

n = 51 for analysis (due to n = 51 known HIV status). TB = tuberculosis; USh = Ugandan Shillings; NTLP = National Tuberculosis and Leprosy Program.

(PDF)

Click here for additional data file.

Modified costing tool.

This tool was adapted from a validated costing tool used in previous work by our group [11]. No questions related to financial expenditure were added or subtracted from the original costing tool. Additional questions were added to aid in discriminating different pathways to care used by study participants.

(PDF)

Click here for additional data file.

Raw data for analysis.

(XLSX)

Click here for additional data file.

11 May 2021

PONE-D-21-07641

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

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Reviewer #1: Summary of the research

The authors set out to characterize the number and type of health care providers visited by patients after a negative TB evaluation. In addition, they sought to estimate both the direct and indirect costs these patents incurred in following these pathways of care. From the participants they surveyed, the authors found that those with negative TB evaluation experience both direct and indirect costs which could be more than what those with positive TB evaluation experience. The findings showed that indirect costs accounted for most of the costs incurred. They found that more than half of the participants surveyed visited health facilities especially private ones after negative TB evaluation with some of them experiencing catastrophic costs especially those with persistent symptoms. These findings show that once someone has negative TB evaluation, that should not be the end of having contact with the person but subsequent follow up on them would be beneficial to enable them to establish the diagnosis and may help minimize the costs. The findings have also highlighted a new area which has received very little focus yet an important area to help achieve universal health coverage in low- and middle-income settings.

Strengths and limitations of the study

The manuscript is well written, easy to follow, and the findings presented clearly. The Participant tracing, the survey and ethical issues have been described clearly. The authors have acknowledged their drawbacks in sampling of the participants, recall bias, study design and generalizability of the findings. They have also highlighted they were not able to do pre-evaluation costs.

Just some minor comments as much as the authors did a convenience sampling for the participants, it is not clear how the four facilities were selected from four geographical areas of Uganda given that there are other facilities in those areas. In addition, for the six participants who reported being diagnosed with TB more than two weeks after their negative index evaluation and were on anti-tuberculous therapy, how was their data handled. More so, two of their references appear to be incomplete.

Examples and Evidence

Major Issues

No major issues

Minor issues

1. In line 87-88,” One community-level TB microscopy Centre was selected per area” can this be described further how the selection was done for instance random, systematically, convenience etc.

2. In figure 1, is it possible to key in the numbers in the participant tracing procedure to show how you ended up with the numbers you surveyed.

In the same figure please give the key for the abbreviations ‘NOK’ and ‘VHT’

3. In Table 1, please state the denominator for the proportions calculated and the units for age.

4. In line 158-160, the six participants who later turned to be positive and were on anti-TB drugs, how did you handle their data?

(i) Were they part of the 31 who visited health care post-evaluation?

(ii) If they were part of the 31, won’t their costs be different from the others who were not on anti-TB drugs?

5. In figure 4, in line 208-209 you have stated what the slices represented, which data did you use to calculate the proportions? One can easily get mixed up with proportions described in line 194 to 199.

6. In line 330, reference 7 and line 372, reference 21 they appear to be incomplete. Are they journal articles? not clear what type of references they are.

7. One of the discussion points, given that majority of those that visited health facilities, visited private health facilities could it explain the high direct medical costs per facility.

8. A suggestion in your recommendations in the conclusion: It would be helpful to do a comparative study between the costs encountered by those having positive TB evaluation and negative TB evaluation in the same population to know the magnitude in both groups.

Reviewer #2: 1. Authors have mentioned it in the limitation, but collecting information on cost incurred over past 9-10 months may have serious recall issues. Have authors tried to access some documents to verify at least the resource use?

2. I would like see more details of indirect cost estimation. How was it estimated if someone was not employed? Was it just by asking how much income they lost for healthcare faculty visit?

3. Figure 2 may not be required and can be explained in text only.

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Reviewer #1: No

Reviewer #2: Yes: Rakesh Kumar

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28 May 2021

For ease of reference, the specific reviewer and editor comments and our associated replies are detailed in a table format in the document uploaded as a response to the reviewers. For ease of access, these are listed here too.

We will address reviewers points below sequentially as raised.

Reviewer 1:

Comment: Line 87-88: One community-level TB microscopy Centre was selected per area” can this be described further how the selection was done for instance random, systematically, convenience etc.

Response: The centres were selected from amongst those used in a trial to assess the efficacy of on-site GeneXpert testing in local community health centres in Uganda - https://doi.org/10.1186/s13012-020-00988-y

One centre was selected at random from each of the four pre-defined areas from those participating in the above trial. These areas were selected a priori to illustrate a wider variety of patient experience.

We have amended the methods section to make this clearer

Comment: In figure 1, is it possible to key in the numbers in the participant tracing procedure to show how you ended up with the numbers you surveyed.

