Improvement in Diagnosis and Management of Tuberculosis in Children.
Submitting InstitutionImperial College London
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Medical Microbiology, Public Health and Health Services
Summary of the impact
In 2006, new diagnostic tools for tuberculosis (TB) were introduced
through the NICE guidelines, assuming they would perform equally well in
adults and children. Research conducted by Imperial College researchers
proved this assumption to be incorrect and that TB diagnostics needed to
be evaluated specifically for children, as performance was different from
adults. The Imperial researchers were the first to conduct the
evaluations. Their results subsequently influenced the use of diagnostics
and overall management of childhood TB, including the design of a public
health tool for contact tracing in the community and inclusion of their
results and recommendations in national and international guidelines.
Key Imperial College London researchers:
Professor Beate Kampmann, Professor in Paediatric Infection & Immunity
Dr Robin Basu-Roy, Academic Clinical Fellow in Paediatric Infectious
Dr Elizabeth Whittaker, Academic Clinical Fellow, then PhD student
Tuberculosis (TB) remains a global threat with an estimated half a
million children (0-14 years) falling ill and 64,000 deaths attributable
to TB in children per year worldwide (1). National and international
guidelines or algorithms for management of TB are usually developed for
management of adult TB and guideline developers assume that they will also
equally apply to children. However, work at Imperial has shown, this is
not the case. TB is different in children, due to the underlying
immaturity of their immune system and lower bacillary burden, which has an
impact on immunological and microbiological diagnostic tools (2). By using
"adult tools", the diagnosis and opportunities for diagnosis and
prevention are often missed.
One powerful example is the 2006 NICE recommendation for use of
interferon-gamma release assays (IGRA) for the diagnosis of TB. Through
the unique work at Imperial all available immuno- diagnostic tests were
evaluated comparatively in a large paediatric cohort within several NHS
Trusts (3). The work at Imperial demonstrated that they do not perform as
reliably in children as they do in adults, should be interpreted with
caution and certainly not be used to exclude active TB (4). This study has
informed many of the International and European guidelines and consensus
TB in children is the result of transmission from an infected adult. In
order to prevent it, contact tracing in TB-affected households has to be
conducted. However, these activities were not previously captured by the
TB register in the UK and therefore the outcome of children traced and
treated in the community was not recorded, unless the children themselves
had become TB cases. As part of the Imperial research programme, in
collaboration with the National TB register and Public Health England
(PHE), Professor Kampmann developed a novel database which enables a link
between children exposed to TB, their management in the community and
later development of disease. Professor Kampmann designed this contact
tracing module which is now implemented as part of the TB reporting system
in the UK and can be used to capture the success or failure of TB
prevention in children.
The evidence gathered from our multi-centre studies has defined the
practices of diagnosis and management of childhood TB in the UK and
internationally. The contact tracing database has made an important
contribution to TB control in the country by enabling follow-up of
patients who are TB exposed but not yet diseased. This illustrates how the
most current research has driven change in the management of TB in both
adults and children. It is facilitated by close links between PHE and
The research work at Imperial has also led to the establishment of a
paediatric TB research network in both the UK and Europe, the ptbnet
(www.ptbnet.org). This network has published evidence from a cohort of
over 1000 children from 5 European countries on the performance of IGRA
for TB diagnosis in children and discovered that BCG vaccination protects
against TB infection (6).
References to the research
(1) Newton, S.M., Brent, A.J., Anderson, S., Whittaker, E., &
Kampmann, B. (2008). Paediatric Tuberculosis. Lancet Infectious
Diseases, 8 (8), 498-510. DOI.
Times cited: 95 (as at 1st November 2013 on ISI Web of
Science). Journal Impact Factor: 19.96
(2) Jones, C., Whittaker, E., Bamford, A., & Kampmann, B. (2011).
Immunology and pathogenesis of childhood TB. Paediatr Respir Rev,
12 (1), 3-8. DOI.
Times cited: 6 (as at 1st November 2013 on ISI Web of Science).
Journal Impact Factor: 2.79
(3) Bamford, A.R., Crook, A.M., Clark, J., Nademi, Z., Dixon, G., Paton,
J.Y., Riddell, A., Drobniewski, F., Riordan, A., Anderson, S.T., Williams,
A., Walters, S., & Kampmann, B. (2010). Comparison of Interferon-gamma
release assays and Tuberculin Skin Test in predicting active tuberculosis
(TB) in children in the UK- a Paediatric TB Network Study. Arch Dis
Child, 95 (3), 180- 186. DOI.
Times cited: 33 (as at 1st November 2013 on ISI Web of
Science). Journal Impact Factor: 3.05
(4) Kampmann, B., Whittaker, E., Williams, A., Walters, S., Gordon, A.,
Martinez-Alier, N., Williams, B., Crook, A.M., Hutton, A.M., &
Anderson, S.T. (2009). Interferon-gamma release assays do not identify
more children with active tuberculosis than the tuberculin skin test. European
Respiratory Journal, 33 (6), 1374-1382. DOI.
Times cited: 57 (as at 1st November 2013 on ISI Web of
Science). Journal Impact Factor: 6.35
(5) Mack, U., Migliori, G.B., Sester, M., Rieder, H.L., Ehlers, S.,
Goletti, D., Bossink, A., Magdorf, K., Hölscher, C., Kampmann, B., Arend,
S.M., Detjen, A., Bothamley, G., Zellweger, J.P., Milburn, H., Diel, R.,
Ravn, P., Cobelens, F., Cardona, P.J., Kan, B., Solovic, I., Duarte, R.,
Cirillo, D.M., Lange, C., TBNET. (2009). LTBI:
latent tuberculosis infection or lasting immune responses to
M.tuberculosis? A TBNET consensus statement. Eur Respir J.,
33(5), 956-973. DOI.
