_______________________________________________________________________________
An Account of Latent Tuberculosis - Prevalence in Immigrants
from High Incidence Countries and Determining Factors of the
Screening to Treatment Cascade
By: Johan Änghagen Fasth
Advisor: Dr Jakob Paues, Dr Karin Sundelin
Date:
2018-01-08
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REGISTER ... 2 POPULÄRVETENSKAPLIG SAMMANFATTNING ... 3 ABSTRACT ... 3 BACKGROUND ... 4 TUBERCULOSIS ... 4 THE TUBERCULOSIS EPIDEMIC ... 4 THE END TBSTRATEGY ... 5LATENT TUBERCULOSIS INFECTION ... 5
TB AND PREVENTIVE INTERVENTIONS IN LOW-BURDEN COUNTRIES ... 7
TUBERCULOSIS IN SWEDEN ... 8
OBJECTIVES ... 9
METHOD ... 9
STUDY DESIGN AND THE POPULATION ... 9
GATHERING OF DATA AND CATEGORISATION OF THE POPULATION ... 9
TREATMENT AND ESTIMATING PREVALENCE OF LATENT TUBERCULOSIS INFECTION ... 10
STATISTICAL ANALYSES ... 10
ETHICAL APPROVAL AND INTEGRITY ... 11
RESULTS ... 11
THE POPULATION AND PREVALENCE OF LTBI ... 11
TREATMENT AND DETERMINING FACTORS OF INITIATION ... 13
DISCUSSION ... 15
PREVALENCE OF LTBI ... 15
TREATMENT OF LTBI ... 16
IDENTIFYING HIGH RISK GROUPS,FAULTS IN THE SCREENING PROGRAM AND ADDITIONAL RESEARCH ... 18
CONCLUSION ... 19
ACKNOWLEDGEMENTS ... 19
Populärvetenskaplig sammanfattning
Tuberkulos är en sjukdom som orsakas av bakterien Mycobacterium Tuberculosis. Sjukdomen sprids genom luften från upphostningar av en sjuk person.
En tredjedel av världens befolkning är smittade och tuberkulos är en av de 10 vanligaste dödsorsakerna i världen. Bördan av tuberkulos är ojämnt fördelad där nära 90 % av de drabbade endast kommer från 30 länder.
I Sverige, som är ett land med låg sjukdomsbörda, fokuserar arbetet med att motverka
tuberkulos på att nå särskilt utsatta grupper (som t.ex. invandrare från länder med hög börda) och om möjligt förebygga tuberkulos genom att behandla latent tuberkulos. Latent tuberkulos är ett tillstånd då en person är smittad av Mycobacterium Tuberculosis men inte har några symtom. Tillståndet riskerar dock att reaktiveras till aktiv sjukdom senare i livet.
Syftet med den här studien var att utvärdera programmet för screening av latent tuberkulos hos asylsökande i Östergötlands län. Studien har tittat närmare på alla de patienter som screenats positivt för latent tuberkulos med fokus på att dels kartlägga gruppen av patienter rörande ursprungsland, ålder, kön m.m. och dels undersöka hur många som har behandlats, vilken
behandling som har valts, vilka faktorer som påverkar beslutet att behandla latent tuberkulos och hur många/vilka som eventuellt har utvecklat aktiv sjukdom.
Särskilt utsatta visade sig patienter från Afrikas horn vara och den viktigaste anledningen att starta behandling var låg ålder.
Abstract
Tuberculosis is a major reason for disease and death in the world. The WHO estimates that one third of the world’s population is infected by Mycobacterium Tuberculosis and ending the tuberculosis endemic is one of their sustainable development goals. There is an epidemiological difference between countries of high tuberculosis burden and low tuberculosis burden. Therefore the strategy to fight tuberculosis must be customised to each local setting. In countries of low burden a pivotal part of the strategy is preventing active disease by treating latent tuberculosis infection and in Sweden, migrants from high burden countries represent the majority of the cases of latent tuberculosis. This is a retrospective study aiming to gather descriptive data about
registered migrants, evaluate the screening program for latent tuberculosis and to specify determining factors of initiation of preventive treatment and it is based on data from several sections of the Swedish Migration Agency and the health care system and information was
gathered from medical records. Three countries (Somalia, Ethiopia and Eritrea) were identified as high burden and low age was identified as being the most influential factor concerning treatment initiation.