In the same figure please give the key for the abbreviations ‘NOK’ and ‘VHT’

Response: Unfortunately, we do not have any more granular data than whether participants were traced by phone, in person, or not at all. This data is available from Table 1. We agree with the authors points about the abbreviations and have amended the legend of the figure.

Comment: In Table 1, please state the denominator for the proportions calculated and the units for age.

Response: We agree and have made the changes suggested by the reviewer.

Comment: In line 158-160, the six participants who later turned to be positive and were on anti-TB drugs, how did you handle their data?

(i) Were they part of the 31 who visited health care post-evaluation?

(ii) If they were part of the 31, won’t their costs be different from the others who were not on anti-TB drugs?

Response: In response to the reviewer:

1) They were part of the 31.

2) If diagnosed with TB, the subsequent healthcare visits after the visit in which that diagnosis was made were not included in this analysis as for our purposes, they constituted a completed healthcare pathway. TB medication itself is free in Uganda as it is provided by the state, but analysis beyond the point of diagnosis would have included further costs from clinic visits etc. that went beyond the scope of the study.

Comment: In figure 4, in line 208-209 you have stated what the slices represented, which data did you use to calculate the proportions? One can easily get mixed up with proportions described in line 194 to 199.

Response: In figure 4, all direct costs incurred by participants were summed, and then broken down by the type of expenditure as shown. The fraction of overall total costs represented by each type of expenditure was then calculated and is presented as the pie chart in figure 4.

We agree with the reviewer that the reference to Figure 4 in the main text is misleading in this regard as it refers to different data. We have corrected this.

Comment: In line 330, reference 7 and line 372, reference 21 they appear to be incomplete. Are they journal articles? not clear what type of references they are.

Response: It appears our referencing software had not fully completed these two references. We have corrected the issue and thank the reviewer for bringing this to our attention.

Comment: Discussion - One of the discussion points, given that majority of those that visited health facilities, visited private health facilities could it explain the high direct medical costs per facility.

Response: The reviewer makes an excellent point. In data that we have not reported in the manuscript, we found that visits to private facilities had a higher median cost than state facilities (59,000Ush for private facilities vs. 37,000Ush for a district hospital and 27,000Ush for a local health centre). However, perhaps due to the small number of participants in the study, this difference was not statistically significant. Other studies done similar populations tend to support this point.

This is unlikely to only factor at play, however. In Ugandan state-funded health facilities, medical services beyond a simple consultation, such as radiographs and medications, are often not free at the point of use and health insurance is non-existent. The reported direct medical costs are therefore likely due to more than just the type of facility attended and likely reflect the generally high out-of-pocket expenditure required in this health system.

We chose not to include these points within the discussion as there were other things we wished to explore in more detail.

Comment: Conclusions - A suggestion in your recommendations in the conclusion: It would be helpful to do a comparative study between the costs encountered by those having positive TB evaluation and negative TB evaluation in the same population to know the magnitude in both groups.

Response: We completely agree with the reviewer and have added this suggestion to the conclusion.

Reviewer 2:

Comment: Authors have mentioned it in the limitation but collecting information on cost incurred over past 9-10 months may have serious recall issues. Have authors tried to access some documents to verify at least the resource use?

Response: We agree with the reviewer that these sorts of documents would assist in validating some of the cost results to some extent. Unfortunately, in the vast majority of cases very few such documents exist, and we were not able to collect any within the limits of the study. Ideally, further prospective research needs to occur to validate cost data, as we suggest in the conclusion.

Comment: I would like see more details of indirect cost estimation. How was it estimated if someone was not employed? Was it just by asking how much income they lost for healthcare faculty visit?

Response: Indirect cost estimation was calculated as the fraction of annual reported income lost based on the number of days of work reported lost due to symptoms after TB evaluation/number of total work-days per annum. Separate data was collected asking participants how much lost income occurred due to individual healthcare visits. This was not added to the total calculated above but reported separately as per the results section. If a participant was not employed (almost always due to subsistence farming being their primary economic activity), they were asked to estimate the cost of their lost time. We also attempted to capture the economic costs to these participants by reporting dissavings in the results.

We have amended the methods to further detail how indirect cost data was calculated

Comment: Figure 2 may not be required and can be explained in text only.

Response: We agree with the reviewer that Figure 2 can be explained in text alone. However, we feel that the simplicity and clarity of the figure is a strength. Given that it remains within the overall figure limit of the paper, we would ideally prefer to keep it in the manuscript.

Submitted filename: Response to the reviewers WWIE v1.0 20210511.docx

Click here for additional data file.

16 Jun 2021

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda

PONE-D-21-07641R1

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7 Jul 2021

PONE-D-21-07641R1

Where will it end? Pathways to care and catastrophic costs following negative TB evaluation in Uganda.

Dear Dr. Samuels:

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