Highlights
- •Bacillus Calmette-Guérin (BCG) protects against tuberculosis (TB) for at least 17 years (vaccine effectiveness 59%)
- •Immigrants in Sweden aged 0-17 years had a relatively high prevalence of latent TB (17%)
- •Tuberculosis is returning to Europe as a result if the high immigration rate
ABSTRACT
Objectives
This study aimed to determine the prevalence of latent tuberculosis infection (LTBI) in immigrant children and adolescents (aged 0-17 years) living or recently arriving in Sweden. It also aimed to estimate the effectiveness of Bacillus Calmette-Guérin (BCG) against LTBI in immigrant children coming to Sweden from high-incidence countries, most of them being asylum seekers. LTBI was defined as a positive Quantiferon or a tuberculin skin test (TST) of ≥ 10 mm in small children from whom it was difficult to obtain 3 mL of blood.
Design
A typical BCG scar was used as a substitute for written documentation of BCG vaccination. The study comprised 1,404 immigrants aged 0-17 years. The arms and legs of all of them were inspected for a BCG scar, and Quantiferon or TST was performed. The study was a retrospective, observational, comparative cohort study.
Results
LTBI was found in 123 of 1,011 (12%) children with a BCG scar and in 116 of 393 (29.5%) without a BCG scar, giving an estimated vaccine effectiveness of 59%.
Conclusions
LTBI was common among the immigrant children (17%). LTBI can progress to active TB and then spread in the immigrant population and to the general population if all immigrant arrivals are not tested and given prophylactic treatment if they have LTBI. The BCG vaccine was found to have a significant effect on LTBI (59%).
Keywords
INTRODUCTION
The licensed vaccine against tuberculosis (TB) – Bacillus Calmette-Guérin (BCG), which is an attenuated strain of Mycobacterium bovis – is the most commonly used vaccine in the world. It was introduced in 1921 (BCG vaccines: WHO position paper;
Fritschi et al., 2020
) and reached a worldwide coverage of > 80% in low- and middle-income countries in 2019 (Who.int. 2020
). As it was introduced such a long time ago, it was not tested in double-blind placebo-controlled trials before its general use; however, both randomized trials and trials with other designs were later performed (Who.int. GHO | By category | BCG - Immunization coverage estimates by country, 2020. https://apps.who.int/gho/data/node.main.A830?lang=en
Dye, 2013
; - Dye C.
Making wider use of the world's most widely used vaccine: Bacille Calmette–Guérin revaccination reconsidered.
J R Soc Interface. 2013; 1020130365https://doi.org/10.1098/rsif.2013.0365
Mangtani et al., 2014
; Barreto et al., 2006
; Fine, 1995
; Fine, 1988
; Hart and Sutherland, 1977
; Roy et al., 2014
; Behr, 2002
; Katelaris et al., 2020
; Michelsen et al., 2014
; Colditz et al., 1994
). The efficacy/effectiveness against tuberculous meningitis and miliary TB was 85% (95% CI: 65-95%) in meta-analyses of randomized clinical trials, but estimates against pulmonary TB are highly variable at 0-80% (Rodrigues et al., 1993
; - Rodrigues LC
- V K Diwan CVK
- Wheeler JG
Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis.
Int J Epidemiol. 1993; 22 (1153.1158)https://doi.org/10.1093/ije/22.6.1154
Bourdin Trunz et al., 2006
). The lower estimates of effectiveness are generally more common (Dye, 2013
; - Dye C.
Making wider use of the world's most widely used vaccine: Bacille Calmette–Guérin revaccination reconsidered.