Background
Tuberculosis
Tuberculosis (TB) is a disease caused by Mycobacterium Tuberculosis (Mtb, which is an intracellular microbe that is most commonly known for causing granulomatous disease in the lungs. However, it can infect other organs and the most common extrapulmopnary sites are lymph nodes and the spinal column (1). If untreated the fatality rate of tuberculosis is over 50% but there is effective treatment available (2). The standard treatment for TB has been the same for several decades and consists of a six month regimen with up to four different drugs, isoniazid, rifampicin, pyrazinamide and ethambutol(3). The global burden of tuberculosis correlates to the distribution of financial assets. Of the world’s new TB cases in 2016, 87% were located in 30 high-burden countries(1) and ending the TB epidemic is one of WHO’s Sustainable Development Goals(4).
The Tuberculosis Epidemic
WHO estimates that about one third of the world’s population is infected by Mtb and that approximately 10.4 million new TB-cases occurred in 2016 Tuberculosis caused the death of about 1.7 million people in 2016, excluding 0,4 million deaths caused by TB in the HIV positive population (4). This makes tuberculosis one of the ten most common causes of death in the world, and this despite the fact that a majority of TB-cases can be cured when treated adequately (1). Many of the factors causing the TB-endemic lack financial, political or social solutions rather than medical. In 2015 the global case-fatality ratio (CFR, TB-deaths/incidence) was 17%, but if all people had the same opportunity to receive adequate diagnosis and treatment the CFR would be low worldwide (1), and the lack of investment in social protection is contributing to the weight of the TB-burden in a number of countries (5). Moreover, there is an increase of cases that are more difficult to treat, such as multi-drug resistant TB (MDR-TB), of which 480 000 new cases were reported in 2015(1).
The WHO has defined three lists of countries suffering from a high TB burden. They differentiate between countries with a solely high TB-burden (high incidence and mortality), countries that suffer from high rates of MDR-TB and countries with high rates of TB in combination with HIV infection(4). Especially afflicted countries and geographical areas according to the WHO are China, India, south east Asia and Africa south of Sahara.
The total number of TB-related deaths fell by 22 % between 2000 and 2015 but the epidemic is still bigger than previously estimated(1) with an incidence >1000 cases/million and year(6). There is also still a gap between reported cases and incidence and between 2013-2015 this gap was estimated to approximately 4,3 million cases(1). Further interventions and preventive work must be made in order to achieve the goals of the End TB Strategy(7).
The End TB Strategy
In 2014 the WHO published their End TB Strategy (ETBS), following up on previous international guidelines like the Stop TB Strategy of 2006 and the Millennium Development goal. The End TB Strategy aims to have reduced TB-deaths by 95%, the incidence rate by 90% and suffering due to economic struggles associated with TB by 100% by 2035. This is to be achieved by working towards a number of large and small-scale goals. Milestone goals in the ETBS include a 75% decline of TB-deaths and a 50% decline of the incidence-rate by 2025. To achieve these goals the rate of decline for both incidence and mortality must approve. In 2015 the global trend showed an incidence decline rate of 1.5% per year. If the milestone of a 50% decline by 2025 is to be reached the decline rate must increase to 10% per year.
The ETBS divides the necessary changes in three pillars. The first pillar focuses on care and prevention of TB and consists of four important key actions. These are (A) early diagnosis of TB and screening of high-risk groups, (B) treatment of all patients with active TB, (C) preventive treatment for high-risk persons with latent tuberculosis infection and vaccination and finally (D) management of co-morbidities with a special focus on individuals with both TB and HIV-infection. The second pillar concerns the supportive systems in relation to TB care and stresses the importance of adequate resources being put aside for the issue at hand, engagement from all parts of society from political to small scale care providers and interventions to elevate socio-economic inequities. It also states the importance of a universal health coverage policy
concerning TB, including case notification and registration. The third pillar regards research and innovation related to TB care. It describes, in addition to intensified medical discoveries, the importance of optimization of the implementation of new research and the need of strategies to detect and treat latent tuberculosis infection (7).
