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 Table of Contents  
ARTICLE
Year : 2012  |  Volume : 1  |  Issue : 1  |  Page : 29-33

Time series cross-correlation analysis of HIV seropositivity and pulmonary tuberculosis among migrants entering Kuwait


1 Department of Community Medicine and Behavioural Sciences, Faculty of Medicine, University, P.O. Box 24923, Safat 13110, Kuwait
2 Ports and Borders Health Division, Ministry of Health, P.O. Box 32830, Rumaithiya 25410, Kuwait

Date of Web Publication28-Feb-2017

Correspondence Address:
Saeed Akhtar
Department of Community Medicine and Behavioural Sciences, Faculty of Medicine, Kuwait University, P.O. Box 24923, Safat 13110
Kuwait
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Source of Support: None, Conflict of Interest: None


DOI: 10.1016/j.ijmyco.2012.01.005

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  Abstract 


Background: There is a paucity of published data on burden and pattern of dual infection with Mycobacterium tuberculosis and HIV among migrants from South Asia, South-east Asia and sub-Saharan Africa entering the Middle-East, particularly Kuwait. Therefore, this study assessed the overall prevalence of HIV infection and pulmonary tuberculosis (TB) and evaluated the ecological relationship between them.
Methods: Time series cross-correlation analysis was used to determine the ecological time-lagged relationship between the monthly proportions (per 100,000) of HIV seropositive and pulmonary TB cases among migrant workers that entered Kuwait between January 1, 1997 and December 31, 2006.
Results: During the study period, overall prevalence (per 100,000) of HIV seropositivity and pulmonary TB among the migrants was 21 (494/23,28,582) (95% CI: 19–23), and 198 (4608/23,28,582) (95% CI: 192–204), respectively. Estimated cross-correlation function revealed a significant positive correlation (0.292±0.093) at lag −3 representing a positive relationship between the proportions of HIV seropositive (per 100,000) migrants tested 3 months earlier and the proportion of pulmonary TB (per 100,000) cases detected among migrants in a given month. Thus, the peak in proportion of pulmonary TB cases preceded the peak in proportion of HIV seropositive migrants indicating a direct time-lagged association between HIV seropositivity and the prevalence of pulmonary TB among migrants.
Conclusions: HIV infection seemed to have played a significant role in the re-activation of latent M. tuberculosis infection in this migrant population. While currently less evident, in near future, however, TB and HIV/AIDS control programmes in the countries of origin of migrants may face a crucial challenge. Knowledge of serious consequences of association between HIV infection and pulmonary TB allows the promotion of public heath education to reduce the exposure to these infections. Future studies may focus on evaluating the impact of public health education programs on this dual burden of HIV infection and pulmonary TB in migrants.

Keywords: HIV, Pulmonary tuberculosis, Cross-correlation, Migrants, Kuwait


How to cite this article:
Akhtar S, Mohammad HG. Time series cross-correlation analysis of HIV seropositivity and pulmonary tuberculosis among migrants entering Kuwait. Int J Mycobacteriol 2012;1:29-33

How to cite this URL:
Akhtar S, Mohammad HG. Time series cross-correlation analysis of HIV seropositivity and pulmonary tuberculosis among migrants entering Kuwait. Int J Mycobacteriol [serial online] 2012 [cited 2019 Jul 22];1:29-33. Available from: http://www.ijmyco.org/text.asp?2012/1/1/29/201195




  Introduction Top


Currently, tuberculosis (TB) is a leading cause of morbidity and mortality among HIV/AIDS patients worldwide [1],[2]. Globally, at least one third of the 39.5 million people estimated to be living with HIV are likely to be infected with Mycobacterium tuberculosis [2]. Co-infection with M. tuberculosis and HIV can lead to increased difficulties in TB diagnosis, an increased frequency of treatment and side effects, and an increased incidence of relapse and re-infection. HIV and M. tuberculosis have a synergistic interaction; each accentuates the progression of the other. The immunosuppression associated with HIV infection is a strong risk factor for the progression of latent infection with M. tuberculosis to active TB and enhanced susceptibility to new infection [3],[4],[5]. The estimated proportion of HIV-attributable TB cases has increased worldwide from 4.2% in 1990 to 13.8% in 2000 [4]. Indeed, the epidemic of HIV infection has had a substantial impact on the diffusion, clinical presentation and management of, and public health issues relevant to TB [5].