J R Soc Interface. 2013; 1020130365https://doi.org/10.1098/rsif.2013.0365
Mangtani et al., 2014
; Barreto et al., 2006
; Fine, 1995
; Fine, 1988
; Hart and Sutherland, 1977
; Roy et al., 2014
; Behr, 2002
; Katelaris et al., 2020
; Michelsen et al., 2014
; Colditz et al., 1994
). In a randomized placebo controlled trial in south India, the efficacy against pulmonary TB was 0% (Tuberculosis Prevention Trial 1979
). These differences may depend, at least in part, on differing effectiveness of the many existing BCG vaccines (Behr, 2002
). If latent TB infection (LTBI) progresses into active TB, usually pulmonary contagious TB, it can spread to nonimmune healthy individuals who then develop LTBI, which can be activated and contagious.This study aimed to investigate the prevalence of LTBI in asylum-seeking children and adolescents, aged 0-17 years, to determine whether this prevalence correlates with BCG vaccination (the presence of a BCG vaccine scar) and to calculate the effectiveness of BCG vaccination against LTBI. In the absence of a written documented BCG vaccination, the presence of a vaccine scar is often used as a substitute (
Katelaris et al., 2020
; Michelsen et al., 2014
; Colditz et al., 1994
; Chapman and Lauzardo, 2014
; Roy et al., 2012
).PATIENTS AND METHODS
Study design
The study was a retrospective, observational, cross-sectional, comparative cohort study. All immigrants arriving in Sweden are offered health examinations free of charge soon after arrival. One important part of the health examination is to look for LTBI with Quantiferon or the tuberculin skin test (TST) in those aged < 5 years. LTBI was defined as a positive Quantiferon test or, in small children from whom it was difficult to obtain 3 mL of blood, as a TST of ≥ 10 mm. Quantiferon is considered to be more specific than TST for diagnosis of LTBI in both adults and older children (
Colditz et al., 1994
; Chapman and Lauzardo, 2014
) and in children aged < 5 years (Ahmed et al., 2020
).- Ahmed A
- Feng PJI
- Gaensbauer JT
- Reves RR
- Khurana R
- Katya Salcedo K
- Punnoose R
- Katz DJ
for the TUBERCULOSIS EPIDEMIOLOGIC STUDIES CONSORTIUM
Interferon-γ Release Assays in Children <15 Years of Age.
Interferon-γ Release Assays in Children <15 Years of Age.
Pediatrics. 2020; 145 (DOI: https://doi.org/)e20191930https://doi.org/10.1542/peds.2019-1930
This study was a retrospective evaluation of the records of immigrant children and adolescents aged 0-17 years (for simplicity, called children) examined from 2010 to 2018 at a health clinic dedicated to health examinations of refugees and other immigrants (Kaserntorget). All underwent clinical examination, and a medical history was obtained with the help of an interpreter. Participants were identified from the computerized records at the health clinic. Individual patient records were also found on the database and data relevant for this study were obtained from these case records. A total of 1,536 patient records were examined; of these, 132 were excluded: 62 because the presence or absence of a BCG scar was not documented, 47 because the results of TST or Quantiferon were not documented, seven because they had been treated for TB in their countries of origin (all had a positive Quantiferon), four because they had active TB, and 12 because they were born in Sweden. It was difficult to obtain 3 mL of blood for Quantiferon in 97 of the youngest patients; LTBI was excluded based on a TST of < 5 mm found in all. Apart from the 1,532 patient records that were reviewed, another 301 immigrants were offered a health examination during the same time period but they did not come to the outpatient clinic, despite a reminder; therefore, 16% of all immigrant children were never tested for LTBI. Four of the children with positive Quantiferon who were referred to the Department of Pediatrics for further investigation had active TB (not included among the 1,404 children described in the Results section).
The following information was collected at the health control: country of origin, gender, age, time in Sweden, accompanied or unaccompanied by an adult relative, and chronic diseases. If Quantiferon was positive, the patient was referred to the Department of Pediatrics of Sahlgrenska University Hospital for further investigation of active TB. If no active TB was found, the patient was given prophylaxis for LTBI with rifampicin + isoniazid for 3 months (
LoBue et al., 2017
; Madhavi and Schluger, 2013
).Ethics
The study was approved by the Ethical Review Board at the University of Gothenburg, including a specific question not to obtain consent for the study from all guardians (registration number 270-16). All children aged < 17 years and arriving alone were given a trustee (“good man” in Swedish) after arrival, who then acted as their guardian.
