Background
Brucellosis is a widespread zoonotic disease regarded as an emerging and re-emerging threat to public and veterinary health worldwide [
1]. Developing nations are often disproportionately afflicted resulting in significant economic losses while at the same time exacting a heavy toll on the health of populations [
2,
3]. Regions most heavily burdened by the disease include countries of the Mediterranean, Central Asia, Middle East, Latin America, Sub-Saharan African and Balkan Peninsula [
4]. The causative agents of the disease are a group of pathogenic bacteria in the genus
Brucella, which primarily infect animal reservoirs. The primary agents of infection in humans are
B. abortus (cattle),
B. melitensis (sheep and goats),
B. suis (swine), and
B. canis (dogs) [
5]. Humans are often secondarily infected through the consumption of unpasteurized dairy products or coming into contact with infected material during animal husbandry or meat processing [
1].
Clinical signs and symptoms of the disease are usually acute and nonspecific, often mimicking other illnesses [
6]. Common reported symptoms include fever, malaise, fatigue, sweats, chills, weight loss, and myalgia [
7,
8]. In some circumstances brucellosis infections can develop into a chronic form, which consists of the continuation of symptoms for greater than twelve months after a diagnosis [
7,
9]. Despite the reduction or elimination of the disease in many countries through vaccination efforts or increased food safety standards it is estimated that there are nearly 500,000 new cases of the disease each year worldwide [
10].
The disease was first diagnosed in Azerbaijan in 1922 and quickly established itself, spreading to more than two thirds of the country’s districts in less than thirty years [
11]. Recent governmental changes brought on by the collapse of the Soviet Union in 1991 have likely contributed to the persistence of the disease during the last two decades, due to decreased funding for surveillance and eradication programs [
4,
12]. Out of the sixty two countries identified as having the highest national incidence of brucellosis, Azerbaijan currently ranks thirteenth with an estimated annual incidence through the year 2000 at over 50 cases per million [
4].
Despite the current status of human brucellosis in Azerbaijan, there have been no known published efforts to map and describe the occurrence of the disease at a local level. In order to better understand the spatial and temporal distribution of human brucellosis in Azerbaijan, geospatial analytical techniques and a geographic information system (GIS) were employed. Previous studies using spatio-temporal methods to investigate the distribution of health events have been successful in uncovering factors related to the occurrence of disease [
13,
14]. Research on brucellosis incorporating spatial analyses identified areas of high human case reporting associated with specific ethnic populations and the consumption of unpasteurized food products in California [
6] and Germany [
15].
There were three primary objectives of this study: 1) to describe the spatial and temporal distribution of human brucellosis in Azerbaijan; 2) identify the potential presence of clusters of the disease in space and time; and 3) identify epidemiological characteristics of individuals that were diagnosed with an infection.
Discussion
This study represents the first attempts to map and describe local (district level) patterns of human brucellosis in Azerbaijan. We used GIS in conjunction with spatial and temporal analytical methods to analyze patterns of cumulative incidence at the district level in Azerbaijan finding evidence of clustering in both space and time. Additionally, our analyzes confirm that human brucellosis persists annually throughout much of the country, particularly the central region. These current analyses affirm the notion that brucellosis has become endemically established since the first documented reporting in the 1920s.
The results of this study indicated variation in the spatial and temporal distribution of brucellosis reporting in Azerbaijan. Spatial clusters of cumulative incidence were identified in each time period indicating localized areas of high case reporting with clusters predominant in the west early in the study during period 1 and then in the east during periods 2 and 3. Temporal clustering was higher during period 1, but persisted across periods 2 and 3. The median reporting of cases during the study period exceeded 500 cases annually with approximately 65% of districts reporting at least one case every year during the study period, suggesting the possibility of local (district level) persistence. The number of reported cases most likely represents a significant underestimation of the actual disease burden across the country as human brucellosis is often misdiagnosed or is unreported [
21]. Additionally, traditional serological tests, like Rose Bengal can have relatively low sensitivity [
22]. In Azerbaijan, these issues are likely confounded by the underutilization of the nation’s healthcare facilities [
23].
The temporal distribution of cases showed that there was a greater proportion of brucellosis reporting during period 1(1995 to 1999). Temporal clusters identified by the EMM test also indicated a greater number of significant temporal clusters during period 1, which further corroborated that a larger proportion of cases occurring earlier in the study period. Transformations in the funding and organization of public health management and surveillance during the transitional phase to independence have likely contributed to the elevated reporting of the disease in Azerbaijan during this period [
23]. However, temporal clustering also suggests that the disease persisted through the more contemporary time period (period 3). The clusters in this most recent period reflect new areas of increased cases reporting that may not be directly attributed to spillover from the Soviet period. This highlights the need for continued surveillance, particularly in those districts identified.
The seasonality of brucellosis can often be attributed to the seasonal birthing of small ruminants (goats and sheep) [
24,
25]. A recent study in Greece indicated that human cases were directly related to the parturition of small ruminants [
26]. In Azerbaijan the birthing of small ruminants occurs in early spring and is often demarcated by an increase in the incidence of livestock brucellosis [
11]. Reporting of brucellosis in this study shows a concordance with the spring/summer birthing of small ruminants, with a greater number of cases reported during the summer and spring months (March - August) with a peak in reporting in July. Similar findings related to the seasonality of the disease were also reported in Uzbekistan and Italy [
27,
28].