Every year, 630,000 new TB cases and 136,000 TB-related deaths occur in the Eastern Mediterranean Region of the World Health Organization. HIV is the most significant risk factor for progression from subclinical infection with M. tuberculosis to active TB. Although the HIV/AIDS threat in the region appears to be relatively modest, so far there has been no evidence of an impact of HIV on TB epidemiology in the region. However, the need for the assessment of the double burden of HIV/AIDS and TB in the region has been indicated [6]. Kuwait has a relatively low incidence of TB with an annual notification rate of 24 active TB cases per 100,000 of the population [7]. Resident non-nationals account for about 75% of these active TB cases per year [7],[8], and nearly 1% of these are identified as multidrug-resistant TB cases [9].

Migrants from countries with a high prevalence of TB and HIV/AIDS, notably from South Asia, South-east Asia and sub-Saharan Africa, bear a disproportionate and increasing share of infection with M. tuberculosis and HIV throughout Western Europe [10]. However, there is a paucity of published data on burden and pattern of dual infection with M. tuberculosis and HIV among migrants from these regions entering the Middle East, particularly Kuwait. Here, the opportunity presented itself for this study to take advantage of the routine screening of migrant workers for pulmonary TB and HIV infection upon arrival in Kuwait from areas with high TB and HIV infection by performing the first large-scale quantification of the ecological relationship between HIV infection and pulmonary TB status of this work population. The specific objective of this study was to evaluate the ecological relationship between HIV seropositivity and pulmonary TB among migrant workers monthly over the period 1997–2006 using time-series cross-correlation analysis.


  Methods Top


Setting and study population

Study setting, population and methods of data collection have been reported previously [11],[12] and briefly outlined here. Migrants constitute about 80% of the labor force in Kuwait, and the majority of them usually are less educated. These migrants originate from TB, high-burden countries predominantly from countries of Southeast Asia, Eastern Mediterranean and African regions wherein prevalence (per 100,000) of TB ranges from 152 to 547 [13]. Similarly, with regard to HIV-infected cases, countries of South and Southeast Asia (7.5 million) are second only to sub-Saharan Africa (25.8 million) [14]. There is a large turnover of these workers; every year thousands of them leave and new ones arrive in Kuwait. Of the migrants, 46% are 20–44 years old and predominantly reside as single, mainly because of their inability to fulfil a legal requirement of minimum wages to be able to bring their families [11],[15]. Health services are free for all citizens and residents in Kuwait. In the public sector, the health-care system is made up of six administratively independent health-care sites; each comprises a general hospital, a health center, specialized clinics and dispensaries [16].

Data source

Monthly aggregates of test results for diagnosis of pulmonary TB and HIV infection among migrants who entered Kuwait between January 1, 1997 and December 31, 2006 were made available for this study. These migrants predominantly come from India (31%), Bangladesh (14%), Sri Lanka (14%), Egypt (12%), Indonesia (9%), Philippine (5%), Pakistan (5%) and the remaining 10% from other countries, including those from African countries such as Tanzania, Mali, Gambia, and Sudan [17],[18]. Routine consensual medical examination procedures were conducted on these workers upon their arrival by the Ports and Borders Health Division of the Ministry of Health, Kuwait.

Diagnosis of pulmonary TB and HIV infection

For the diagnosis of TB, migrants were screened by the serial application of various tests. For each migrant a chest radiograph was taken. In the presence of any suspicious lesion in the lungs, confirmatory TB diagnosis was made by sputum smear examination for acid-fast bacilli (AFB) using Ziehl–Neelsen technique and bacterial culture. Subsequently, the migrant worker was classified as a case of TB if the sputum smear and/or bacterial culture were positive for AFB. For the diagnosis of HIV infection, serum samples were tested in the Virology Laboratory of the Department of Public Health using commercially available third generation enzyme-linked immunosorbent assay (ELISA) kits (Abbott). All the ELISA positive samples were further confirmed by Western blot analysis (Bio-Rad test) [19].

Ethics

As noted above, upon arrival to Kuwait, migrants were screened for various infections, including M. tuberculosis and HIV, before issuance of a residency permit. Verbal consent was solicited after fully informing each migrant about the purpose of screening. These procedures were performed according to a stated governmental policy. The study protocol was approved by the Ethics Review Committee of Faculty of Medicine, Kuwait University.