Latent Tuberculosis Infection
Latent tuberculosis infection (LTBI) is a state a person is in when infected with Mtb but lacking evidence of any clinical illness(8). Following inhalation of the microbe an immunologic response takes place. In the majority of cases the response leads to the elimination of the bacteria but in some cases the microbe is immunologically contained instead of eliminated. This containment is dependent on a specific T-cell mediated response, which in turn, through INF-γ, will activate
macrophages and ensure control of the mycobacteria (9). If the control is lost, the mycobacteria can proliferate and cause disease, so called reactivated TB. The lifetime risk of TB reactivation is low, around 10 %, but approximately one third of the world’s population is infected by Mtb and reactivation accounts for a significant part of the new TB cases in the world (10). In a high endemic setting the majority of patients are not due to reactivation of a latent TB but in low incidence countries reactivation accounts for approximately 80% of new cases (11)(12). Thus in low incidence countries, prevention of LTBI reactivation is important to prevent active TB (4). There are several important factors that increase the risk of reactivation. The factors that infer the highest increase of risk are, among others, in falling order AIDS, HIV-infection, organ transplantation, jejunu-ileal by-pass, silicosis, chronic renal disease, treatment with anti-TNF-α haematological malignancy, steroid treatment, illicit alcohol/drug use and diabetes mellitus(13). Children under the age of five also suffer from a higher than average risk of reactivation (12). Smoking also increase the risk as well as having served time in a prison recently(13)(14). Another important factor to consider concerning reactivation is the time since infection. It has been shown that 50% of cases of reactivation occurs within 2 years of first screening positive for LTBI(9). The suggestion has been made that immigrants from high-incidence countries have a higher risk of reactivation (15) but it can be argued that higher than average incidence of active TB in this group depends on a higher prevalence of LTBI (11).
There is no perfect method for detecting LTBI but traditionally a tuberculin skin test (TST) has been used. This is a relatively cheap method that doesn’t require advanced equipment but it can’t differentiate between those with infection and those who have been vaccinated with bacille Calmette-Guérin (BCG). Furthermore it is lacking in specificity concerning non-tuberculous mycobacteria and sensitivity in immune-compromised patients (8)(16). The alternative is the interferon gamma release assay (IGRA). In this method response (release of interferon gamma) from T-cells exposed in vitro to antigen of Mtb is measured. The use fewer and more Mtb specific antigens generates a result of higher specificity compared to the TST (18). Further, specificity is higher due to less cross-reactivity with nontuberculous mycobacteria(18). Studies also suggest that IGRA will be cheaper than TST as a screening tool in a vaccinated population. This is because of the added costs of additional examination due to TSTs lack of specificity (19). Treatment of LTBI aims to reduce the risk of reactivation. Since this requires long regimens of antibiotics and drug-resistance is a major problem in TB care, some important aspects must be considered. There are several possible regimes with different perks and disadvantages. Originally isoniazid was used and studies in the 1950s-60s showed an increasing efficacy for daily
recommended(8). However, later studies showed little or no difference in treatment efficacy between a 6 month or a 12 month regime of isoniazid (20). Preventive treatment with rifampicin is also an option and the most commonly used regime is daily administration for four months. Some studies indicate that shorter treatment regimes with rifampicin relates to equal or lower rates of reactivation, causes less hepatotoxicity and have higher rates of treatment completion than longer regimes with isoniazid (21)(22)(23). Other studies show contradictory results were longer regimes with isoniazid correlates to higher rates of treatment completion(24). Altogether, the field is inconclusive on this issue and there are several different treatment regimes for LTBI is in use today(8)(25)(26).
TB and Preventive Interventions in Low-burden Countries
The ETBS emphasizes the importance of a system for care and prevention of tuberculosis that is customised for the epidemiology and healthcare system of every country. Even though there is significant variation between different low-burden countries some characteristics of the
epidemiology include a low transmission rate, a majority of TB-cases within certain high-risk groups and immigrants, and a high percentage of active cases originating from reactivation of LTBI (6)(26).
To optimize TB care and prevention in low-burden countries some adaptations to the ETBS must be made. Since the burden of tuberculosis in society is altogether low there is a risk that the issue could lack in visibility. A consequence could be low commitment from health care system and politicians with potential negative results on LTBI-related care (1,6,27). Efforts must be made to reach vulnerable groups with higher than average risk of disease such as homeless people, illicit drug or alcohol users or those living with HIV/AIDS. The process of customising begins with the definition of the specific vulnerable groups in each local setting(6). Furthermore, the interventions to reach these groups must be tailored to the local environment (27). An
important group that is at high risk in many low-burden countries is migrants. Migration has increased in recent years as a result of the geopolitical situation. Often, the country of origin of the migrant is a high-burden country. Further, the journey itself could expose the person to TB, e.g. refugee camps, prison and crowded living conditions(6). In addition, there are difficulties such as language and social alienation that increases the risk of not completing treatment in some groups of migrants(28). Research must focus on identifying which groups of migrants suffer from a higher risk of TB/LTBI and if there are any relatable variables(6,29).
