Trends of Tuberculosis Treatment Outcomes of Notified Cases in Three Refugee Camps in Sudan: A Four-year Retrospective Analysis, 2014–2017

Background: Refugees are vulnerable to tuberculosis (TB) infection. Tracking of program performance is needed to improve TB care and prevention. The objective of this study was to assess the trends of TB treatment outcomes of notified cases in three refugee camps in Sudan from 2014 to 2017. Methods: This study was a historical cohort study. Sex, age, type of TB, TB patient category, and treatment outcome of all TB cases registered in three refugee camps (Al Kashafa, Shagarab, Wadsherify) from January 1, 2014 to December 31, 2017 were collected from the TB register. Multivariable logistic regression was performed to explore factors for unsuccessful TB treatment. Results: A total of 710 TB cases of which 53.4% were men, 22.1% children (<15 years), and 36.2% extrapulmonary TB (EPTB) were registered. Overall, the TB treatment success rate was 75.7% with a declining trend from 86.2% in 2015 to 63.5% in 2017. On average, 11.4% were lost to follow-up (LTFU), 6.6% died, 5.9% were not evaluated, and in 0.3% the treatment failed. Being 15–24 years old and having EPTB were significantly associated with unsuccessful treatment outcome. Conclusion: The treatment success rate in the refugee camp in 2017 (63.5%) was far lower than the national treatment success rate (78%) and the End TB global target (≥90%) that needs to be improved. LTFU, died, and not evaluated outcomes were high which indicated the necessity to improve the TB treatment program.


Introduction
Tuberculosis (TB) is a major public health challenge around the globe. According to the World Health Organization (WHO) report, in 2017, 10 million TB cases and 1.6 million TB deaths (HIV-negative) were recorded worldwide. In Sudan, the estimated TB incidence and mortality rate (HIV-negative) per 100,000 population in 2017 were 77 and 12, respectively [1]. Although, TB burden has been falling in the past 20 years worldwide [1], it still remains a primary cause of death from a single infectious agent since 2011 [1,2].
By the end of 2018, nearly 71 million refugees and asylum seekers were registered globally [11]. Majority (>86%) of refugees are from and stay within developing countries where the TB burden is higher [12]. Studies have shown an increase in the prevalence of TB [13,14] and TB case notification [14,15] when the number of refugee population increases. Thus, key populations such as refugees have been given special focus in the Stop TB [16] and End TB [2] WHO strategic documents so as to achieve the global targets by 2035.
Sudan (with a population size of 41 million in 2017) is among the countries with high TB incidence rates (≥20/100,000 population) in the world [1]. Sudan has a long history of hosting refugees. By the end of 2019, the country had hosted >1.1 million refugees living in camps and out of camps (70%) in over 130 localities across the country's 18 states As defined in the End TB strategy, the 2020 TB treatment success rate target is at least 90% [2]. Generally, TB treatment success in the refugee population can be affected by factors including less adherence to treatment, death, noncompletion due to lost to follow-up (LTFU), malnutrition, and other coexisting illnesses such as HIV coinfection [8,20,21]. Studies showed lower treatment success rate among refugees in Ethiopia (75.1%) [22] and in refugees hosted in different countries (ranging from 63.6 to 77.5%) [23][24][25][26][27][28].
The TB program in Sudan including in the refugee camps is guided by the National TB Program (NTP), under the Communicable and Non-Communicable Disease Department, in the Ministry of Health (MOH) [22]. The NTP in Sudan has a surveillance system but it largely focuses on the government-owned health facilities run by Federal and State Minsters of Health. However, there is no specific study on the trends of treatment outcome and factors associated with unsuccessful treatment outcome in the refugee camps. Hence, this study aimed to investigate trends of TB treatment outcomes of notified TB cases and assess factors for unsuccessful treatment outcomes in three refugee camps in Sudan from 2014 to 2017.

Study settings and participants
In Sudan, TB program in the refugee camps is led and coordinated by the NTP and is implemented according to the national TB guideline [22]. The data collection for the TB surveillance system occurs at TB management units (TBMUs) that utilize patient cards and registers [22].
This study was a refugee health facility based which used Unit TB registers in the refugee camps as data source. According to the inclusion criteria, all refugee health facilities which provided TB diagnosis and treatment at least since January 2017 were included. Thus, three health facilities which fulfilled the inclusion criteria in three refugee camps (Al Kashafa, Shagarab, Wadsherify) located in White Nile and Kassala states were included. The study participants were all TB cases registered in these three refugee camps from January 1, 2014 to December 31, 2017.