Statistical methods

The monthly aggregates of the daily number of migrants tested, the number of pulmonary TB cases detected and the number of migrants with HIV seropositive results were used to generate the monthly series of proportions of pulmonary TB cases (per 100,000) and HIV seropositive (per 100,000) migrants over a period of 120 months, from January 1, 1997 to December 31, 2006. These monthly proportions (per 100,000) of pulmonary TB cases and HIV seropositive migrants were used in this study for all further analyses unless stated otherwise. Overall prevalence (per 100,000) of TB cases and HIV seropositivity along with their 95% confidence intervals (CI) were calculated.

Cross-correlation analysis

Cross-correlation analysis generates a series of correlation coefficients between two time series by overlaying and temporally shifting the two series over a range of successive time lags [20]. This allows the determination of the time lag that maximizes the strength of the correlation between the two time series. However, estimates of successive cross-correlation coefficients of any two time series exhibiting seasonality and/or trend may be spuriously correlated even if the series inherently are un-correlated. In order to overcome this problem, pre-whitening was performed by filtering both series to obtain two series of independently identically distributed random variables. Therefore, both the series were decomposed to adjust for the seasonal and trend components prior to cross-correlation analysis. Seasonal adjustment of the series was accomplished using the moving average smoothing method by applying a 13-point (months) moving average filter. Subsequently, series were de-trended by differencing the series at level 1. Based on the known biological relationship of HIV and TB, seven positive and seven negative lags in cross-correlation function were chosen [21]. Statistical significance was defined as a correlation coefficient greater than twice the standard error. The standard errors for correlation coefficients were calculated on the assumption that the series are un-correlated and that one of the series is white noise.


  Results Top


Descriptive statistics

During the 10-year study period, overall HIV seroprevalence (100,000) was 21 (494/23, 28, 582) (95% CI: 19–23). Also, overall prevalence (per 100,000) of pulmonary TB cases detected among the migrant workers during the same study period was 198 (4608/23, 28, 582) (95% CI: 192–204). The time-series characteristics of HIV and pulmonary TB data have been previously described and are briefly outlined here. During the entire study period, the proportions of detected pulmonary TB cases among migrants exhibited seasonality, showing a peak in the third week of April each year. Furthermore, these proportions of pulmonary TB cases showed a nonlinear trend with an initial significant decline followed by a slight but significant increase towards the end of the study period. HIV time series data depicted a significant periodicity of 3 months' duration (see [Figure 1]). However, seasonal and trend components in the HIV seropositive proportions were statistically non-significant.
Figure 1: Monthly proportions of HIV seropositive (a: observed; b: transformed) and pulmonary tuberculosis (c: observed; d: transformed) cases among migrants entering Kuwait: 1997–2006.

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Cross-correlation analysis

Estimated cross-correlation function revealed a significant positive correlation (0.292±0.093) at lag −3 and a significant negative correlation (−0.217±0.092) at lag −2. Since each lag represents a difference of 1 month, thus a significant cross-correlation at a lag −3 represents the positive relationship between the proportions of HIV seropositive (per 100,000) migrants tested 3 months earlier and the proportion of pulmonary TB (per 100,000) cases detected among migrants in a given month (see [Table 1] and [Figure 2]). This indicates that a peak in proportion of pulmonary TB cases preceded the peak in proportion of HIV seropositive migrants.
Table 1: Cross-correlations between proportions (per 100,000) of HIV seropositive and pulmonary tuberculosis cases among migrant workers entering Kuwait: 1997–2006.

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Figure 2: Cross-correlation function of the time-series of proportions of HIV positive and pulmonary tuberculosis cases among migrants entering Kuwait: 1997–2006.