Diagnostic analyses
Tuberculin skin test (TST)
0.1 mL containing 2 T.U. PPD RT 23 (Statens Seruminstitut, Copenhagen, Denmark) was intracutaneously injected into the volar part of the lower arm. Two experienced nurses measured the diagonal diameter of the swelling after 72 hours. Previous studies showed that TST can be falsely positive when compared with Quantiferon (
Chapman and Lauzardo, 2014
; Gudjónsdóttir et al., 2016
; Dockrell and Smith, 2017
).Quantiferon TB Gold-In-Tube
The sampling and analyses were performed with QuantiFERON TB Gold-In-Tube, according to the manufacturer's instructions (Cellestis Ltd., Chadstone, Victoria, Australia). One mL of blood was collected into each of three different tubes: a nil control tube with no additions; a TB antigen tube containing ESAT-6, CFP-10 and TB7.7; and a Mitogen tube (positive control) containing phytohemagglutinin-P, which is a non-specific stimulator of T-lymphocytes. ESAT-6, CFP-10, and TB7.7 are specific for the Mycobacterium tuberculosis complex and a few other mycobacteria; they are not present in any BCG vaccine. The first TB antigen tube mostly stimulates CD4 T lymphocytes. The Quantiferon test has subsequently been developed into a four tube test, with two tubes for TB antigens, one with ESAT-6 and CFP 10, which specifically stimulates CD4 cells, and one with a peptide, which specifically stimulates CD8 cells (Quantiferon TB Gold Plus); that test was unavailable when the present study was performed. The samples were transported to the laboratory within 16 hours, where the tubes were incubated at 37°C for 16-20 hours and subsequently centrifuged at 2,300 g for 15 minutes. The concentration of interferon gamma in the resulting plasma was measured by ELISA and related to a concentration standard. The absorbance was measured in a Vmax Kinetic Microplate Reader (Molecular Devices, USA) and the optical density (OD) values were calculated using the QFT®-TB Gold in tube analysis Software version 2.50. According to the producer of QuantiFERON TB-Gold- In-Tube, a difference between TB antigen and nil tubes of ≥ 0.35 was considered positive if the TB antigen was ≥ 25% of the nil value. A QuantiFERON TB-Gold- In-Tube was repeated if the difference between the TB antigen and the Nil tubes was < 1 and the second result (which was always negative) was used.
Statistics
Statistical analyses were performed with the SPSS version 22 software (IBM Corp., Armonk, NY, USA). Categorical variables were presented as the number of observations (n) and the percentage of total observations (%). Age and elapsed time in Sweden was presented as the mean (range). The relative risk (RR) with 95% CI for having LTBI based on the presence of a BCG scar was calculated for the whole study cohort as well as for patients from specific countries. Relative risk was estimated from a 2 × 2 contingency table in SPSS. Vaccine effectiveness was calculated as VE = (1-RR)*100.
RESULTS
A total of 1,404 records were used for final analysis. Table 1 shows the basic characteristics of the children. The patients came from 61 countries, the most common being Afghanistan (N=368), Somalia and Ogaden (N=326), Syria (n=241), Eritrea (N=94), and Iraq (N=99); 854 (61%) came alone without an accompanying adult (Table 1). Eighty-three patients (3.8%) had concomitant chronic diseases, the most common being chronic hepatitis B (HBsAg pos, HBeAg neg, no symptoms, and normal liver function tests) (Table 1).
Table 1Characteristics of asylum-seeking children and adolescents (aged ≤ 17 years) in Sweden.
| Country of origin | Age | Male gender | Unaccompanied minors | Months in Sweden |
|---|---|---|---|---|
| Overall, n=1,404 | 15 (0-17) | 1,023 (73%) | 854 (61%) | 5 (0-180) |
| Afghanistan, n=368 | 16 (3-17) | 346 (94%) | 325 (88%) | 5 (0-36) |
| Somalia and Ogaden, n=326 | 15 (0-17) | 225 (69%) | 266 (82%) | 4 (1-96) |
| Syria, n=241 | 10 (0-17) | 156 (65%) | 81 (34%) | 4 (0-60) |
| Eritrea, n=94 | 16 (0-17) | 61 (65%) | 85 (90%) | 4 (0-180) |
| Iraq, n=99 | 11 (1-17) | 69 (70%) | 24 (24%) | 5 (1-60) |
| Other countries, n=276) | 11 (0-17) | 166 (60%) | 73 (26%) | 6 (1-120) |
Results are presented as median (range) or n (%)
Table 2 shows the number of children with and without BCG scar and with and without LTBI. Of all the immigrant children, 17% had LTBI; the highest prevalence was seen in those from Somalia, including Ogaden, with a prevalence of 36% (Table 2). Among the 854 adolescents aged 13-17 years and arriving unaccompanied, 164 (19%) had LTBI, which was similar to those arriving with their families. Of the total group of 1,404 children, 1,011 (72%) had a typical BCG scar and 393 had no scar, with no major differences between countries except that Afghanistan and Somalia (including Ogaden) had the lowest proportion of children with BCG scar at 56% and 63%, respectively (Table 2).
