Understanding the trend of incidence and mortality of tuberculosis is critical in monitoring the effects of tuberculosis control programmes. Furthermore, it has been suggested that, in addition to the increasing incidence of multidrug resistant TB (MDR-TB), underreporting and under-diagnosis of TB threaten the realization of the 95-95-95 end TB strategy targets [6]. These developments are particularly problematic in remote parts of SSA. Therefore, there is a need for contemporary data on multiple themes on TB in SSA. To address these important gaps, we investigated the incidence of tuberculosis in Nakfa district, the spatio-temporal distribution of cases, and associated factors. Major results include the fact that age-adjusted TB rates in Nakfa district increase from 57.95 per 100,000 populations in 2007 to 91.67 per 100,000 in 2018. Subsequently, a steep decline was observed (38.48 persons per 100,000 in 2020). This outcome is below the WHO estimates. According to this report, the age-adjusted rate (aAR) of TB incidence decreased from 200 per 100,000 in 2000 to 81 in 2021 [11]. A previous population survey that used the sputum smear microscopy method conducted in people <15 years in 2005 reported a crude incidence rate of 83 per 100,000 (95% CI, 41–124 per 100,000 people) and an age and sex adjusted prevalence rate of 50 per 100,000 people [12]. From 2007 to 2021, the highest incidence rates per 100,000 population were recorded in 2017 (AAR= 124.87) in females & in 2018 (AAR=94.06) in males. In the same period of time, the average incidence rate per 100,000 population was lower than in other African countries, including Ethiopia (AAR=108) [13], Burundi (AAR= 27-456) [14], Mozambique (AAR=527.8) [15] and Morocco (AAR=188) [16]. However, the incidence rates were higher than those reported in high-income or middle-income countries such as Japan (AAR= 13.9) and Iran (AAR= 10.88) [17]. The average annual incidence rate of notified cases per 100,000 persons is one of the parameters recommended by the WHO to pilot TB control around the world [4]. In this study, notification rates reported were noted.
Furthermore, our analysis shows that the incidence rate of TB in the Nakfa region increased from 2007 to 2018 (APC = 11.3%) and decreased by -38.5% in subsequent years (2019-2021). However, the average APC in the incidence of tuberculosis was - 6.6% (p-value = 0.199) throughout the study period. This indicates that APC in the incidence of tuberculosis is comparatively stable. A similar finding has been reported in some African countries in the region. In Burundi, the annual change rates of the incidence of PTB were between -32.9% and 5.22% in all clinical types of PTB and ~ -12.2% and 1.1% in TB. The reports further suggest that since 2010, there have been reductions in the incidence of tuberculosis of at least 4% per year in Kenya, Zambia, Ethiopia, Lesotho, Namibia, Tanzania and Zimbabwe [6].
Obviously, the observed increase in APC of TB from 2009-2018 should raise concern. However, it is difficult to untangle the extent to which this increase in TB burden was associated with an enhanced transmission rate or active case finding. This determination is informed by several considerations. First, Eritrea implemented the direct observation treatment short course (DOTS) as the standard care strategy for TB. In subsequent years, Eritrea implemented and subsequently met all WHO Millennium Development Goals (MDG) TB specifications in this period. This included meeting the benchmarks for microscopy laboratory coverage of one to 100,000 persons, one drug susceptibility testing (DST) laboratory, and one culture laboratory to five million persons, extensive training of laboratory technicians on sputum microscopy and sample collection. In the same time frame, physicians and laboratory scientists with degree-level training were posted to the medical facility. Globally, a annual decrease in the incidence of TB was reported [18] with some reports attributed these otherwise marginal declines to modest to minimal or no decreases in the incidence of TB in intermediate and high incidence of TB incidence countries[5, 11]. Reconciling these developments with a rise in the TB transmission in Nakfa district is definitely difficult unless the increase in incidence is attributed to improvements in case detection rates (CDR). In Eritrea, previous reports suggested that CDR was below 70% and that improvements should be within the 1.6 – 5-fold range [12]. Therefore, the achievement of MDG TB specifications in Eritrea should correspond to improvements in CDR and a corresponding increase in the incidence of TB.
The possibility that improvements in CDR may be the principal factor behind the perceived increase in TB is augmented by data on number of sample collected, time and geospatial distribution/or trends. For example, the increase in incidence from 2013-2019 can partly be attributed to a concatenation of programmatic interventions. The significant increase in the number of extra pulmonary TB from 2013 is probably linked to posting of physicians to this facility. Previously, patients were attended to by trained non-physician clinicians (midwives and nurses). The 2016-2018 peak in smear (+) and (-) samples coincides with the introduction of the more sensitive fluorescent microscopy (direct Auramine – Rhodamine (AO) stained smears) and non-routine active case-finding activities involving mobile sputum sample collection from community hospitals, health centers, and local health stations in the district. For comparison, the decrease in cases from 2019-2020 likely reflects the termination of sputum pooling efforts and the impact of COVID 19 restrictions. The drop in CDR due to COVID 19 has been reported elsewhere. In China, comparisons of national TB CDR in February 2020 and February 2019 reported a 20% drop. In India, 75% (mean of 11367 weekly cases) was reported in the three weeks after 22 March [19].