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  Discussion Top


During the 10-year study period, the overall proportion of migrant workers diagnosed as HIV seropositive was 21 per 100,000 and the overall proportion of pulmonary TB cases detected among these workers was 198 per 100,000. To establish whether an ecological relationship exists between these two variables observed over time, the sample cross-correlation function was computed between the values of the bivariate process. The time-series cross-correlation between the proportions of HIV seropositive and pulmonary TB cases among migrant workers entering Kuwait displayed significant coefficients at lag −2 and lag −3 months (see [Table 1]). Cross-correlation function displayed no statistically significant correlation coefficient for any of the positive lags. The peak in the proportion of TB cases was achieved at a lag of −3 months. It would be reasonable to postulate that the identified 3-month lag may be an average time length required for TB to develop to a stage detectable by the routine diagnostic work-up in this migrant population who mostly originated from South Asia and the South-east Asian region wherein 40–70% of HIV infected people have M. tuberculosis infection [22]. Highly significant positive cross-correlation between HIV seropositivity and pulmonary TB case status at lag −3 supports the known role of HIV infection in accelerating the natural history of latent TB with progression from infection to disease occurring within 3 months [23]. As noted earlier, HIV infection is now considered the most potent risk factor for TB; it not only increases the risk of reactivating latent M. tuberculosis infections, but also leads to the rapid progression of clinical TB soon after natural infection. The pathogenesis of both M. tuberculosis infection and the disease relates directly to cell-mediated immunity (CMI), especially CD4+ T-lymphocytes. Concurrent HIV infection induces CD4+ T-lymphocyte depletion, which leads to defective immunological response to M. tuberculosis. The pathogenesis of TB can be altered by HIV infection either through reactivation of latent M. tuberculosis infection to active disease (more common), or by causing rapid progression from recent infection with M. tuberculosis to active TB. With the progress of HIV infection, CD4+ T-lymphocytes decline in number and function, and the immune system is therefore less able to prevent the growth and local spread of M. tuberculosis [23],[24].

A significant negative correlation coefficient at lag −2 showing inverse relationship between the proportions of HIV seropositive and pulmonary TB cases is not readily explained by the current concept of relationship/co-infection by HIV and M. tuberculosis. However, based on contemporary literature, some probable explanations for such an inverse relationship between HIV seropositivity and proportion of TB cases among migrants at lag −2 may be suggested, as the presentation of pulmonary TB among HIV-infected individuals depends on the degree and stage of immunosuppression. Therefore, diagnosis of TB in HIV-positive patients is difficult for several reasons: (i) frequently negative sputum; (ii) atypical chest radiographic; (iii) higher prevalence of extra-pulmonary TB, especially at inaccessible sites; and (iv) resemblance to other opportunistic pulmonary infections [22],[25].

Limitations of the study

Some limitations of this study need to be considered while interpreting the results. First, constrained by its ecological design, this study could not measure the causal link between HIV infection and TB status of migrants, since it is unknown, in particular, whether the individuals infected with HIV are the ones who eventually developed TB. Secondly, the inaccessibility to demographic data, including individual-level identification of country of origin of migrants and specific location within the country precluded the control of confounding owing to these variables. Finally, some of the migrants may be at an early phase of infection with HIV and/or development of TB, but could not be identified by the current laboratory investigations thus biasing the magnitude of proportions of HIV seropositive and/or TB cases among migrants.


  Conclusions Top


Notwithstanding the aforementioned limitations, significant time-lagged association in this study flags a plausible potential role of HIV infection in TB burden in this migrant population, and these findings corroborate those reported from elsewhere [26],[27]. In particular, HIV infection seemed to have played a significant role in the re-activation of latent infection with M. tuberculosis in this population. This positive linear relationship between the proportions of HIV seropositive and TB cases among migrants demonstrates that the rapid spread of HIV may lead to an increasing burden of TB as suggested previously [28]. The increasing burden of co-infection with HIV and M. tuberculosis is a crucial issue for public health authorities in the countries of origin of these migrants, which needs to be addressed and made a priority. At present, the overall impact of these co-infections in the region is not yet considerably evident. However, TB and HIV/AIDS control programs in these high burden countries may face a significant challenge in the near future unless concerted efforts are made to reach the vulnerable and socially marginalized populations most at risk. Knowledge of association between HIV infection and TB and the grave consequences thereof allows the promotion of public health education to reduce the exposure to these infections. The final conclusion of specific significance to public health authorities in Kuwait and perhaps other Gulf countries is that there is a need to maintain the current policy of entry screening augmented with more sensitive protocol following improved therapeutic management of detected cases. Future studies may focus on monitoring this dual burden by recording the individual-level status on HIV and TB in migrants and evaluating the impact of the public health education program.


  Authors' contributions Top


Saeed Akhtar conceived, designed, analyzed, interpreted the data and drafted the manuscript. Hameed Mohammad supervised the data collection and reviewed the manuscript. Both the authors have read and approved the final manuscript.


  Acknowledgements Top


Funding source: The study was funded by the Kuwait University Research Administration Grant No. MC 01/05.

Ethical approval: The study protocol was approved by the Ethics Review Committee of Faculty of Medicine, Kuwait University.

Conflict of interest: The authors have no conflicts of interest to declare.



 
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