Risk factors for Mycobacterium tuberculosis infection among children in Greenland
Bolette Søborg a, Aase Bengaard Andersen b, Mads Melbye a, Jan Wohlfahrt a, Mikael Andersson a, Robert J Biggar a, Karin Ladefoged c, Vibeke Ostergaard Thomsen d & Anders Koch a
a. Department of Epidemiology Research, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark.
b. Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
c. Department of Internal Medicine, Queen Ingrid’s Hospital, Nuuk, Greenland.
d. International Reference Laboratory of Mycobacteriology, Statens Serum Institut, Copenhagen, Denmark.
Correspondence to Bolette Søborg (e-mail: email@example.com).
(Submitted: 26 November 2010 – Revised version received: 08 July 2011 – Accepted: 10 July 2011 – Published online: 24 August 2011.)
Bulletin of the World Health Organization 2011;89:741-748E. doi: 10.2471/BLT.10.084152
Although Greenland has experienced steady improvement in general living standards since World War II, tuberculosis (TB) remains a major health problem throughout the country.1,2 Overall TB incidence in Greenland doubled in the 1990s3 and still remained at 130 cases per 100 000 in 2010.1 The proportion of TB cases comprised of children under the age of 15 years rose from 8% in 1990 to 25% in 1997.3 Because of this resurgence of TB, in 1999 national health authorities launched a TB control programme consisting of the vaccination of all neonates with bacille Calmette–Guérin (BCG), early case detection and the monitoring of treatment outcomes.4 In 2007 the programme was revised to include routine screening of children for Mycobacterium tuberculosis infection (MTI) at the ages of 6 and 16 years. Despite this effort, TB incidence and the risk of MTI among children remain high.4,5 Surprisingly, the resurgence of TB in Greenland is not linked to human immunodeficiency virus (HIV) infection or to multidrug resistant TB, both of which are still very uncommon in the country. As of 2010, only 157 HIV-positive cases had been registered despite free HIV testing and only one case of multidrug resistant TB had been documented.1,6 Instead, it appears to result from microepidemic outbreaks in small towns and remote settlements. TB is 20 times more common among the Inuits of Arctic Canada and Alaska than among non-native white populations.7–11 This elevated risk suggests that even in resource–rich countries, TB control is difficult in small, hard-to-reach communities with limited health resources.
In 2009, a World Health Organization group proposed a revision of current TB control, targeting strategies to minimize exposure to TB as measured by the presence of MTI.12 The revision raises the need to better understand the risk factors associated with MTI, especially at the local and regional level, since risk factor profiles vary from place to place and one programme will not necessarily be effective everywhere. The objective of this study was to explore the risk factors for MTI among Greenlandic children to help identify the children at highest risk of infection.
Study sites and population
An ice cap covers 82% of Greenland’s territory, permitting settlements only in coastal areas. The population, which numbers 57 000, is 90% Inuit. Greenland is an integral part of the Kingdom of Denmark but is self-governing. Although its population is less affluent than that of Denmark, it is nonetheless wealthy by developing country standards, with a gross national product per capita of 20 000 United States dollars. Health care is provided by the government at Danish standards.13 The capital, Nuuk, has one national hospital; a local hospital exists in each of the country’s five administrative districts, along with additional health centres and nursing stations or clinics. Care is free of charge. However, inequities have not been fully eradicated mainly because small and isolated communities have limited health-care resources and the least experienced health-care workers.14 Physicians, typically from Denmark, have difficulty communicating with the Inuit population and are usually on short-term assignments, so that gaps between postings sometimes occur. Living in a small community is an independent risk factor for TB disease.15
The current study, cross-sectional in design, included all schoolchildren in five different towns and nearby settlements across Greenland: Tasiilaq (November, 2005) in eastern Greenland; Narsaq (May, 2006), Qaqortoq (August, 2006) and Nanortalik (September 2006) in southern Greenland; and Sisimiut (May, 2007), in western Greenland. School attendance is mandatory everywhere in the country for children aged from 6 to 16 years. On 31 December 2006, the study area had 2880 eligible children in that age group (i.e., 25% of the entire Greenlandic population of children 6 to 16 years old), all of whom were invited to participate in the study. We included all schools and identified the children through school protocols.