Low-burden countries should have screening-programs for TB and LTBI in use for high-risk groups. If screening programs for active TB is to be cost-effective it must focus on targeted groups with especially high-risk since large amounts of people need to be tested in order to
identify TB cases in low-burden settings(30). The fact that incidence and transmission rates are low in most low-burden countries and that a majority of new cases of active TB come from reactivation of LTBI suggests that screening of LTBI might be more impactful than screening for active disease with chest X-ray.(31). However, as described above, the risk of reactivation is overall relatively small and side effects, of treatment is significant(21). Therefore LTBI should only be treated after the risk of reactivation has been assessed.
Tuberculosis in Sweden
Sweden is a low-burden country with an estimated TB-incidence of 8,2/100 000, and mortality of 0,25/ 100 000 in 2016 (32). A majority of the world’s low-burden countries experienced a declining incidence of TB in the seconds half of the 20th century. In most of these countries the declining trend has continued during the last 15 years(6). However, this is not the case in Sweden, which reached its lowest incidence around 2000 and has until 2015experienced an increasing trend. In 2015 the highest number (835) of cases so far were diagnosed, which was an increase of over 100% in 12 years(6,33). According to the Public Health Agency of Sweden thes increase is completely relatable to migrants from countries with a high TB burden(33).
The details of how the screening program for migrants is designed vary between the Swedish counties. In Östergötland the way from screening to potential LTBI treatment consists of three parts. When a migrant applies for asylum in Östergötland he or she is registered with the Swedish Migration Agency (SMA). The SMA then notifies the Medical Clinic of Migrants in Östergötland (MCM) of all registered migrants and the latter invites them to a health
examination. If the migrant is from a high burden country (>100 new cases/100 000
persons/years), or because of other reasons is considered to suffer from higher risk of TB, this health examination will include anamnestic questions concerning possible exposure, symptoms of TB, risk factors and comorbidities and an IGRA screening test. If the screening test comes back positive the MCM will order a chest X-ray and refer the patient (using a referral template for TB specifically) to the Department of Infectious Diseases in Östergötland (DID). There, further examination aims to primarily investigate whether the patient has active disease (trough clinical evaluation, X-ray and in some cases sputum sample for smear microscopy/bacterial culture), and secondarily diagnose the patient with LTBI. If the patient is diagnosed with LTBI the DID evaluates risk factors for reactivation and initiates treatment in relevant cases. Factors taken into consideration by the DID is <2 years since probable contagion, age<25, time since arrival in Sweden, previous imprisonment, previous residence in refugee camps, illicit drug use, HIV-infection, treatment with anti-TNF-α, kidney disease and diabetes mellitus.
Objectives
This Study aims to be an evaluation of the clinical practice concerning the screening to treatment cascade of LTBI in Östergötland. The study has two main objectives. Primarily it aims to supply descriptive data about the population of asylum seekers in Östergötland and to calculate an estimate of prevalence of LTBI within groups of migrants from high burden countries.
Secondarily it aims to identify determining factors concerning initiation of treatment of LTBI.
Method
Study Design and the Population
This is a retrospective cohort study focused on the LTBI affected population of migrants in Östergötland county in Sweden between January 2014 and October 2016. LTBI is defined as a state where an individual has a positive screening test (IGRA or tuberculin skin test) and no clinical manifestation of active Tuberculosis. The screening test in use in Östergötland is the IGRA-test QuantiFERON-TB Gold® by Qiagen (QTF).
This study is primarily based on the potential TB/LTBI cases referrals referred from the Medical Clinic for Migrants (MCM) to the Department for Infectious Diseases in Östergötland (DID). The Swedish Migration Agency (SMA) supplied additional data concerning the set of the migrants (categorised by country of origin), which arrived in Östergötland during the studied time period and the Department of Microbiology supplied information about the QTF-analyses ordered by the MCM during the studied period.
In total 678 referrals was sent within the studied time period. The large majority of referrals send from the MCM to the DID concerns either TB or hepatitis and this study was limited to the referrals made using the referral template for Tuberculosis. The purpose of this template is to include all cases concerning TB and due to lack of time this limitation of the material was necessary. The material was further more reduced due to the elimination of duplicates in the original list. Ultimately 432 cases were included in the study.
Gathering of Data and Categorisation of the Population
The county of Östergötland has digitalized medical records, using Cosmic® (Cambio
Healthcare systems) and the medical records of the 432 patients were retrieved from this system and searched for 20 independent variables: age, sex, time in Sweden (until health examination by the MCM), date of health examination, date of referral, date of first visit to the CID,
BCG-vaccination, IGRA, Tuberculin skin test (TST), HIV, chest X-ray (CXR), symptoms associated with active TB, sputum sample for smear microscopy/bacterial culture, initiated LTBI treatment, treatment regime, completion or early termination of LTBI treatment, reason for early
termination of treatment, active TB discovered at contact with the MCM/DID, active TB developed after decision to abstain from LTBI treatment, and relocation out of the county. The data was further analysed in order to examine median age, distribution of sex, vaccination rates, categorised by country of origin, The implementation rates for sputum sample for smear
microscopy/bacterial culture was examined and the proportion of chest X-rays with findings was also calculated. X-ray findings were defined as all referral responses that indicated a difference from normal findings.
