Analysis of Tuberculosis Cases Notification and Treatment Outcomes Among Refugee Camps In Kenya: Four Year Retrospective Study, 2014-2017


 Background: Tuberculosis (TB) is more severe in refugee populations. Analyzing the key indicators of TB program performance is important to improve the effectiveness of TB control in the refugee camps. This study aimed to analyze trends in TB case notification, treatment outcomes and factors associated with unsuccessful TB treatment in Dadaab and Kakuma refugee camps in Kenya. Methods: In this descriptive retrospective study, demographic and clinical data all TB cases registered in the refugee camps from January 2014 to December 2017 were extracted. Multiple logistic regression analysis was used to estimate odds ratios and 95% confidence intervals for variables associated with unsuccessful TB treatment.Results. A total of 2055 TB cases of whom 56.8% men and 57.7% age 15-44 years were registered. Number of notified cases decreased from 532 in 2014 to 473 in 2016 (11.1% decrease) then increased to 554 in 2017(16.9% increase in one year). From 2014 to 2017 there was consistent increase in percentage of EPTB (16.2% to 21.1%), and in contribution of children (<15 years) to total TB cases (20.3% to 25.8%) and to EPTB (36.1% to 44.4%). Proportion of bacteriologically confirmed new and relapse pulmonary cases increased from 49.5% to 60.9%. Treatment success rate remained higher at 92.6% to 94.4%. On average 41.7% were cured, 2.3% lost to follow-up (LTFU) (increasing from 1.3% to 3.2%), 2.2% died (decreasing from 2.4% to 1.6%), 1.6% not evaluated (decreasing from 3.2% to 1.3%), and 0.5% treatment failed. Unsuccessful treatment outcome was significantly associated with pretreatment weight < 40 Kg, being male, smear positive PTB, HIV infection, and age >15 years (increased with age).Conclusions: Number of notified TB cases has decreased from 2014 to 2016, but increased in 2017. There was continuous increase in percentage of EPTB and childhood TB. Proportion of bacteriologically confirmed new and relapse pulmonary cases has increased overtime. Treatment success remained higher above global target (90%) which should be maintained. Special socioeconomic support and follow-up is required for TB patients who are at higher risk of unsuccessful treatment.


Background
Tuberculosis (TB) is an ancient infectious disease caused primarily by Mycobacterium tuberculosis [1]. Although the burden of TB has been declined in the past 20 years (58 million lives have been saved and TB incidence was declined 1.6% per year), TB remains to be the leading cause of death from single infectious agent above HIV/AIDS. In 2018, there were an estimated 10 million incident TB cases and 1.6 million TB deaths among HIV negative in the globe [2]. Kenya, is among the 30 high burden countries for TB, TB/HIV and MDR-TB. By 2018, the estimated TB incident, HIV negative TB mortality, and noti ed TB cases in Kenya was 150000, 96478 and 38 000, respectively [2]. Overall, based on the global success stories, but also taking into account the existing challenges to control TB (missed TB cases, TB/HIV, MDR-TB, TB in high risk groups, budget gaps), the global plan is to end the TB epidemic by 2035 (less than10 cases per 100 000 population) [3]. TB, however, is a major health problem in key populations (refugees, immigrants, prisoners, homeless, internally displaced persons (IDPs). The reasons for which are poor shelter/housing, inadequate living conditions, limited health service access/use, poor nutritional status, coexistent illness like HIV, overcrowding, and inadequate TB care and prevention, [4,5,6]. Thus, TB infection and disease progression [4][5][6], acquiring or developing multi-drug resistant (MDR) TB [7] and unsuccessful TB treatment outcome [8] is higher among refugees.
Reports showed armed con icts and population displacements are associated with up to 20-fold increase in the risk of TB [6]. In 2018, there were 70.8 million refugees, asylum seekers and persons displaced by wars and con icts Worldwide [9]. Usually, majority (> 85%) of refugees originate from and remain within countries with high burdens of TB [10]. A recent systemic review and meta-analysis showed that TB prevalence in refugees and asylum seekers varied more according to countries of origin than the host country [11], whereas others reported association between continuous immigration (increase in migrant population) and increase in prevalence of PTB and EPTB [12], in TB case noti cation [13] and in case detection rate [14].
To address the TB burden in the key populations, and also to achieve the global targets and end TB by 2030, special focus has been given to these key populations in the WHO Stop TB (2006)(2007)(2008)(2009)(2010)(2011)(2012)(2013)(2014)(2015) [15] and End TB (2016-2020) [3) strategic documents. The proposed targets for high-risk groups are to screen 90% of the population for TB and to obtain at least 90% treatment success by 2020 [3].
In summary, considering the factors including high TB burden in the host country (Kenya) [2] and in the countries of origin of the refugees in Kenya [14], the large refugee population residing in the host country [14], and the higher vulnerability of the refugee population to TB infection and disease [4][5][6], to MDR-TB [7] and to unsuccessful TB treatment outcome [8], TB can be a major health challenge in the refugee populations in Kenya. In north-east Kenya in 1994, the incidence of new infectious TB patients in camps was four times the rate in the local population [10].
Hence, in order to prevent and control TB in the refugee camps effectively, the performance of TB programs need to be monitored and evaluated regularly. Among the main indicators for TB program performance are TB case noti cation and treatment outcome [17,18]. In countries that have highperformance of surveillance and monitoring and evaluation systems, noti cations of TB cases provide good proxy information on TB incidence (TB burden), whereas TB treatment outcomes provide information on the effectiveness of TB treatment program [18]. In this study, therefore, we aimed to investigate the trends of TB case noti cation, TB treatment outcome, and factors associated with unsuccessful TB treatment outcomes in refugee camps in Kenya in the past four years (2014-2017).