The surveys were conducted through all local schools in the designated survey areas. Prior to the surveys, the school sent every student home with information about the study and a questionnaire in both Danish and Greenlandic. Enrolment required informed consent signed by a parent or guardian. During the survey a nurse or doctor measured every child’s height and weight using a scale and a measuring tape. These measures were used to derive a body mass index (BMI) with a BMI percentile calculator specific for children. The calculation used the basic BMI formula: body weight in kilograms divided by the square of the height in metres. Results compare BMI-for-age percentiles with BMI-for-age growth charts.16 In Greenland, neonates have been vaccinated with BCG since 1949 except during the period from 1991 to 1996. We ascertained the BCG status of participating children retrospectively by inspecting detailed vaccination records maintained by community nurses at local health-care facilities. We drew a venous blood sample from each child and administered a tuberculin skin test (TST) to each of them.
We extracted demographic information on each child from the civil registration system (CRS), which contains information on all Greenlanders.17 This included parents’ place of birth, number of siblings, distance between siblings (next younger and next older), birth order and mother’s age when the child was born. Children whose parents were both born in Greenland were considered Inuit, as this method has been shown to accurately identify children of Inuit heritage.18 By having parents or caretakers complete a standardized self-administered questionnaire, we also obtained information on crowding in the household (total number of dwellers, number of adults and number of children), parents’ educational level, health status of the study child and type of heating in the household.
Mycobacterium tuberculosis infection
The venous blood sample was used to test for MTI using the Quantiferon TB-Gold In-Tube (QFN) (Cellestis, Carnegie, Australia) interferon gamma release assay. The QFN was performed according to the manufacturer’s instructions. All tests were corrected for background reactivity. Interferon-γ (IFN-γ) results from white blood cell stimulation by the TB antigens were provided by the kit manufacturer (ESAT6, CFP-10 and TB 7.7). A test was considered positive and indicative of MTI if IFN-γ production was ≥ 0.35 international units per millilitre (IU/ml).
The TST was applied to the dorsal aspect of the forearm by the intradermal Mantoux method using 2 tuberculin units (0.1 ml) of RT-23 purified protein derivative (PPD) (Statens Serum Institut, Copenhagen, Denmark), and the result was read 72 hours later by an experienced examiner. According to current Greenlandic TB guidelines, an induration ≥ 12 mm in diameter at the injection site indicates a positive response. Some TST results were missing because testing was refused or the child was lost to follow-up before the reading of the TST.
A child was considered to have MTI only if he/she tested positive both on the QFN and on the TST, regardless of clinical status. Children with negative results on both tests were classified as uninfected.
We treated all children with discordant test results as in need of evaluation for MTI and referred them for the same clinical evaluation and possible TB prophylaxis as children who were dually positive.
The study was approved by the Commission for Scientific Research in Greenland (approval No. 505–105). All participants with positive results on either the QFN or the TST were referred to the local medical centre for further evaluation, including a chest X-ray and clinical examination. Children diagnosed with clinically active TB were offered standard TB treatment; those with MTI were treated prophylactically with isoniazid.
We used logistic regression with the Proc Genmod procedure (SAS, Cary, USA) to calculate odds ratios (ORs) for the association between MTI and potential risk factors. We accounted for clustering of MTI within families by using generalized estimation equations. Initially, ORs were adjusted for age and sex only. Variables found to be statistically significant were then entered into fully-adjusted models, which included ethnicity, maternal age, age gap between child and next older sibling, and region of residence. All adjustment variables are presented in the tables.
Since contact with a known TB case has been reported to be a main predictor for MTI,19 we further explored whether such contact modified the risk factor pattern. We determined whether a risk factor was modified by contact with a TB case by assessing for interactions between the risk factor and TB contact after adjustment for each adjustment variable. We estimated age trends using the median age within each age group as a continuous variable. We examined the association between MTI and having an older sibling found to be infected during the survey for all children who had at least one older sibling in the study.