Treatment and Estimating Prevalence of Latent Tuberculosis Infection
Prevalence of LTBI in the entire study population was calculated by a comparison of the performed QuantiFERON analyses and those with a positive result.
Prevalence categorised by country of origin could not be calculated this way. Instead the estimation was based on the number of individuals, from each nationality, that applied for asylum in Östergötland during the given time period. The number of patients referred to the DID (with a positive QTF-test and in which active TB was ruled out) was used as an approximation of the number of LTBI-affected individuals during the same time period. In combination these two figures was used to calculate an estimate of the prevalence of LTBI for the main migrating nationalities.
The circumstances concerning treatment of LTBI were also investigated. The complete material of referred patients was examined with focus on treatment initiation, completion, early termination, reason for early termination and regime. A comparison between the usage
frequencies of every treatment regime was made throughout the years 2014, 2015 and 2016 in order to examine if/how the preference of regime changed.
In order to define the determining factors related to the initiation of LTBI treatment a logistic regression analysis was used. The population of patients referred to the DID was split into two groups; treatment and non-treatment. Eight variables were tested for differences between the groups using univariate analysis. These variables included age, sex, country of origin, time in Sweden before health examination by the MCM, waiting time for the first visit to the DID, CXR-findings, sputum sample for smear microscopy/bacterial culture and symptoms associated with TB.
Statistical Analyses
The data included in the univariate analysis and later in the multiple regression analysis followed different statistical scales and required different approaches in the univariate analysis. A t-test was used for quote scale data that followed a normal distribution, such as time in Sweden and time between referral and first visit to the DID. A Chi2-test was used for all nominal data such as
sex, CXR-findings, sputum sample and symptoms of TB. Country of origin was also viewed as nominal data and analysed, one at a time, with a Chi2-test. Quote scale data that seemed (but could not for certain be assumed) to be normally distributed, such as age was analysed with a Wilcoxon analysis. All univariate analyses were performed in Microsoft Office: Excel 2011®. All variables that showed a difference between the treatment- and non-treatment group and reached an α-value of p<0.2 was included in the regression analysis(34)(35).
The multiple logistic regression analysis was performed in SPSS software by IBM®, to assess potential association between the gathered variables and the initiation of treatment of LTBI. In this analysis adjusted odds ratios (ORs) was calculated with a 95% confidence interval (CI 95%) and associations that reached significance (p<0.05) was noted.
Ethical Approval and Integrity
Since this study is a retrospective evaluation of health care quality, it did not require ethical approval. All gathered data was anonymous.
Results
According to the SMA, about 13800 individuals applied for asylum in Östergötland between 2014-01 and 2016-10. The MCM reports that approximately 80% of the individuals who are offered a health examination accept, and that about 6200 individuals were examined during the period studied. Consequently approximately 55% of the registered migrants did not undergo health examination. 1852 adult individuals were screened for tuberculosis with a QTF-test. 535 of the tests showed a positive result or a threshold limit value on the positive side.
In total, 678 referrals came to the DID from the MCM during the time period. Of the 678 referrals, 432 were made using the referral template for tuberculosis and were therefore included in the study. These 432 individuals came from a total of 32 countries of origin. However, the large majority of individuals came from six of these countries wherefore only those countries were included in all further analyses, concerning country of origin. Gathered data concerning these six countries were categorised and compared to data from the SMA as
shown in table 1.
The Population and Prevalence of LTBI
Based on the positive share of QTF-analyses the prevalence of LTBI in the entire adult migrating population was approximately 29%. The patients referred to the DID were of 32 different
nationalities but 89% of the 432 individuals were from Syria, Somalia Eritrea, Afghanistan, Iraq or Ethiopia. The estimated prevalence of LTBI is shown in table 2.
