DOI: 10.5061/dryad.gxd2547wv
title: Does cytomegalovirus infection increase the risk of tuberculosis in UK children?

description: 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.
description: <strong>Participants</strong> 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. <strong>Study design</strong> In this cross-sectional NIKS sub-study, samples were obtained from three clinical groups: children with TB disease, those with <em>Mtb</em> infection, and those with TB exposure (household TB contact, but no evidence of <em>Mtb</em> 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 <em>Mtb</em> sensitisation had a negative TST and IGRA. <strong>Samples</strong> Serum samples were obtained from the participants’ first clinic visit. Samples had been stored at -80 degrees Celsius. Samples with &lt;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. <strong>Laboratory analyses</strong> 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 &gt;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<sup>®</sup> 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. <strong>Statistical analysis</strong> Stata<sup>TM</sup> 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, <em>Mtb</em> infection, and TB exposure as three independent groups. An odds ratio was performed to determine the association between CMV seropositivity and TB clinical state.
description: # Does cytomegalovirus infection increase the risk of tuberculosis in UK
 children? Dryad
 DOI:  [https://doi.org/10.5061/dryad.gxd2547wv](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* (&gt;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. 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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.