The census recorded 2880 children of eligible age as residents of the study areas. However, migration of households is common in Greenland and the exact number in residence is uncertain. Initially 2218 children (77% of the estimated 2880 children) returned signed consent forms. Of these children, 1886 (85%) were successfully tested with both the QFN and TST. Eighty nine subjects had discordant QFN and TST results: 46 had a positive TST and a negative QFN; 25 had a positive QFN and a negative TST, and 18 had an inconclusive QFN and a negative TST. These subjects were not included in the main analyses. Thus, 1797 (81% of 2880 estimated children) had a definitive MTI assessment. The demographic characteristics of participating children and of children across Greenland in the same age groups are shown in Table 1. Age, gender, mother’s age when she gave birth to the child, mother’s total number of children and ethnicity were similar in the study population as in the total population of children in Greenland.
Table 1. Comparison of demographic characteristics of schoolchildren in study population (n = 1797) and Greenlandic schoolchildren in general
In total, 152 (8.5%) of the 1797 children included in the analysis were positive for MTI. This included 48 (26.7%) of the 180 children with a known TB contact (10% of the whole) and 104 (6.4%) of the 1617 children without a known TB contact. Of the 180 children with a reported TB contact, 31% reported a household contact, 22% reported a school contact and 47% did not specify the type of contact. Of 180 children with TB contacts, 122 (68%) reported the time elapsed since the contact. In 52 such cases the contact was reported as having occurred within the past year. Positivity on both tests did not correlate with the time elapsed since the first known TB contact. Of the children who had a known TB contact but whose older siblings were uninfected, 13.9% were MTI positive, as opposed to 35.7% of the children who had at least one infected older sibling (sex- and age-adjusted OR:3.48; 95% CI: 0.80–15.1). An age gap of less than one year between the child and the closest older sibling was a risk factor (OR: 2.48; 95% CI: 1.33–4.63). Among children without a known TB contact, 2.9% were positive for MTI when no older sibling was infected, whereas 27.3% were positive when at least one older sibling was infected (sex- and age-adjusted OR: 14.2; 95% CI: 5.75–35.0). During clinical follow-up of children dually positive, four were diagnosed as having clinically active TB as defined by positive X-ray findings or microbiological evidence of MTI.
Table 2 (available at: http://www.who.int/bulletin/volumes/89/10/10-084152) presents age- and sex-adjusted and fully adjusted OR with 95% CIs. After adjustments for age and sex only, the following variables were significant risk factors: increasing age, Inuit ethnicity, young maternal age, narrow age gap (< 1 year) to next older sibling and region of residence (southern, highest; eastern, intermediate; western, lowest). After multivariate adjustment (full adjustment) the following variables were significantly associated with MTI: increasing age, Inuit ethnicity, narrow age gap to next older sibling and region of residence. Variables that were not associated with the risk of infection included: crowding as measured by the total number of dwellers or the number of children in the household, birth order, age difference in years between the child and the next younger sibling, co-morbidity in the child, father’s education level and type of heating facilities.
Table 2. Potential risk factors for Mycobacterium tuberculosis infection (MTI) among 1797 Greenlandic schoolchildren, 2005–2007
Table 3 (available at: http://www.who.int/bulletin/volumes/89/10/10-084152) shows the association between having MTI and each of the potential risk factors encountered in children with and without a reported TB contact. We checked whether the effect of each variable was modified by the presence or absence of a known TB contact. The variables whose effect was significantly modified by the presence of a known TB contact were domestic crowding (increased risk: P = 0.009) and mother’s education (decreased risk: P = 0.05). Region of residence was only associated with MTI among children without a known TB contact (P = 0.03), with children in southern Greenland having the highest risk.
Table 3. Odds ratios (ORs) for Mycobacterium tuberculosis infection (MTI), by potential risk factors, among 1797 Greenlandic schoolchildren stratified by TB contact
This study is, to our knowledge, the first one to have examined the rates of MTI and its risk factors in children living in the Arctic region. We found that contact with a patient with clinically active TB, increasing age, Inuit ethnicity, and a narrow age difference between the child and the next older sibling were significantly associated with positivity for MTI. However, stratifying for contact with a known TB case modified this picture somewhat. Among the children in the study who had a known TB contact (10%), domestic crowding and low maternal educational level were significant risk factors for MTI, while the only significant risk factor for MTI among children without a known TB contact was the region of residence.