Table 2Numbers of children with and without BCG scar and with and without LTBI. Relative risk and effectiveness of the BCG vaccine against LTBI using BCG scar as substitute for written documentation of vaccination is also shown.
| Country of origin | BCG scar LTBI | BCG scar No LTBI | No BCG scar LTBI | No BCG scar No LTBI | RR | RR 95% CI | p-value | VE | VE 95% CI |
|---|---|---|---|---|---|---|---|---|---|
| Overall | 123 | 888 | 116 | 277 | 0.412 | 0.329-0.516 | < 0.0001 | 58.8 | 48.4-67.1 |
| Afghanistan | 28 | 224 | 25 | 91 | 0.516 | 0.315-0.844 | 0.010 | 48.4 | 15.6-68.5 |
| Somalia and Ogaden | 62 | 144 | 55 | 65 | 0.657 | 0.494-0.873 | 0.006 | 34.3 | 12.7-50.6 |
| Syria | 8 | 203 | 6 | 24 | 0.190 | 0.071-0.509 | 0.003 | 81.0 | 49.1-92.9 |
| Eritrea | 4 | 61 | 4 | 25 | 0.446 | 0.120-1.662 | 0.246 | 55.4 | -66.2-80.0 |
| Iraq | 6 | 75 | 4 | 14 | 0.333 | 0.105-1.061 | 0.080 | 66.7 | -66.2-89.5 |
| Other countries | 15 | 181 | 22 | 58 | 0.278 | 0.152-0.508 | < 0.0001 | 72.2 | 49.2-84.8 |
Vaccine effectiveness in the whole group and in immigrants from the five countries with the largest numbers of immigrants is shown in Table 2; the overall effectiveness was 59%. Significant effectiveness was also separately seen in Afghanistan, Somalia, including Ogaden, and Syria (Table 2). Significant effectiveness was also seen in the combination of smaller groups of children coming from 56 countries. The study failed to show effect in children from Eritrea and Iraq, probably due to the lower number of patients from these two countries.
The effectiveness of the BCG vaccine, using a scar as a substitute of documented vaccination, is shown in Table 2. To see whether there was any decrease over time, vaccine effectiveness was calculated separately in three age groups: 0-5, 6-11, and 12-17 years. The effectiveness was similar in all groups and varied between 57%-60% (details not shown).
It was not possible to make a systematic follow-up of the 301 children who did not come to the health examination, but by pure coincidence five of them (four boys, one girl) were seen by one of the authors (BT) at the TB unit at the Department of Pediatrics at Sahlgrenska University Hospital with active TB; all were aged 14-17 years. Four of them came from sub-Saharan Africa and one from south-east Asia. Two had pulmonary TB (one with caverns), two had solitary lymph nodes on the throat, and one had widespread lymph nodes in the whole abdomen. The TB diagnosis was verified with positive TB culture from biopsies or bronchoalveolar lavage in all cases.