Study settings and populations
In Kenya, the structure of health service delivery is hierarchical with six tiers, namely community level followed by dispensaries, health centres, primary referral, secondary referral, and tertiary facilities. TB control and prevention program in Kenya, which is integrated to the general health care delivery system, is implemented by the National TB, Leprosy and Lung Disease Programme (NTLD-P), in the Department of Disease Prevention and Control, under the Ministry of Health (MOH). In Kenya, there are 3320 treatment facilities, 1920 diagnostic, and 295 TB control Zones located in 47 counties [19]. Similarly, health facilities in the refugee camps in Kenya (Dadaab, Kakuma and other urban areas) deliver general health care services including TB prevention and control to the refugee population. The TB programs in the refugee camps are led by the NTLD-P according to the national guideline for integrated Tuberculosis, Leprosy and Lung disease in Kenya [19].
Dadaab and Kakuma, which are among the world's largest refugee camps, hosted above 90% of the refugees in Kenya. Dadaab refugee camp located in Garissa County has three camps namely Dagahaley, IFO and Hagadera. Dagahaley and IFO are located in Lagdera sub-county and Hagadera is located in the neighbouring Fa sub-county. Kakuma refugee camp, located in Turkana County, has two areas of operation which are Kakuma Camp and Kalobeyei Integrated Settlement both located in Turkana West sub-county [16].
According to the inclusion critrea, heatlh facilites which have both TB diagnosis and treatment services starting from January 2017 will be included to address the objectives of this study. Thus, three health facilites loacted in three camps in Dadaab (Dagahaley, IFO1 and Hagadera) and two health facilities In this four year (2014-2017) refugee health facility based descriptive retrospective study, basic demographic and clinical data of each TB cases registered in Dadaab and Kakuma refugee camps were extracted from TB patient register. Data collection was done by trained health o cers and nurses using pretested data collection forms from January to April 2019. The data collection forms were pre-tested during the training of the data collectors, supervisors and coordinators. During the training, a previously lled in and archived TB register in the refugee health facilities was used as a sample to show each trainee on how to extract data from the TB register and on how to ll the data collection form. Finally, the data collection forms were revised as per the suggestion and comments received from pre-test exercise.
To ensure data quality, data collectors, study coordinators and supervisors were trained; supervision was done on daily basis by eld supervisors and on weekly basis by study coordinators during data collection; and then 10% of the data collected were randomly selected by the study coordinators, re-collected by the eld supervisors, and were checked page by page.

Data entry and statistical analysis
Data were coded and double entered into Epi-info version 7 by two trained data clerks and then crosschecked for consistency. During the preliminary analysis we looked for errors and corrected them by rechecking the data collection Forms. Binary logistic regression analysis was done to identify independent variables associated with unsuccessful treatment outcome. Finally, multivariate logistic regression analysis was used to measure the independent effects of each predictor variable on unsuccessful treatment outcomes. Variables with a P-value of < 0.05 in the bivariate analysis were included in the multivariate model. The independent variables used were age, sex, baseline weight, type of TB, category of TB, and HIV and ART status. Statistical signi cance level was considered at a P-value < 0.05. Odds ratios with 95% con dence interval were used to assess the strength of association between variables.