Thus, two different risk factor patterns for MTI exist among children in Greenland, with the presence or absence of a known TB contact being the definitive factor. Among children with a known TB contact, the increased risk of MTI associated with living in crowded conditions may be the result of both easier transmission of M. tuberculosis because of closer contact between family members or because more family members are infected with M. tuberculosis. Similarly, low maternal education, insofar as it is linked to low socioeconomic status, may favour transmission of MTI within the household because of suboptimal hygienic standards and care for cases with TB. Other studies have also found low socioeconomic status to be associated with poorer general health, which may increase susceptibility to MTI among children living in households with fewer resources.20
Even in children without a known TB contact, the source of infection appears to be within the household. A child’s risk of MTI was 14 times higher when an older sibling was found to be infected, even when the source of the infection was not known to be within the family. When two children within a family have MTI, both may have been exposed to a third active TB case or one child may have been sequentially exposed to the other. The finding that geographical region of residence was a risk factor for MTI in children without a known TB contact underlines the greater likelihood of community exposure when prevalence is high in the area. While this increased risk would also be true among children with known TB contact, M. tuberculosis exposure within the family dominated MTI risk, adjusting away the community-associated risk
In children with and without TB contacts, the increasing risk of MTI with increasing age points to a cumulative risk of acquiring MTI over time, a finding also observed in other studies.21,22 We have previously reported that the annual risk of MTI in Greenland is 0.8% per year, which translates into a prevalence of MTI of about 13% by the age of 18 years.5
Inuit ethnicity was also associated with a higher risk of MTI in children with or without a known TB contact. Both genetic and environmental factors may be at play. Overall, little is known about the genetic susceptibility to tuberculosis, but some have reported that polymorphisms in the genes for mannose binding lectin and for the interferon gamma receptor are associated with susceptibility to M. tuberculosis.23–25 In Greenland, social determinants probably increase the risk of MTI among Inuit children, since Inuit families tend to be larger, to live in more crowded conditions and to be less educated than families in which at least one parent is Danish.26
A narrow age gap between a child and a next-older-sibling with MTI was a risk factor for TB both among children with a known TB contact and those without. This finding has been documented in studies of other infectious agents27,28 but not, to our knowledge, in studies on MTI. Traditionally, children with active TB disease are not considered infectious because they excrete few bacteria. However, in adolescence TB begins to resemble the adult form of the disease and can become sputum positive, as in adults, which poses the risk of transmission.29–31 It is also possible that a narrow age gap between siblings acts as a proxy for closer interaction with elder siblings or a common social circle, both of which could make for a shared source of infection.
In 2007, the Greenlandic Directorate of Health revised the national TB programme by adding public information campaigns and educational materials for disease prevention programmes.32 Our findings, based on MTI as the outcome, suggest that future campaigns should primarily target the Inuit population living in high-incidence regions and the inhabitants of small communities and settlements, and that efforts should be made to enhance contact tracing within families of low socioeconomic status. In Greenland, TB screening is routinely performed when children enter school and again when they graduate. This study has shown that if a child screens positive for MTI, intensive investigation of all members of the family should be undertaken promptly.
Our study has several strengths. The study population comprised approximately 17% of the total population of Greenland in the relevant age groups. The sample population was almost identical in its demographic characteristics to the population of Greenland as a whole. Because enrolment in the study was based on school attendance, which is mandatory in Greenland, our study sample is not likely to be biased by differences in access to health care. We know from previous experience that school lists, which form the basis for registering children in the communities, often include children temporarily or permanently absent from the area. We therefore consider a participation rate of 62% to be acceptable and the sampled population to be representative of the entire population of Greenland. Furthermore, we diagnosed MTI conservatively (i.e. requiring positivity on both QFN and TST), which minimizes the chances of misclassification. However, it is possible that earlier TB treatment mitigated the response to QFN and TST in some children33 Finally, the use of information from national registers minimized recall bias, but bias resulting from the non-participation of sick children cannot be ruled out. Furthermore, the responses to the questionnaire may be subject to recall bias. However, since the study participants did not know their MTI status, any misclassification was non-differential and would, if anything, underestimate the true effect of our association with MTI.