As brucellosis is not a contagious disease, spatial clusters of human cases are most likely a result of shared food sources, animal processing, more intensive agricultural production zones, or similar socio-cultural practices [
6]. Clusters of disease in this case are also most likely indicative of a larger underlying prevalence of the disease in the local livestock population. High-High districts identified by the LISA analysis during the three time periods indicated a potential shift in the pattern of high case reporting as clusters of the disease present in the west during period 1were absent in periods 2 and 3. Spatial differences in the reporting of brucellosis over time may be a result of changes in agricultural production, with steep declines in production noted during the period 1991 through 1996 followed by efforts to gradually restore sustained agricultural output [
29]. These changes have resulted in the subsequent spatial restructuring of agricultural production brought on by the abandonment of government controlled collective farms and animal processing facilities post-collapse of the Soviet Union [
30]. Decollectivization marked a shift towards privatization of animals and farms beginning in 1996 [
31] resulting in decreased control of veterinary health management policies [
22,
32]. This has consequently allowed for eased restrictions on the location of agricultural operations as well as trans-boundary movements and production of animals throughout the country [
11]. The move towards a more privatized market has fueled expansion around larger cities particularly in the east around the capital Baku [
31]. Additionally, the conflict with Armenia, which shares a border with the west of the country has resulted in the displacement of nearly 500,000 Azerbaijani citizens, the occupation of ~20% of Azerbaijan’s land, migration of human and animal populations, and the absence of sanitary-veterinary surveillance; further exacerbating diminished control efforts.
The gender and age distribution of reported cases indicated a higher burden of disease in males (71.8%) compared to females in all age groups. The disproportionate infection rates in males can possibly attributed to differences in the traditional gender roles of men and women in this region. In Azerbaijan, men tend to take on the responsibility of the handling and slaughter of animals in addition to increased occupational hazards such as sheep herding or working in abattoirs [
11]. The reporting among age groups showed that individuals age 20 to 29 accounted for the highest percentage of cases (43%) across all age groups and genders, which may reflect on the types of work that are available for individuals in this age group. These finding on the age and gender distribution of cases in Azerbaijan were very similar to those of the neighboring Republic of Georgia [
33]. The increased burden of disease in males within the Caucuses is not seen everywhere. For example, in Kampala, Uganda case reporting indicated women represent a higher proportion of brucellosis seropositives [
34] whereas in Germany there were equal proportions of reporting between gender groups [
15]. Gender differences in case reporting between places may be due to variation in exposures related to occupation or cultural practices such as food preparation. Additionally, there is potential reporting bias between places due to the insidious nature of the disease as well as the utilization and access to healthcare. In Azerbaijan gender differences in the utilization of healthcare facilities may be a source of bias in the reporting of cases. Clark et al. [
23] showed that men have a greater tendency not to use healthcare facilities in rural areas when compared to women. However, reporting bias related to occupational exposures are more likely to be biased towards males potentially skewing the case reporting.
The gender and age distribution of cases suggests that food-borne illness may not be the predominant means of transmission for the disease in Azerbaijan. While food-borne illness undoubtedly plays a role in the high incidence of the disease, the male dominated patterns of reporting and skewed age distribution point to high levels of occupational exposure related to transmission of the pathogen. Yet, despite the potential occupational burden of the disease efforts also need to be focused on reducing food-borne transmission as previous research has found that the epidemiology of human brucellosis in some areas can potentially shift away from a disease of those who directly handle animals to a food-borne illness [
8]. Several intervention strategies to reduce the burden of brucellosis among human populations have been suggested including: increasing local knowledge of proper food handling techniques of dairy products such as pasteurization [
35], decreasing occupational exposures, and vaccination programs aimed at reducing the prevalence of disease in livestock [
36]. However, Havaas et al. [
37] noted that changing cultural and social behaviors in areas of the Trans-Caucasus region would most likely prove to be difficult and control efforts aimed at vaccinating livestock have been shown to be the most effective [
35].
Limitations
The data presented here were taken from historical records that most likely represent an under reporting of the disease. Analyzing cases obtained from government health care facilities may have introduced biased since individuals in more rural areas may not readily have access to care. Additionally, those individuals in a lower socio-economic strata (SES) may not be able to afford care, medication, or travel to government facilities. These populations within rural areas in a low SES are also more likely to participate in an agricultural related occupation, which may thereby have resulted in underreporting of the burden of disease in this study. Since the onset of brucellosis is often insidious the time of diagnosis was used as the date of infection rather than the onset of the disease. Furthermore, cases obtained from healthcare facilities may not be representative of the general population. This may have skewed the monthly reporting of cases since the incubation period can be greater > 1 month and an individual may not immediately seek care [
7]. However, most cases occurred during the spring and summer months and most likely did not dramatically impact cumulative or yearly incidence risk estimates.
There are also limitations to the sensitivity of serological tests for brucellosis and no data were available on the percentage of human cases that were confirmed on bacterial culture, the gold standard for Brucella species. Spatial analyses were limited to district level reporting and may not reflect localized areas of infection inside of a given district. The age of individuals also could not be tied back to their district of origin and so no adjustments were made. While it was hypothesized that food was not the main source of infection in Azerbaijan there were limited epidemiological data associated with cases in this study and the data do not provide a definitive link to occupational exposure. Furthermore, the dummy regions created to improve the synthesis of reporting for the results do not represent or delineate national recognizable zones.
Competing interests
The authors declare that they have no competing interests.
Authors’ contribution
ITK and JKB designed the experiments. RA, RI, NU, AT, ITK constructed the historical GIS data sets. ITK, JKB, RA performed the spatial analysis. ITK performed the spatio-temporal analysis. ITK, JKB, RA, RI drafted the manuscript. All authors read the final draft of the manuscript. RA and ITK contributed equally to this work. All authors read and approved the final manuscript.