Does cytomegalovirus infection increase the risk of tuberculosis in UK children?
Data files
Nov 04, 2025 version files 15.69 KB
Abstract
There is a hypothesised association between pre-existing cytomegalovirus (CMV) infection and risk of acquiring tuberculosis (TB). We aimed to explore if CMV seroprevalence and CMV IgG levels in children were associated with TB disease or Mycobacterium tuberculosis (Mtb) infection compared to children who were exposed to TB but remained well. In this cross-sectional analysis from an observational cohort study of children exposed to TB in their household in the United Kingdom, we examined samples from seventy-five participants, of whom 40 (53%) were male. Median age of the cohort was 6 years (interquartile range: 3-11 years). Twenty-one (28%) children had TB disease, 27 (36%) had Mtb infection, and 27 (36%) had TB exposure only. There was no increased risk of TB in children who were CMV-seropositive (OR 2.18 (0.75-6.48)), and there were no differences in CMV IgG quantification by TB category. There was no detectable CMV viraemia in any of the children in our study. We found higher levels of CMV seroprevalence (49%) than previously described in the United Kingdom. In this small study of children exposed to TB, in a low TB burden setting, we found no association between CMV serostatus or CMV IgG titre and TB status.
Dryad DOI: https://doi.org/10.5061/dryad.gxd2547wv
Description of the data and file structure
We have submitted our raw data. This file contains data for 75 participants (children and adolescents) who had been exposed to a household TB contact. They had subsequently been categorised as having active TB disease, LTBI (Mtb sensitisation), or no evidence of TB. CMV seropositivity and CMV IgG levels were obtained for these patients.
Files and variables
File: Does_cytomegalovirus_infection_increase_the_risk_of_tuberculosis_in_UK_children_csv.csv
Descriptions
Variables
- ID- identification
- sex- (birth sex) binary female/male
- BCG- (Bacillus Calmette-Guérin) received (Y/N)
- TB_diagnosis- active TB/ latent TB/ no evidence of latent TB infection
- TB_all_diagnoses- TB group (active or latent TB: Yes- 1, no evidence of TB: No-0)
- agegrp- age in bands (0 to 2, 2 to 5, 6 to 10, 11+ (y))
- start_n - (date of entry to study, pseudo-anonymised to first date of the month)
- Mean_Antibody_level- (CMV level (IU/ml))
- CMV_seropositivity (>1.1 = positive)
- AvgConc (average concentration)
- Antibody_level (by tertile)
- OD- optical density (nm)
- OD2- optical density two (nm)
- SD- standard deviation
- CV- coefficient of variation
References
1. Togun T. Childhood tuberculosis in high burden settings. EBioMedicine. 2021;63:103181.
2. Dodd PJ, Yuen CM, Sismanidis C, Seddon JA, Jenkins HE. The global burden of tuberculosis mortality in children: a mathematical modelling study. The Lancet Global Health. 2017;5(9):e898-e906.
3. Rabie H, Frigati LJ, Nkosi N. Cytomegalovirus and tuberculosis disease in children. The Lancet Global Health. 2021;9(12):e1636-e7.
4. Cobelens F, Nagelkerke N, Fletcher H. The convergent epidemiology of tuberculosis and human cytomegalovirus infection. F1000Res. 2018;7:280.
5. Bates M, Brantsaeter AB. Human cytomegalovirus (CMV) in Africa: a neglected but important pathogen. J Virus Erad. 2016;2(3):136-42.
6. Olbrich L, Stockdale L, Basu Roy R, Song R, Cicin-Sain L, Whittaker E, et al. Understanding the interaction between cytomegalovirus and tuberculosis in children: The way forward. PLoS Pathog. 2021;17(12):e1010061.
7. Kua KP, Chongmelaxme B, Lee SWH. Association Between Cytomegalovirus Infection and Tuberculosis Disease: A Systematic Review and Meta-Analysis of Epidemiological Studies. J Infect Dis. 2023;227(4):471-82.
8. Swanepoel J, van Zyl G, Hesseling AC, Johnson SM, Moore DAJ, Seddon JA. Human Cytomegalovirus Immunoglobulin G Response and Pulmonary Tuberculosis in Adolescents: A Case-Control Study. Open Forum Infect Dis. 2023;10(11):ofad487.