In conclusion, the present study revealed that family crowding as well as increasing age, Inuit ethnicity, region of residence and age difference between siblings are factors associated with MTI among children in Greenland. However, having had known contact with a person with active TB markedly modified the risk factor profile. Domestic crowding and low maternal educational level emerged as risk factors among children with a known TB contact but not among those who had no known contact with a TB patient. These findings can be used to target future public health interventions specifically at Greenlandic children with the highest risk of MTI.
We thank Katrin Kristiansen, Karen Laursen, Jannie Hein Pedersen and her colleagues, Turid Skifte, Melanie Veber and Jette Weismann for their valuable contributions to this study. Finally, we thank the staff at the schools and health-care facilities for their cooperation.
- Annual report from the Chief Medical Officer in Greenland, 2009. Nuuk: Chief Medical Officer; 2010.
- Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976; 57: S1-58 doi: 10.1016/0041-3879(76)90059-3 pmid: 797076.
- Søborg C, Søborg B, Pouelsen S, Pallisgaard G, Thybo S, Bauer J. Doubling of the tuberculosis incidence in Greenland over an 8-year period (1990–1997). Int J Tuberc Lung Dis 2001; 5: 257-65 pmid: 11326825.
- Thomsen VO. Assesment of the Greenlandic Tuberculosis Programme. Copenhagen: Institute of International Health, Immunology & Microbiology, University of Copenhagen; 2009.
- Soborg B, Koch A, Thomsen VO, Ladefoged K, Andersson M, Wohlfahrt J, et al., et al. Onoing tuberculosis transmission to children in Greenland. Eur Respir J 2010; 36: 878-84 doi: 10.1183/09031936.00015510 pmid: 20516050.
- Lohse N, Ladefoged K, Obel N. Implementation and effectiveness of antiretroviral therapy in Greenland. Emerg Infect Dis 2008; 14: 56-9 doi: 10.3201/eid1401.071117 pmid: 18258077.
- Hoeppner VH, Marciniuk DD. Tuberculosis in aboriginal Canadians. Can Respir J 2000; 7: 141-6 pmid: 10859400.
- Nguyen D, Proulx JF, Westley J, Thibert L, Dery S, Behr MA. Tuberculosis in the Inuit community of Quebec, Canada. Am J Respir Crit Care Med 2003; 168: 1353-7 doi: 10.1164/rccm.200307-910OC pmid: 14500266.
- Orr P. Adherence to tuberculosis care in Canadian Aboriginal populations, Part 2: a comprehensive approach to fostering adherent behaviour. Int J Circumpolar Health 2011; 70: 128-40 pmid: 21524358.
- Funk EA. Tuberculosis contact investigations in rural Alaska: a unique challenge. Int J Tuberc Lung Dis 2003; 7: S349-52 pmid: 14677821.
- Schneider E. Tuberculosis among American Indians and Alaska Natives in the United States, 1993–2002. Am J Public Health 2005; 95: 873-80 doi: 10.2105/AJPH.2004.052456 pmid: 15855468.
- Lönnroth K, Jaramillo E, Williams BG, Dye C, Raviglione M. Drivers of tuberculosis epidemics: the role of risk factors and social determinants. Soc Sci Med 2009; 68: 2240-6 doi: 10.1016/j.socscimed.2009.03.041 pmid: 19394122.
- Young K. Health transitions in Arctic populations. Toronto: University of Toronto Press; 2008
- Bjerregaard P. Living conditions, lifestyle and health – a population based survey in Greenland 2005-2009. In: Government of Greenland; 2010. Danish.
- Ladefoged K, Rendal T, Skifte T, Andersson M, Søborg B, Koch A. Risk factors for tuberculosis in Greenland: case-control study. Int J Tuberc Lung Dis 2011; 15: 44-9 pmid: 21276295.
- Childhood BMI calculator. Atlanta: Centers for Disease Control and Prevention; 2010.