In terms of case distribution, 2017 and 2018 had the highest spread of cases. Importantly, cases in the pre-2018 era were clustered in areas close proximity to Nakfa hospital. Previous studies have described the clustering of TB cases in regions closer proximity to main hospitals [20]. Therefore, the geographically distant low-rate clusters observed in this study likely reflect suboptimal CDR arising from access challenges or other factors. Highlighting this problem, the UNICEF Annual Office Country Report 2020 noted that the rugged topography of Eritrea and the long distances between health facilities and communities may restrict service delivery. This problem is compounded by the seasonal migration of nomadic communities from the lowlands and the highlands. Collectively, these findings indicate that tuberculosis is largely underdiagnosed in remote or difficult-to-reach locations within the Nakfa region.
Other factors pointing to underdiagnosis as a problem include the exclusive reliance (up to 2016) on direct microscopy of unconcentrated sputum smear using the Ziehl Neelsen (ZN) technique. According to some reports, ZN has a highly variable sensitivity (range of 20% to 80%) for PTB [21]. Moreover, much lower sensitivities have been observed for paucibacillary disease (eg, pediatric and HIV-associated TB) [22]. Invariably, poor sensitivity can lead to underdiagnosis or delays in diagnosis and progression to advanced tuberculosis. The large number of additional pulmonary TBs observed in this district highlights this possibility. Research shows that most cases of tuberculosis are not clinically apparent and that evidence of its presence is hard to uncover. However, in late chronic TB in people of advanced age or poor immunity (from HIV / AIDS or malnutrition – privational or non-privational); a continuous growth of the blood may develop and lead to extrapulmonary disease [22].
Programmatic gaps can also lead to failure to detect TB in individuals with limited contact with health facilities or failure to detect the disease because infected individuals are not seeking care (patients may be resorting to options like spiritual healing, traditional medicines, or due to financial and geographical barriers). Confirming some of these concerns, a study based on the GeneXpert MTB/RIF Assay conducted in Zambia uncovered a large undiagnosed and subclinical load of TB cases in adults [23]. Furthermore, recent data from several national TB prevalence surveys found patients with relatively advanced disease (based on chest radiographs) who had not sought care [6]. In Nakfa Hospitals, advanced TB due to late presentation is not uncommon. Overall, it is our position that closing the detection (use of GeneXpert MTB/RIF Assay) and treatment gaps, particularly in remote communities within Eritrea, will have a big impact on tuberculosis. To achieve these objectives, local data will be required. Therefore, research on factors associated with underdiagnosis of tuberculosis in remote communities in Eritrea and incorporation of these findings into national strategic plans for the prevention should be prioritized.
Lastly, our analysis demonstrated that the incidence of tuberculosis in the Nakfa region is higher in patients aged > 45 years of age. In this age band, a higher incidence rate per capita was observed in women. This outcome has been reported in studies that have linked TB transmission and burden to age, gender, race, education level, and lifestyle. According to Kawatsu et al., women are at increased risk of TB infection [24]. Patients older than 65 years presented a faster increase in incidence rates from 2007 to 2017 with an APC of 16.1%. Furthermore, they had a higher annual prevalence rate per 100,000 during the study years. The connection between age and susceptibility has been attributed to a number of factors (Diabetes mellitus (DM), malignancies, immunosuppression, cardiopulmonary disorders, and malnutrition) [25]. Furthermore, the results of treatment in the elderly are usually unfavorable due to their vulnerability to intensified and prolonged therapy [26]. Additional structural determinants of TB epidemiology include physical challenges, poverty levels, smoking, HIV infection, living conditions, and nutritional status [27]. Based on the above observations and similar country reports, the data raise a number of questions pertaining to the health of elderly women (a group neglected by researchers in SSA), in remote regions in Eritrea.
Strength and Limitations
As with any statistical analysis, this study has several important limitations. First, medical records typically suffer from missing data problems, and variables captured can be limiting. Despite this, Nakfa’s hospital records remain a good source of comprehensive TB data in the district. Secondly, the patient addresses captured in the medical records corresponded to where the patients lived at the time of diagnosis. However, a significant number of people in this district are seminomadic pastoralists. Thus, some residential addresses may not reflect the locations where infection occurred. This notwithstanding, concerns about the potential effects this phenomenon should not be over-played. Last but not least, sputum smear microscopy remains the primary diagnostic tool in this setting. However, research has shown that this technique is associated with underdiagnosis and underestimation of TB.