DISCUSSION
The present study shows that the BCG vaccine has a significant effect on LTBI. The effectiveness was 59%, which is similar to some other studies (
Nguipdop-Djomo et al., 2016
; Benn et al., 2020
; Channabasavaiah et al., 1993
) that reported protection against LTBI ranging from 36%-72%. The effectiveness varied greatly between countries in the current study. The current study and these three studies showed that BCG protects against infection with M. tuberculosis, not only against the progress of LTBI to active TB. The lowest effectiveness (48.4%) was seen in Afghanistan and the second lowest (34.3%) in Somalia and Ogaden. Both these countries are highly endemic for TB, due to poverty and a civil war for several years, so it is possible that vaccine effectiveness was affected by crowding, malnutrition, and large-scale exposure. The majority of unaccompanied children also came from these countries. The highest effectiveness was surprisingly seen in Syria (87%), which also has an ongoing civil war but not for so many years. A relatively high level of effectiveness (72%) was also seen in the combination of 56 countries with small numbers of immigrants per country. Many of the immigrants from these countries came from middle-income countries like Thailand, South Africa, and Mexico, and who left for Sweden with their families because their fathers had found work there.The overall proportion of immigrants with a BCG scar was 72%, which is lower than the coverage in low- and middle-income countries of > 80%, according the World Health Organization (WHO) (who.int (GHO | By category | BCG - Immunization coverage estimates by country, 2020). It is obvious that the level of effectiveness in the adolescents (12-17 years) remained relatively high at 57%. A Norwegian study also reported a long duration of BCG-induced protection against active TB, which is not totally relevant for the present study on LTBI (
Nguipdop-Djomo et al., 2016
).Retrospective studies of this kind have three unavoidable weaknesses. First, it was unknown when the children were vaccinated, but since the WHO recommends that all newborns are BCG vaccinated during the first year of life (
Benn et al., 2020
), it can be assumed that they were vaccinated at an early age. Even though many countries use their own vaccination schedule, all countries recommend BCG vaccination during the first year of life. Second, it was impossible to determine when the children were exposed and infected: in their countries of origin or during the journey to Sweden. When talking to the children, especially those who were unaccompanied by an adult, it was obvious that they could have been infected when travelling to Sweden in crowded vans and tents. Many of the adolescent boys also spent long periods in crowded prisons in Libya or Turkey, where they were maltreated and sexually abused. It is therefore believed that most of the children in the present study were vaccinated at an early age and exposed in their teens. If this is correct, the effectiveness of BCG is rather long lasting. Third, documented evidence of BCG vaccination was missing; the presence of a typical BCG scar had to be used instead as a substitute for written documentation of vaccination, which is quite common (Shaaban et al., 1990
; Fjällbrant et al., 2008
; Fritschi et al., 2020
; Katelaris et al., 2020
; Michelsen et al., 2014
; Colditz et al., 1994
; Chapman and Lauzardo, 2014
; Roy et al., 2012
), even though it is known that some BCG vaccines do not result in a scar (Benn et al., 2020
) and since BCG scars can fade with time (Channabasavaiah et al., 1993
). The presence of a BCG scar was evaluated both by an experienced nurse and a physician; the agreement of scar evaluation was 100%.One incidental finding in the study was that the definition of a positive Quantiferon should be revised: a value of TB antigen – nil between 0.35 and 1 should be regarded as possibly positive and be controlled.
The high rate of LTBI in this study population indicates that northern and western Europe, which receive refugees, can expect a growing public health problem; TB had almost been eradicated in these parts of the world. There were also many examples of children with cervical nodes and long-lasting cough who sought medical attention at outpatient clinics in Gothenburg without anyone thinking of TB. There is now a great risk that TB will return. In the present study, 17% of all asylum-seeking immigrant children and adolescents had LTBI. Since not all immigrants undergo a health examination and receive prophylaxis if needed, a large number of active cases of contagious TB can be expected in the future; therefore, Swedish and other European physicians should refresh their knowledge about the disease. The risk that LTBI will progress to active contagious TB is estimated to be 5%-10% (
Salgame et al., 2015
). The spread mainly occurs in the home, but it can also take place in schools with adolescent pupils (Trollfors et al., 2013
).In conclusion, this study shows that BCG vaccination leaving a remaining scar is 59% effective and that the prevalence of LTBI in immigrant children (mainly refugees) is 17%, which can cause major health problems in the future. Because BCG protects against LTBI it should also protect against all forms of active TB (including pulmonary TB), all of which are usually preceded by a period of latent TB.
Acknowledgements
Dr Andreas Sparud who made some of the protocols as a part of his mandatory scientific module to obtain his medical exam. He was offered co-authorship but declined.
Conflicts of interest
None declared.
Funding
Financial support was obtained from the Department of Pediatrics, Sahlgrenska University Hospital, Gothenburg, Sweden and the outpatient clinic for Health Examinations of immigrants (Kaserntorget), Gothenburg, Sweden.
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Who.int. GHO | By category | BCG - Immunization coverage estimates by country, 2020. https://apps.who.int/gho/data/node.main.A830?lang=en
Article info
Publication history
Published online: June 23, 2021
Accepted:
June 20,
2021
Received in revised form:
June 18,
2021
Received:
April 25,
2021
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