- Pedersen CB, Gøtzsche H, Møller JO, Mortensen PB. The Danish Civil Registration System. A cohort of eight million persons. Dan Med Bull 2006; 53: 441-9 pmid: 17150149.
- Krause TG, Koch A, Poulsen LK, Kristensen B, Olsen OR, Melbye M. Atopic sensitization among children in an arctic environment. Clin Exp Allergy 2002; 32: 367-72 doi: 10.1046/j.1365-2222.2002.01316.x pmid: 11940065.
- Nguyen TH, Odermatt P, Slesak G, Barennes H. Risk of latent tuberculosis infection in children living in households with tuberculosis patients: a cross sectional survey in remote northern Lao People’s Democratic Republic. BMC Infect Dis 2009; 9: 96- doi: 10.1186/1471-2334-9-96 pmid: 19534769.
- Adler NE, Boyce T, Chesney MA, Cohen S, Folkman S, Kahn RL, et al., et al. Socioeconomic status and health: the challenge of the gradient. Am Psychol 1994; 49: 15-24 doi: 10.1037/0003-066X.49.1.15 pmid: 8122813.
- Sutherland I, Bleiker MA, Meijer J, Stýblo K. The risk of tuberculous infection in the Netherlands from 1967 to 1979. Tubercle 1983; 64: 241-53 doi: 10.1016/0041-3879(83)90021-1 pmid: 6606884.
- Sutherland I, Fayers PM. The association of the risk of tuberculous infection with age. Bull Int Union Tuberc 1975; 50: 70-81 pmid: 1218289.
- Søborg C, Madsen HO, Andersen AB, Lillebaek T, Kok-Jensen A, Garred P. Mannose-binding lectin polymorphisms in clinical tuberculosis. J Infect Dis 2003; 188: 777-82 doi: 10.1086/377183 pmid: 12934195.
- Cooke GS, Campbell SJ, Sillah J, Gustafson P, Bah B, Sirugo G, et al., et al. Polymorphism within the interferon-gamma/receptor complex is associated with pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174: 339-43 doi: 10.1164/rccm.200601-088OC pmid: 16690980.
- Rossouw M, Nel HJ, Cooke GS, van Helden PD, Hoal EG. Association between tuberculosis and a polymorphic NFkappaB binding site in the interferon gamma gene. Lancet 2003; 361: 1871-2 doi: 10.1016/S0140-6736(03)13491-5 pmid: 12788577.
- Kuemmerer JM, Comstock GW. Sociologic concomitants of tuberculin sensitivity. Am Rev Respir Dis 1967; 96: 885-92 pmid: 6059198.
- Koch A, Krause TG, Krogfelt K, Olsen OR, Fischer TK, Melbye M. Seroprevalence and risk factors for Helicobacter pylori infection in Greenlanders. Helicobacter 2005; 10: 433-42 doi: 10.1111/j.1523-5378.2005.00351.x pmid: 16181354.
- Goodman KJ, Correa P. Transmission of Helicobacter pylori among siblings. Lancet 2000; 355: 358-62 doi: 10.1016/S0140-6736(99)05273-3 pmid: 10665555.
- Rieder HL. Epidemiologic basis of tuberculosis control. Paris: International Union Against Tuberculosis and Lung Disease; 1999.
- Curtis AB, Ridzon R, Vogel R, McDonough S, Hargreaves J, Ferry J, et al., et al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med 1999; 341: 1491-5 doi: 10.1056/NEJM199911113412002 pmid: 10559449.
- Marais BJ, Gie RP, Hesseling AH, Beyers N. Adult-type pulmonary tuberculosis in children 10–14 years of age. Pediatr Infect Dis J 2005; 24: 743-4 doi: 10.1097/01.inf.0000173305.04212.09 pmid: 16094237.
- The National Greenlandic Tuberculosis Strategy 2007-2012. Nuuk: Chief Medical Officer; 2007.
- Chee CB, KhinMar KW, Gan SH, Barkham TM, Koh CK, Shen L, et al. Tuberculosis treatment effect on T-cell interferon-gamma responses to Mycobacterium tuberculosis-specific antigens. Eur Respir J 2010.36:355-61