The age of the referred patients varied, but 65 % of the adult population was between 18 and 38 years old and the number of patients declined with increasing age; see figure 1. Out of the
referred population, 65 % were male but the distribution by sex varied with country of origin; see figure 2. On average an individual had been in Sweden for 5.6 ± 3.6 months before undergoing a health examination by the MCM, and the average time between referral and the first visit to the DID was 46±30 days. Concerning vaccinations, 20% of the patients had been BCG-vaccinated and 15 % had not. The large majority, 65% of the patients could not say for sure whether they had been BCG-vaccinated. The vaccination rates were the highest in patients from
Country of Origin Migrants Registered in the County of Östergötland (n) Referred to the Department of Infectious Diseases (n) Median Age (years) Aged 30 years or less (% of total) Sex ratio Male/Female (% females) Previous BCG-vaccinatio n (%) Syria 5134 69 37(30-45) 30 50/19(28) 29(42) Somalia 909 137 30(25-41) 70 78/59(43) 23(16) Eritrea 619 80 31(27-39) 37 61/19(24) 14(18) Afghanistan 2257 57 37(24-50) 24 32/25(44) 8(14) Iraq 1645 17 34(31-41) 4 13/4(24) 3(18) Ethiopia 141 23 24(21-36) 13 16/7(30) 2(1) Country of origin
Migrants Registered in the County of Östergötland (n) Patients referred to the DID (n) LTBI Prevalence (%) Syria 5134 69 1,3 Somalia 909 137 15,1 Eritrea 619 80 12,9 Afghanistan 2257 57 2,5 Iraq 1645 17 1,0 Ethiopia 141 23 16,3
Table 1. Descriptive data concerning the number of migrants registered with the Swedish
Migrations Agency and referred to the Department of Infectious Diseases between January 2014 and October 2016.
Table 2. Prevalence of latent tuberculosis infection calculated as a comparison between
registered migrants and confirmed cases of infection (patients referred to the Department of Infectious Diseases with positive QuantiFERON and were active tuberculosis was ruled out)
Syria (42%) and the lowest in Ethiopian patients (1%). Further, 57 patients (13%) had findings possibly associated with TB/LTBI on their chest x-ray and 39 patients (9%) had TB-associated symptoms. Out of these, 13 patients (3%) had both findings on their CXR and TB-associated symptoms, and 3 of these patients were diagnosed with active TB and treated as such. In total, seven cases of active TB were diagnosed through the screening program, during the studied time
period. One individual developed active TB after a decision to abstain from treatment of LTBI.
Treatment and Determining Factors of Initiation
Of the 432 patients referred to the DID 73 initiated treatment for LTBI. Out of the 73, 38 patients had already completed their treatment, at the time of this study, 21 patients were in on-going treatment and 14 patients had terminated their treatment early. The most common cause of early
termination of treatment was side effects due to the medication (5 cases), followed by moving out of the county (4 cases) and difficulties in communication (2 cases). Three different treatment regimens were used; a 9 month treatment with 300 mg daily isoniazid (INH 9), a 6 month treatment with 300 mg daily isoniazid (INH 6) and a 4 month treatment with 600 mg daily rifampicin (RIF 4). The most commonly used regime was INH 9, which was used in 49 cases (67%), followed by INH 6 (16 cases, 22%), and RIF 4 (8 cases, 11%). This has changed over the studied period with RIF 4 being the most frequently used regime in 2016, as comparison in figure 4.
Figure 1. Distribution of age within the population of
patients referred to the Department of Infectious diseases between January 2014 and October 2016.
Figure 2. Distribution of sex in the population
referred to the Department of Infectious Diseases categorised by country of origin.
The material was divided in one treatment group and one non-treatment group. These groups were then
compared and tested with univariate analysis including 8 different variables. These variables were age, sex, country of origin, time in Sweden before health examination, time between referral and the first visit to the DID, CXR-findings, symptoms of TB and preformed sputum culture/microscopy.
The analysis showed that median age in the treatment group was significantly lower than the median age in the non-treatment group (23 years versus 37 years p<0.001). The analysis also showed that patients from Syria (p<0.01), Afghanistan (p<0.01) or Ethiopia (p<0.05) were less likely to receive treatment of LTBI. The analyses did not show a significant difference between the groups concerning origin in Somalia or Iraq but the analysis reached the α-value of p<0.2 and these variables were therefore included in the multiple logistic regression analysis. Average time in Sweden before health examination was 6,0 months in the treatment group and 7,4 months in the non-treatment group (p<0.05). The average waiting time for first visit to the DID was 47 days in the treatment group and 40 days in the non-treatment group (p<0.2). Although this was not significant on its own it was included in further analysis. There were no significant differences, between those who received treatment and those who did not, concerning sex, findings on CXR, symptoms of TB or performed sputum sample for smear microscopy/bacterial culture.