Study design and data collection
This study was a historical cohort study. Variables included in the Unit TB register such as sex, age, type of TB, TB patient category, and treatment outcome of all TB cases registered in three refugee camps (Al Kashafa, Shagarab, Wadsherify) were collected.
Data collection tool was developed and pretested. Nurses and program officers were recruited as data collectors and supervisors, respectively, and received training on data collection tools including practical exercise. Data were collected from January to April 2019.
Data quality was assured through provision of training to data collectors and supervisors and undertaking daily field supervision by the field supervisors. In addition, 10% of the data collected were randomly selected and recollected by the field supervisors and checked page by page.

Data analysis
Epi-info statistical software version 7 was used for data entry, and data were exported to STATA version 13 (Stata Corp, College Station, TX, USA) for analysis. Frequencies, proportions, and ratios were calculated to describe treatment outcome variables.
Bivariate and multivariable logistic regression analysis were done to assess factors associated with unsuccessful treatment outcome. The independent variables used were age, sex, baseline weight, type of TB, category of TB patient, refugee camps, year of treatment, and HIV infection. Odds ratios (OR) with 95% confidence interval was used to assess the strength of association between variables. Statistical significance level was considered at a P-value < 0.05.

Operational definitions
The operational definitions of TB cases and TB treatment outcome categories in this study are based on the National TB management guideline in Sudan [29] and the WHO document [30] included in Supplement 1.

TB cases by diagnostic and age categories
Overall, the number of notified TB cases in the camps increased from 143 in 2014 to 341 cases in 2017. We further analyzed the notified cases disaggregated by diagnostic category and gender (Table 1) (Table 1).

Notified TB cases by HIV status
Among the 710 notified TB cases in the four-year period, HIV testing was done for 42.7%. The proportion of notified TB cases who did not receive HIV test and results increased from 30% in 2015 to 62.5% in 2017. The TB-HIV coinfection rate decreased  (Table 1). All identified HIV-positive TB cases in each year were put on ART.

TB treatment outcomes from 2014 to 2017
Treatment outcome was determined for 143, 80, 146, and 341 TB cases of all forms that were notified in 2014, 2015, 2016, and 2017, respectively (

Demographic and clinical characteristics associated with unsuccessful TB treatment outcomes in Sudan refugee camps (2014-2017)
Using a simple bivariate logistic regression analysis, age group and type of TB were seen to be associated with unsuccessful treatment outcomes. More specifically, age  (Table 3).

Discussion
The findings of this study generate evidence on trends of treatment outcomes of notified case during the study period (2014-2017), which is relevant to improve the quality of TB program in Al Kashafa, Wadsherify, and Shagarab refugee camps in Sudan.

Notified TB cases
In countries with good TB diagnoses and reporting system, case notifications can be used as a proxy for TB incidence estimates [19]. Moreover, bacteriologic diagnosis of TB allows patients to be correctly diagnosed and started on the most effective treatment regimen. In this study, the absolute number of notified new and relapse cases showed an increment during the study period which could be due to the increment of refugees or new influxes following the conflicts in South Sudan. Similarly, an increase in notified TB cases (from 138 cases in 2014 to 588 in 2017) was reported in refugee population hosted in refugee camps in Ethiopia [22]. In contrast, notified incident TB cases among Syrian refugees in Jordan has declined from 79 cases in 2013 to 58 cases in 2015 [28].
In this study, 45.3% of the new and relapse PTB cases in the refugee camps in 2017 were bacteriologically confirmed, which is lower than the 2018 WHO report for Sudan (49%), African Region (66%), and for the globe (56%) [1], and the End TB global target where 80% of the new and relapse TB patients need to be bacteriologically confirmed by 2020 [2]. The low proportion of bacteriologically confirmed cases may reflect gaps in capacity for accurate diagnosis.
Analyzing the notified TB cases by type of TB is important for targeted interventions.
In this study, proportion of EPTB increased from 29.4% in 2014 and reached 39.3% by 2017. This is higher than the proportion of EPTB among new cases in Darfur conflict zone in Sudan (2004-2014) (35%) [31], in the globe (14%), and in Sudan (26%) in 2017 [1]. The higher proportion of EPTB in the refugee settlements can be due to demographic factors (age, sex), origin of refugee population, host factors (immune status due to comorbidities such as HIV coinfection) [32,33], or due to pathogen factor (phenotypes of the tubercle bacilli) [34]. Thus, operation research aimed to investigate the factors attributed to the higher and increased trend in EPTB in the refugee settlements is recommended.
TB largely affects productive age groups. Similar to 2018 WHO TB report [1] and studies done in other developing countries [35,36], our study findings also showed that the highest notified cases were in the age groups 15-34 (30.4%) and 35-54 (26.0%) years (Table 1). Thus, TB programs should strengthen case-finding efforts focusing on these age groups.
High childhood TB is an indication of high missed cases among adults and continuity of TB transmission [23].