De nitions Of Variables And Terms
As shown in Supplement 2, TB case de nition and TB treatment outcomes were de ned according to the standard de nitions in the National guidelines for integrated TB, Leprosy and lung disease in Kenya [19] and the WHO guideline [17].

Characteristics of the study participants.
The clinical and demographic characteristics of all TB cases noti ed is shown in Table 1. of the total TB cases, respectively. Of the total TB cases, 1685 (82.0%) were PTB, 364 (17.7%) EPTB, and no record found for 6 (0.3).
By treatment history, 2034 (99.0%) of the total cases were new and relapse patients of whom 1767 (86.0%) were PTB patients. Among the new and relapse pulmonary patients, 988 (55.9%) were bacteriologically con rmed and 779 (44.1%) were clinically diagnosed.
By refugee camps, 1094 (53.2%) of the noti ed cases were from Dadaab and 961 (46.8%) cases were from Kakuma camp. The number of noti ed cases in Dadaab continuously decreased from 2014 (332 cases) to 2017 (242 cases), while in Kakuma refugee it increased from 2014 (200 cases) to 2017 (232 cases). The number of TB cases registered in the three health facilities in Dadaab refugee camp, and in two health facilities in Kakuma refugee camp is shown in Supplement 1.  New and relapse -PTB patients: Bacteriologically con rmed By treatment history, new and relapse patients remained stable and highest (98.3%-99.4%), whereas on average treatment after failure, lost to follow up to treatment, "others", and missed (no record) patients constituted 0%, 0%, 0.3%, and 0.7%, respectively.  (Table 1).
Trends in TB case noti cation by age categories There was a variation in number of noti ed cases by age groups (Fig. 2). Younger age groups (15-  Trends in TB case noti cation segregated by gender and age groups TB affects people of both sexes in all age groups but the highest burden was in men (Fig. 3). The percentage of noti ed TB cases was higher for men (> 50%) than for women in all age groups (