The variables included in the multiple logistic regression analysis were age, country of origin (Syria, Afghanistan, Ethiopia, Somalia and Iraq), time in Sweden up until health examination and time between referral and the first visit to the DID. In this analysis age was shown to differ significantly between the groups. Country of origin for Somalia, Ethiopia, and Iraq did not differ
0" 5" 10" 15" 20" 25" 30" 2014" 2015" 2016" INH"9" INH"6" RIF"4"
Figure 3. The distribution of age within the group
of patients for which treatment of latent tuberculosis infection was initiated.
Figure 4. Regimes of treatment of latent
tuberculosis infection used by the Department of Infectious Diseases categorised by year between January 2014 and October 2016.
significantly between the groups but patients from Syria and Afghanistan were less likely to be in the treatment group as shown in table 3.
Discussion
Prevalence of LTBI
The estimation of prevalence of LTBI was made with two different methods. The calculation based on the positive share of positive QTF-analyses is likely accurate. This study had access to data on all analyses during the given time period and since the clinical practice during the same period was to refer and examine all individuals with a positive QTF it is unlikely that cases of active TB was mistakenly included in the count of patients with LTBI. The prevalence of LTBI was calculated to approximately 29% (not categorised by country of origin) but it could be argued that this is an underestimation. The WHO estimates that the prevalence of LTBI worldwide is about 1/3(1) but since the Medical Clinic for Migrants only include screening of TB, in their health examination, if an individual comes from a country of higher TB burden or suffers from other risk factors the prevalence in the screened population should assumingly be higher. One potential source of error is the criteria used by the MCM when choosing whom to screen for TB, which needs to be investigated further in order to ensure that the screening
program does not miss infected individuals. Further, this analysis should not be compromised by Treatment Treatment Non value P- Ratio Odds CI 95% Odds Ratio
Lower Higher
Median Age (Q1-Q3) 23.5
(20-29 37(30-45) <0.001 0.827 0.783 0.874
Country of Origin Syria (n) 5 57 <0.05 0.262 0.078 0.88
Country of Origin Afghanistan 2 34 <0.05 0.195 0.039 0.977
Table 3. Results of the multivariate analysis. Odds Ratios concerning the probability of
receiving treatment of latent tuberculosis are being calculated with confidence intervals of 95%.
the fact that approximately 55% of the registered migrants does not attend a health examination by the MCM.
One goal of this study was to estimate the prevalence of LTBI categorised by country of origin. The data was lacking in this regard however. As described data was gathered from different instances (e.g. Swedish Migration Agency, Department of Infectious Diseases) and a problem was that the two pieces of information needed to calculate prevalence (total population by country of origin and individuals with LTBI) was not available within the same agency. The SMA naturally lacked data concerning tuberculosis infection and information about country of origin was only available within data from the SMA or in the group of patients referred to the DID. The method of calculating prevalence as a proportion of the confirmed LTBI-infected patients referred to the DID and the total number of registered migrants with the SMA is
theoretically possible assuming that the screening program includes all people in every step from screening to treatment. As described above, the MCM only examine about 45% of the registered migrants and therefore the estimated prevalence can be assumed to be greatly underestimated. Further research, aiming to calculate prevalence more exactly, should focus on finding a new source of data in which information about both LTBI infection and country of origin is available. Despite the fact that the exact figures are underestimated conclusions can be drawn from the prevalence calculations. In order to optimize the screening cascade vulnerable groups must be identified(6) and this study shows that almost 90% of the LTBI affected migrating population derives from six countries of origins. Further, it can be assumed that migrants of the Horn of Africa (Somalia, Ethiopia and Eritrea) are afflicted to a greater extent than those from the Middle East (Syria, Afghanistan and Iraq). The estimation of prevalence of LTBI was drastically higher for the counties of the Horn of Africa and this stands in agreement with current available
epidemiologic data(4).
Treatment of LTBI
An important part of evaluating the treatment is including long enough follow up, which this study does not. Of the 432 adults who screened positive for LTBI only one developed active TB after decision to abstain from treatment. The gathered data concerned the period between
January 2014 and October 2016. At the end of the study period, in the majority of cases, less than 2 years had passed, since the decision concerning treatment was made. Studies aiming for a more thorough evaluation of the screening cascade must therefore follow concerned cases for a longer duration of time. Since the risk of reactivation decreases with time (50% within 2 years of infection) it would be desirable to at least preform a 2 year follow up on all cases(9). The low
reactivation rate must still be considered as a positive indication of the present screening program though.