9. Rojo P, Moraleda C, Tagarro A, Dominguez-Rodriguez S, Castillo LM, Tato LMP, et al. Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: study protocol for a multicenter, open-label randomized controlled clinical trial. Trials. 2022;23(1):531.
10. Pembrey L, Waiblinger D, Griffiths P, Wright J. Age at cytomegalovirus, Epstein Barr virus and varicella zoster virus infection and risk of atopy: The Born in Bradford cohort, UK. Pediatr Allergy Immunol. 2019;30(6):604-13.
11. Pembrey L, Waiblinger D, Griffiths P, Patel M, Azad R, Wright J. Cytomegalovirus, Epstein-Barr virus and varicella zoster virus infection in the first two years of life: a cohort study in Bradford, UK. BMC Infect Dis. 2017;17(1):220.
12. Winter JR, Taylor GS, Thomas OG, Jackson C, Lewis JEA, Stagg HR. Factors associated with cytomegalovirus serostatus in young people in England: a cross-sectional study. BMC Infect Dis. 2020;20(1):875.
13. Zuhair M, Smit GSA, Wallis G, Jabbar F, Smith C, Devleesschauwer B, et al. Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Rev Med Virol. 2019;29(3):e2034.
14. Gkrania-Klotsas E, Langenberg C, Sharp SJ, Luben R, Khaw KT, Wareham NJ. Seropositivity and higher immunoglobulin G antibody levels against cytomegalovirus are associated with mortality in the population-based European Prospective Investigation of Cancer-Norfolk cohort. Clin Infect Dis. 2013;56(10):1421-7.
15. Hameiri Bowen D, Sovershaeva E, Charlton B, Schive C, Odland J, McHugh G, et al. Cytomegalovirus-Specific Immunoglobulin G Is Associated With Chronic Lung Disease in Children and Adolescents from Sub-Saharan Africa Living With Perinatal Human Immunodeficiency Virus. Clin Infect Dis. 2021;73(1):e264-e6.
16. Whittaker E, Lopez-Varela E, Broderick C, Seddon JA. Examining the Complex Relationship Between Tuberculosis and Other Infectious Diseases in Children. Front Pediatr. 2019;7:233.
17. Martinez L, Nicol MP, Wedderburn CJ, Stadler A, Botha M, Workman L, et al. Cytomegalovirus acquisition in infancy and the risk of tuberculosis disease in childhood: a longitudinal birth cohort study in Cape Town, South Africa. The Lancet Global Health. 2021;9(12):e1740-e9.
18. Stockdale L, Nash S, Nalwoga A, Painter H, Asiki G, Fletcher H, et al. Human cytomegalovirus epidemiology and relationship to tuberculosis and cardiovascular disease risk factors in a rural Ugandan cohort. PLoS ONE. 2018;13(2):e0192086.
19. Kampmann B, Seddon JA, Paton J, Nademi Z, Keane D, Williams B, et al. Evaluating UK National Guidance for Screening of Children for Tuberculosis. A Prospective Multicenter Study. Am J Respir Crit Care Med. 2018;197(8):1058-64.
20. van der Heijden YF, Zhang B, Chougnet CA, Huaman MA. Cytomegalovirus infection is associated with increased prevalence of latent tuberculosis infection. Open Forum Infectious Diseases. 2021.
21. Voigt S, Schaffrath Rosario A, Mankertz A. Cytomegalovirus Seroprevalence Among Children and Adolescents in Germany: Data From the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), 2003-2006. Open Forum Infect Dis. 2016;3(1):ofv193.
22. Koidl C, Bozic M, Marth E, Kessler HH. Detection of CMV DNA: is EDTA whole blood superior to EDTA plasma? J Virol Methods. 2008;154(1-2):210-2.
23. Dioverti MV, Lahr BD, Germer JJ, Yao JD, Gartner ML, Razonable RR. Comparison of Standardized Cytomegalovirus (CMV) Viral Load Thresholds in Whole Blood and Plasma of Solid Organ and Hematopoietic Stem Cell Transplant Recipients with CMV Infection and Disease. Open Forum Infect Dis. 2017;4(3):ofx143.
