Tuberculosis control in Sweden

Abstract: Sweden is a low tuberculosis (TB) incidence country with an incidence of 5.3 cases per 100 000 inhabitants 2017. The majority of new TB cases in Sweden are diagnosed among migrants from high TB incidence countries. Data from TB surveillance is analysed to identify risk groups, follow trends, discover new risk groups or outbreaks and update policies and guidelines, with the ultimate goal of reducing the number of new cases. Today all isolates from TB cases diagnosed in Sweden are genotyped to detect clustering which may reveal unknown links between cases and risk of transmission that has been overlooked. The methods of molecular genotyping have improved over time and reduced the risk of false clustering. In paper I we compared two different methods of molecular genotyping, Restriction fragment length polymorphism (RFLP) and Mycobacterial interspersed repetitive units – variable number of tandem repeats (MIRU-VNTR). There was an 82 percent concordance between the two methods. Compared to epidemiological data, around 50 percent of the clusters were judged as being false with both methods. As turn-around time for MIRU-VNTR is much faster than for RFLP it was the preferred method. Latent tuberculosis infection (LTBI) is defined as having a detectable immune response towards TB but no signs or symptoms of active disease. The tuberculin skin test has gradually been replaced by Interferon Gamma Release Assays (IGRA’s) to detect immune response towards the Mycobacterium tuberculosis (M.tb) specific antigens ESAT-6 and CFP-10. With QuantiFERON Gold In tube, the most widely used IGRA, there are challenges in interpreting results close to cut-off (0.35 IU/mL) due to the variability of the test method. In paper II we investigated the effect of a borderline range (0.20–0.99 IU/mL) around cut-off where repeated testing was recommended. Of negative (0.20–0.34 IU/mL) and positive (0.35–0.99 IU/mL) results in the borderline range, 66.1 percent and 42.5 percent respectively were negative below the borderline range (< 0.20 IU/mL) when retested. None of the subjects with initial result in the borderline range and a negative second test, developed incident active TB during a period of minimum two years of follow-up. We recommend re-testing of individuals with a result in the borderline range for a more reliable result. Multidrug resistant TB (MDR-TB) is an increasing problem worldwide and also in Sweden but on a smaller scale. In paper III we analysed a Swedish cohort of 158 MDR-TB cases diagnosed from 1992–2014. Treatment outcome was successful in 83.5 percent which is similar to treatment outcome for susceptible TB in Sweden. Treatment with pyrazinamide (PZA) in cases with PZA susceptible M.tb strains, shortened time to sputum culture conversion (aHR 2.25 (95% CI 1.27–3.99) p=0.005) (median difference 30 days). Increasing minimum inhibitory concentration of levofloxacin was correlated to unfavourable outcome (aHR 1.77 95% CI 1.15–2.71 p=0.009), as was diabetes (aHR 5.52 (95%CI 1.42–21.55) p= 0.014) and increasing age (age >40 years, aHR 4.51 (95% CI 1.74–11.67) p=0.002). The majority of people with LTBI will not develop active TB but there are factors increasing this risk, like for example human immunodeficiency virus or any other condition affecting the normal immune response. As pregnancy temporarily alters the immune response, we wanted to investigate if the risk of active TB increases during pregnancy and postpartum. In paper IV, a retrospective register-based cohort study of all women who gave birth in Sweden during the study period 2005–2013, we showed an incidence rate ratio of 3.0 (95% CI 2.3–3.9) and 4.2 (95% CI 3.2–5.5) of active TB during pregnancy and postpartum respectively compared to outside these risk periods. The increased risk was concentrated to women from high TB incidence countries. We recommend that women from high TB incidence settings should be screened for both active and latent TB when pregnant.