Discussion
This study provides evidences on trends of the key indicators of TB program performance (case noti cation, treatment outcomes, and factors associated with unsuccessful treatment outcomes), which are very important to improve the effectiveness of TB control and prevention programs in Dadaab and Kakuma refugee camps in Kenya.
In settings TB surveillance system is well established (with very minimal underdiagnoses and underreporting of TB cases), TB case noti cations can be used as a proxy for TB incidence estimates. In the two refugee camps, there was 11.1% decline in the number of noti ed TB cases in three years (2014 to 2016), but increased by 16 (Table 1 and Fig. 1).
Overall to 2017 (60.9%). However, by 2017, the percentage of bacteriologically con rmed new and relapse pulmonary patients in this study (60.9%) was lower than the WHO 2018 report for Kenya (67%) and for Africa Region (66%) [21]. The increase in bacteriologically con rmed cases could be due to improved access/use of diagnostic services, improvement in recording and reporting, an increase in real TB transmission, or only highly presumptive cases were tested (leading to missed cases). In addition, on average, 39.1% of the pulmonary new and relapse cases in 2017 were diagnosed clinically (Table 1), which is higher than the WHO 2018 report for Kenya (34%) [21]. This implies, signi cant number of patients may lead to unnecessary TB treatment, economic burden and psychological stress.
Putting together the gaps observed in TB diagnosis in the refugee camps (low bacteriological con rmation, high clinical diagnosis) can be addressed by improving the quality-assured TB diagnostics laboratories, referral system, early case identi cation, access/use of advanced diagnostics, recording and reporting, and refresher training.
Evidence on TB epidemiology by type of TB (PTB and EPTB) is important to plan and implement targeted TB diagnostic, treatment and prevention services. In this study, percentage of EPTB increased by 30.2% in four years (2014-2017). Thus by 2017, EPTB contributed to 21.1% of the total cases noti ed which is higher than the global (14%) and national/Kenya (16%) share of EPTB reported by WHO 2018 [21].
Therefore, the increased trend in the proportion of EPTB in the refugee camps which could be due to expansion of TB diagnostic services (Gene Xpert, culture and/or histopathology) or due to real change in the epidemiology of TB, need to be investigated.
We further analyzed how age and gender contributed to the total cases noti ed which is important for targeted intervention. Several studies evidenced gender inequity in TB cases [21][22][23][24]. In this study, noti ed TB cases were predominated by men during the study period (Table 1) in almost all age categories across the years (Fig. 3). However, the share of men by 2017 (54.7%) was lower than the WHO 2018 report for the globe (64%) and for Kenya (67.1%) [21]. Similarly, the M:F ratio for noti cation by 2017 (1.2), was lower than WHO 2018 report for the global (1.7) and for African and Asian countries (2.7) [21]. Although there is need for further study, this could indicate women in the refugee camps may be accessing TB services at better level than in the general population in Kenya.
It is not well de ned whether the high TB burden in men is due to gender-speci c sociocultural factors in uencing TB exposure and/or access to healthcare, or due to biological reasons that women are less susceptible to TB infection and reactivation [25][26][27][28]. However, studies showed that women are less likely than men to report or show evidence of typical symptoms of pulmonary TB [29,30]. Hence, the lower case noti cation for women in the refugee camps (despite that > 70% of refugees are women and children) emphasize the need of special TB case detection and diagnosis targeting women.
TB affects all age groups. People in the age group 25 − 24 years in the globe [21] and age groups 25-44 years in Kenya [20] were disproportionately affected by TB. Similarly, the rst and second largest contributors to the total TB cases noti ed across the study period in this study were age groups 15-29 years (31.9%-37.6%) and 30-44 years (21.0%-25.8%) ( Table 1). Therefore, since people in the age group 15-44 years is of reproductive age and represents an active component of the workforce, TB programs should strengthen interventions and case nding efforts focused on this age group.
Usually, the source of infection for children is an infectious adult mainly in the household. Therefore, paediatric TB has been considered as a sentinel marker for TB transmission [30,31]. In this study, the third higher contributor to the total noti ed TB cases across the study period were children < 15 years (20.3%-25.8%). Nonetheless, the contribution of childhood TB has increased by 27.1% in four years (2014 to 2017) ( Table 1). By 2017 therefore, whereas 25.8% of the TB cases in this study were children, only 10% of the estimates TB incidence in the globe [21], and 9% of all TB cases noti ed in Kenya [20] by 2017 were children. Although overestimation is possible that need further investigation, the increase in childhood TB in the refugee camps could be due to increase in TB transmission, increase in number of children (> 70% of refugees in the region are women and children), introduction of improved diagnostics like Gene Xpert, or improved community mobilization and contact tracing.
It has been a national mandate to test everyone diagnosed with TB for HIV infection. By 2017, HIV testing was performed in 97.1% of the TB patients in the refugee camps, among those 7.4% were HIV positive, which is lower than the 28% TB/HIV co infection in Kenya in 2017 [20]. Moreover, 97.5% of the HIV positive TB patients in the refugee camps in 2017 were on ART. This is higher as compared to the 95% ART coverage for HIV positive TB patients in Kenya in 2017 [20]. Together, results of this study evidenced the strong collaboration between TB and HIV programmes, and collaboration among NTLP and other health care givers in the refugee camps which need to be maintained.
According to WHO global target, at least 90% treatment success rate need to be achieved by 2020 among people on TB treatment in order to end TB by 2035 [21]. Treatment success rate for all TB patients registered in the refugee camps during the study period was higher and stable at 92.6-94.9%. This is higher than the 90% global target of treatment success [20]; than the TB treatment success achieved for new and relapse TB cases in the global (82%) and in Kenya (81%) registered in 2016 [21], for Syrian refugees in Turkish (63.6%) [32], and for Gambella refugees in Ethiopia (74.2%) [31].