Treatment outcomes
TB treatment outcome is a good indicator for the overall quality of TB program and in particular the TB treatment program [19]. According to the WHO End TB global plan, at least 90% of all TB cases on treatment need to achieve treatment success rate by 2020 [2]. In the refugee camps, on average 75.7% (range 63.5-86.2%) of the TB cases achieved treatment success during the study period.
The declining trend in treatment success rate in the refugee camps started in 2016, and this was probably due to the increase in influx of new refugees in 2016 and 2017 and high mobility of the refugees. This was due to high LTFU, mortality, and unevaluated treatment outcomes, which called for action by the refugee health and NTP. Overall, the mean treatment failure (0.3%), LTFU (11.4%), and died (6.6%) in the refugee camps (

Conclusion
The proportion of EPTB (from 29.4 to 39.3%) and TB <15 years (from 8.4 to 34.3%) increased over the study period. TB treatment success rate was at a range 63.5-86.2%.
The 2017 treatment success rate in the refugee camps (63.5%) was lower than the report for Sudan (78%) and the End TB target for 2020 (≥90%), which needs to be addressed.
There was a high LTFU, mortality, and non-evaluation, which showed that there was a gap in the TB treatment program in the refugee heath facilities. Future research is recommended to investigate the increase in EPTB.
The study has generated useful evidence of treatment outcomes of notified TB case from 2014 to 2017 that will support to plan effective TB care and prevention programs in the refugee camps in Sudan. However, as this study was conducted retrospectively based on secondary data, it had some limitations. Although, socioeconomic factors (occupation, education, and income level), health system factors, and patient-related factors were reported to be associated with unsuccessful treatment outcome in other studies, we were not able to include these variables in our analysis as we used secondary data. We used only independent variables available in the Unit TB register to assess factors associated with unsuccessful treatment outcomes.

Ethical Considerations
Individual consent was not required as the data used were secondary, collected from the TB register in the refugee camps. Ethical approval and permission were obtained

Competing Interests
The authors declare that they have no competing interests.

Availability of Data and Materials
All analyzed data were included in this manuscript. However, patient-level data, which were analyzed, can be received with permission of NTP, Communicable and Non-

Supplement 1
Operational Definitions TB case notification: TB is diagnosed in a patient and is reported within the national TB surveillance system.

TB cases:
A patient in whom TB has been diagnosed. A TB case is defined as: (i) A bacteriologically confirmed TB case: is one from whom a biological specimen is positive by smear microscopy, culture, or WHO-approved rapid diagnostics (such as Xpert MTB/RIF).
(ii) A clinically diagnosed TB case: is one who does not fulfil the criteria for bacteriological confirmation but has been diagnosed with active TB by a clinician or other medical practitioner who has decided to give the patient a full course of TB treatment.
Bacteriologically confirmed or clinically diagnosed cases of TB are also classified according to anatomical site of disease, history of previous treatment, drug resistance, and HIV status.

Classification based on anatomical sites:
(i) Pulmonary tuberculosis (PTB): any bacteriologically confirmed or clinically diagnosed case of TB involving the lung parenchyma or the tracheobronchial tree. (iii) Treatment failed: a TB patient whose sputum smear or culture is positive at month 5 OR later during treatment.
(iv) Lost to follow-up (LTFU): a TB patient who did not start treatment OR whose treatment was interrupted for two consecutive months or more.
(v) Died: a TB patient who dies for any reason before starting OR during the course of treatment.
(vi) Not evaluated: a TB patient for whom no treatment outcome is assigned. This includes cases "transferred out" to another treatment unit as well as cases for whom the treatment outcome is unknown to the reporting unit.
(a) Successful treatment: sum of cured and treatment completed outcomes.
(b) Unsuccessful treatment: sum of died, treatment failed, and LTFU outcomes.