24. Payne H, Lawrie D, Nieuwoudt M, Cotton MF, Gibb DM, Babiker A, et al. Comparison of Lymphocyte Subset Populations in Children From South Africa, US and Europe. Front Pediatr. 2020;8:406.
25. Chappell E, Lyall H, Riordan A, Thorne C, Foster C, Butler K, et al. The cascade of care for children and adolescents with HIV in the UK and Ireland, 2010 to 2016. J Int AIDS Soc. 2019;22(9):e25379.
26. Turkova A, Chappell E, Judd A, Goodall RL, Welch SB, Foster C, et al. Prevalence, incidence, and associated risk factors of tuberculosis in children with HIV living in the UK and Ireland (CHIPS): a cohort study. Lancet HIV. 2015;2(12):e530-9.
Human subjects data
Data has been de-identified by direct and indirect identifiers being removed/changed. For example, age bands have been used, and there are less than 3 indirect identifiers in the data set. Any unnecessary data which may include any unique information has been eliminated.
Participants aged 0-16 years were recruited between January 2011 and December 2014 from 11 paediatric TB clinics in the United Kingdom, as part of the NIKS Cohort Study. In 2006, the National Institute for Health and Care Excellence (NICE) in the United Kingdom recommended that, following household TB exposure, children should be evaluated using tuberculin skin testing (TST). Those with positive TST results should undergo interferon-gamma release assays (IGRA) evaluation, and only those with positive results would be eligible for TB preventive treatment. The NIKS Cohort Study sought to evaluate the negative predictive performance of interferon-gamma release assays in TST-positive children. Serial serum samples were taken at baseline and over the period of follow-up (19). Children who had previously had a positive test for TB were excluded. Of the 392 participants of the NIKS Cohort Study, samples were only available from a subset of 75 children from six of the study sites (The Royal London, Birmingham, Bristol, St Mary’s, Northwick Park, and Southampton hospitals). Data available included age, sex, TB symptoms at first clinic appointment, TB diagnosis, TB treatment, Bacillus Calmette-Guérin (BCG) status, TST result, and IGRA results.
Study design
In this cross-sectional NIKS sub-study, samples were obtained from three clinical groups: children with TB disease, those with Mtb infection, and those with TB exposure (household TB contact, but no evidence of Mtb sensitisation). Evaluation for TB disease in the original NIKS Cohort Study for TB disease included history, examination, chest radiography, TST and IGRA tests, and microbiology if indicated. TB disease was diagnosed based on NICE guidelines for children above the age of 2 years, in conjunction with the clinical context, by paediatricians(19).
Mtb infection included children with a positive TST and/or a positive IGRA. A positive TST was defined as a transverse diameter of the induration was ≥6 mm in BCG-unvaccinated children and ≥15 mm in vaccinated children, in line with the 2006 NICE recommendations. The child was classified as IGRA positive if either the baseline or the 2-month IGRA was positive. Further details are available in the NIKS Cohort Study(19). Children who were a household TB contact and had no evidence of Mtb sensitisation had a negative TST and IGRA.
Samples
Serum samples were obtained from the participants’ first clinic visit. Samples had been stored at -80 degrees Celsius. Samples with <250 microlitres were excluded due to insufficient sample remaining for both polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) to be carried out.
Laboratory analyses
CMV-specific IgG was measured using GenWay Biotech Cytomegalovirus IgG ELISA as per the manufacturer’s instructions, and optical density was used to estimate the quantity of CMV-specific IgG using the VersaMax ELISA Microplate reader. Seropositivity was defined as a CMV IgG detected at >1.1 IU/ml. QIAGEN QIAamp® Blood Kit was used to extract DNA from serum, and CMV DNA was quantified by real-time PCR using the BioMérieux ARGENE CMV R-GENE® kit. Samples were run in triplicate on the Applied Biosystems StepOnePlus Real-Time PCR system. The maximum sensitivity of the assay was 446 copies per ml. Presence of CMV IgG in serum was taken to represent any time exposure to CMV, and presence of CMV DNA in serum was defined as acute infection.
Statistical analysis
StataTM 16.1 was used for all analyses. A Kruskal-Wallis equality of proportions rank test was carried out for CMV IgG level and evaluated children with TB disease, Mtb infection, and TB exposure as three independent groups. An odds ratio was performed to determine the association between CMV seropositivity and TB clinical state.