Over the study period, there was a decline in percentage of death and not evaluated cases but an increase in treatment failed and LTFU (Table 2). Furthermore, by 2017, the percentage of treatment failed (0.5%), LTFU (2.3%), died (2.2%), and not evaluated (1.6%) in the refugee camps were far lower than death rate (6%), "not evaluated" (4%), and LTFU (5%) for the 2016 cohort of TB cases in Kenya [20]. These unfavorable treatment outcomes can be further improved by enhancing TB recording and reporting system, refresher training, supportive supervision, regular monitoring and evaluation, communication and collaboration health care providers, and by engaging patients and community mobilizers in lost to follow up tracing.
Identify, treat and cure infectious TB patients with smear-positive pulmonary TB is the most effective means of reducing TB transmission in the family and community. In the refugee camps, the percentage of cured patients increased by 49.4% in four years (2014 to 2016) (52.0%), and then decreased by 23.7% in one year (2016 to 2017). This was far lower than the percentage of cured patients (69%) for the 2016 cohort in Kenya [20]. Percentage of cured patients can be increased by improving follow-up sputum smear and culture examination, recording and reporting system, refresher training, and engagement of patients, care giver and communities.
Understanding factors associated with unsuccessful TB treatment outcomes can help to design evidence based intervention and to reduce morbidity and mortality. In this study, the risk of unsuccessful treatment outcomes were age > 15 years (which increased with age), pretreatment weight < 40 Kg, being male, being smear positive PTB (PTB+) and HIV infection as discussed below.
The association of older age with successful treatment outcomes in this study is in support to other reports (33,34]. The possible reasons for the unsuccessful treatment outcomes among older TB patients are higher lost to treatment follow ups rates and deaths [35] and atypical clinical presentations in the elderly which can affect early TB diagnosis leading to increased mortality [36]. We showed also being female was less likely to have unsuccessful treatment outcome compared to male patients (OR = 0.49) ( Table 3) and trend of treatment success was higher for women than for men across the years (Fig. 4B). Other studies also showed gender variation in treatment outcomes [37][38][39]. It is possible, therefore, there may be gender speci c sociocultural factors which in uence response to treatment outcome [38,39]. Although poorly understood and need to be investigated, other biological reasons (gender-speci c pharmacodynamics in particular) could contribute for the observed differences in the treatment outcome [39]. In addition, the fact that women are more likely than men to adhere to full course of treatment could result in better treatment outcomes [39].
Our results that HIV infected patients are more likely to have high probability of unsuccessful treatment outcomes compared with HIV negative TB cases is in line with other reports [40]. This could be due to less adherence of HIV patients to TB treatment due to drug burden or it could be due to less drug absorption related to drug-drug interaction. In summary, our multivariate analysis showed the need for special socioeconomic support and monitoring for patients who are at risk for unsuccessful treatment outcomes who are older age, pretreatment weight < 40 Kg, PTB + and HIV infected.
There are limitations in this study need to be considered Since this study was conducted retrospectively based on secondary data from the TB register in the refugee health facilities, data incompleteness could be an issue. However, maximum effort was done to maintain the data quality standards during data extraction including intensive training to data collectors and supervisors, supervision and data re-entry at the eld, and veri cation during data analysis. In addition, the use of secondary data did not permit us to analyse socioeconomic factors, health system factors and patient related factors that may be associated with unsuccessful treatment outcomes Strength of the study Despite these limitations, we have provided useful information of four year timespan on the performance of TB program (TB case noti cation, pro le, treatment outcomes, factors associated with unsuccessful treatment outcomes) that will help to guide and improve future TB control and prevention efforts in Dadaab and Kakuma refugee camps.

Conclusions
This study has provided evidences which will help to improve TB programs in the refugee camps. There was a decline in the number of noti ed TB cases from 2014-2016 (11.1% decrease) but increased in 2017 (16.9% increase in one year). Case noti cation was predominated by men and age 15-29 years during the study period. There was increased trend in percentages of EPTB, and in contribution of children (< 15 years) to total TB cases and to EPTB. Proportion of bacteriologically con rmed new and relapse pulmonary patients increased overtime. TB treatment success during the study period (92.6%-94.4%) was higher than the global target (90%) and need to be maintained. There was a decreased trend in death and not evaluated treatment outcomes but an increase in LTFU. Special follow up and support is recommended for TB patients who are at risk of unsuccessful treatment (older age, pretreatment weight < 40 Kg, HIV infected). Future study is recommended to investigate the reasons for decreased trend in case noti cation (but increased in 2017), and increased trend in childhood TB and EPTB. Ethics and Scienti c Review Committee (ESRC), Kenya. This study was based on secondary data from the TB register in the refugee camps. Since patient registration number were used to maintain the study participant's con dentiality, written informed consents from the participants were not required due to the anonymous nature of the data.

Consent for publication
Not applicable Availability of data and materials All data generated or analysed during this study are included in this Manuscript

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