This study contributes little to the question of the choice of treatment regime. The most frequently used regime was a 9-month treatment regime of isoniazid followed by 6 months of isoniazid and then 4 months of rifampicin. Since the studied population did not include a single case of reactivation after completed treatment there is no way to assess treatment efficacy. The most frequent reason for early termination of treatment was side effects due to medication but since the rate of early termination was altogether low is was not possible to significantly differentiate between regimes concerning side effects. Since treatment of LTBI entails long treatment regimens for a patient that does not experience any symptoms, in combination with the fact that the afflicted groups are suffering from social alienation and language barriers to a higher extent, adherence can be a problem(8). The low rate of treatment termination is therefore a positive indication but since a big part of the patients was still on treatment when this study was conducted, further following up is needed.
Determining factors of treatment initiation is an important part of the evaluation of the present screening program. The most impactful factor in relation to treatment initiation was young age (median = 23,5 years). These results are in agreement with regional guidelines for treatment of LTBI, during the studies time period, which said to only treat patients under 25 if no other risk factors existed. Not only patients aged less than 25 years received treatment however. This study could not reveal specific reasons to treat LTBI within patients older than 25. No cases of HIV-infection or disease demanding anti-TNF-α treatment were found in this material. Other risk factors associated with a higher risk of reactivation such as renal disease, diabetes mellitus or recent incarceration was not specifically investigated in this study and their association to treatment initiation in Östergötland could therefore not be assessed. Previous research concerning screening programs presses the importance of identifying and treating vulnerable groups in each local setting(6,27) and identifying which groups of patients that are being selected for treatment by the current screening program is a pivotal part of this process. The field would therefore benefit from further investigation and research concerning factors related to initiation of treatment.
This study also indicates that the probability of receiving treatment of LTBI is slightly lower within the groups of patients originating in Afghanistan or Syria. No definitive reason for this can be offered at this point but the results were significant and need to be addressed. There is no thinkable medical reason for patients from Afghanistan or Syria to receive treatment to a lesser extent and that could indicate a bureaucratic or social issue speculatively. Social alienation is a
risk factor in relation to being infected by Mtb and reactivation (1,6) and measures to ensure that all groups have the same access to preventive treatment must be taken. In the present screening program country of origin only affects the decision to screen for LTBI. That suggests that, if further research would strengthen the suspicion that this is a relevant issue, it would require a social/bureaucratic solution rather than one related to health care organization.
Identifying High Risk Groups, Faults in the Screening Program and Additional Research
The main goal in study is as described to evaluate the current screening to treatment program and to increase knowledge about which groups suffer from higher risk of tuberculosis infection or reactivation, or may benefit the most from treatment of LTBI. Migrants constitute, as described and because of several different factors, a group of importance(6,28,33). To minimize the impact of the tuberculosis, within this group and on society in general, effective screening, treatment and follow up must be performed(6). A piece of important information brought forth by this study is the fact that only about 45% of the migrant registered with the Swedish Migration Agency undergo health examination by the Medical Clinic For Migrants. The latter reports that approximately 80% of the individuals that are offered a health examination accept. That leads to the conclusion that a big part of the migrant population is not offered examination. This is an issue that needs to be addressed. Speculatively, and in relation to prevalence of 1/3 and a 5-15% lifetime risk of reactivation, this means that the screening program missed approximately 125-380 future cases of active tuberculosis between 2014-01 and 2016-10. The possible reasons why a large part of the registered migrants are never offered a health examination lie outside the scope of this study however.
Apart from the previously mentioned this study offers no concrete suggestion of possible improvement within other parts of the screening program but this needs to be investigated further. There are several aspects of the subject of discussion in this study that would benefit from additional research. The cases included in this study should be subject to extended follow up in order to evaluate treatment efficacy, side effects and rates of reactivation. The material should also be complemented with information concerning comorbidities, such as diabetes mellitus, renal disease and incarceration, which were not included in this study. New methods to calculate prevalence categorised by country of origins should be developed to further specify which groups suffer from the highest risk of infection and reactivation.
Conclusion
The screening program for latent tuberculosis between January 2014 and October 2016 was evaluated and descriptive data on the matter was gathered. The majority of affected individuals came from six countries (Afghanistan, Eritrea, Ethiopia, Iraq, Syria and Somalia) and the highest prevalence was estimated within the countries of the horn of Africa. Determining factors of treatment initiation was investigated and young age proved to be the most significant factor in correspondence to the present regional guidelines.
Acknowledgements
The Author would like to thank Dr Jakob Paues and Dr Karin Sundelin of the Department of Infectious Diseases in Östergötland. The Swedish Migration Agency, The Medical Clinic for Migrants and the Department of Microbiology should also be acknowledged for their help with this paper.