Times cited: 152 (as at 1st November 2013 on ISI Web of
Science). Journal Impact Factor: 6.35
(6) Basu Roy, R., Sotgiu, G., Altet-Gómez, N., Tsolia, M., Ruga, E.,
Velizarova, S., & Kampmann, B. (2012). Identifying predictors of
interferon-03b3 release assay results in pediatric latent tuberculosis: a
protective role of bacillus Calmette-Guerin?: a p TB-NET collaborative
study. Am J Respir Crit Care Med., 186 (4), 378-384. DOI.
Times cited: 11 (as at 1st November 2013 on ISI Web of
Science). Journal Impact Factor: 11.04
• Wellcome Trust (1999-2003, £378 000), Principal Investigator (PI) B.
Kampmann, Training Fellowship.
• Wellcome Trust (2005-2009, £705 000), PI B. Kampmann, Career
• NIHR (2009-2014, £1.3 million), PI B. Kampmann, Senior Research
Details of the impact
Impacts include: public policy and services, practitioners and services,
health and welfare Main Beneficiaries include: Patients, practitioners,
NICE, PHE, NHS, UK and nternational Government, ECDC, WHO, NIH
The World Health Organisation (WHO) currently estimates that half a
million children (0-14 years) falling ill and 64,000 deaths are
attributable to TB per year worldwide (WHO
figures). Research at Imperial College has developed the evidence
base for the diagnosis and management of childhood TB nationally and
In May 2012 the NICE guidelines were changed to a pathway approach. The
guidelines now contain separate guidelines for the management of children
in separate age groups. The work performed at Imperial informed the age
stratification . The contribution of IGRA to the diagnostic process has
been downgraded significantly and the approach advocated by Professor
Kampmann and colleagues at Imperial for synergistically using IGRA and a
tuberculin skin test to increase sensitivity has been adopted and the need
for childhood-specific management internationally acknowledged.
At a European level the European Centre for Disease Prevention and
Control (ECDC) has utilised Imperial research in the ECDC guidance for the
use of interferon-gamma release assays for TB diagnosis . The
algorithms resulting from the Imperial research have been used to develop
several European consensus statements from the Tuberculosis
Network in Europe [2, 3]. The ECDC conducted a campaign for advocacy
in childhood TB, which included an extensive review of the burden of
childhood TB in Europe and a feature broadcasted on Euronews in March 2011
in 22 languages. (World Tuberculosis Day 2011: Three key messages on
childhood tuberculosis .
The notion of TB as a family disease has been adopted by many centres now
holding joint adult and paediatric TB clinics, including the establishment
of family clinics for TB in Prof Kampmann's international TB work linked
to The Gambia. The Stop TB partnership now specifically mentions the
The ability to link exposed, infected and diseased individuals on the UK
TB register has been facilitated by Imperial research and development of
the contact tracing module by Professor Kampmann. The TB register has
important ongoing implications for TB control in the UK. This UK TB
Register and the contact tracing module are now utilised by other
international organisations and settings .
Imperial research has also influenced and directed policy and guidance
documentation produced by the WHO and National Institutes of Health (NIH).
The research has impacted the TB diagnosis methodologies undertaken and
the policies employed internationally in the following ways:
- Use of interferon-03b3 release assays (IGRAs) in tuberculosis control
in low and middle income settings .
- Recommendations for investigating contacts of persons with infectious
tuberculosis in low- and middle-income Countries 
- Development of a novel case definition for childhood TB by the NIH 
Many of the policies and practices now embedded in the NHS have been
adopted in other overseas healthcare systems. For example, the Stop TB
partnership recently published a press release which provides evidence for
the impact of the Imperial led research on long-term efforts to tackle
childhood TB in The Gambia, where Professor Kampmann has implemented a
childhood TB research program. As a result of the Imperial research
children identified through the contact tracing programme are now given
prophylactic drugs .
The Imperial research has been formulated into expert review documents
and educational reference chapters. These document impact the way
clinicians and health practitioners are educated and results in the wide
adoption of best practice. Professor Kampmann is the author of the chapter
"How to use IGRA in children" . The education and practice papers in
Archives of Diseases of Childhood serve as a guide for general
paediatricians. This journal has the full readership of the Royal College
of Paediatrics and Child Health as it is published by the Royal College.
It is the leading source of information for general paediatricians on this
issue. The European Respiratory Society (ERS) is the leading professional
organisation in its field in Europe. It is broad-based, with some 10,000
members and counting in over 100 countries. Its scope covers both basic
science and clinical medicine. ERS seeks to alleviate suffering from
respiratory disease and promote lung health through research, sharing of
knowledge and through medical and public education. The Imperial College
research has contributed to this mission through publications in the ERS
handbooks and also on line teaching sessions.
Sources to corroborate the impact
clinical guidance on Tuberculosis 117 (March 2011). Archived
on 1st November 2013
 Solovic, I., Sester, M., Gomez-Reino, J.J., Rieder, H.L., Ehlers, S.,
Milburn, H.J., Kampmann, B., Hellmich, B., Groves, R., Schreiber, S.,
Wallis, R.S., Sotgiu, G., Schölvinck, E.H., Goletti, D., Zellweger, J.P.,
Diel, R., Carmona, L., Bartalesi, F., Ravn, P., Bossink, A., Duarte, R.,
Erkens, C., Clark, J., Migliori, G.B., Lange, C. (2010). The
risk of tuberculosis related to tumour necrosis factor antagonist
therapies: a TBNET consensus statement. Eur Respir J., 36
(5), 1185-1206. DOI.
 Bumbacea, D., Arend, S.M., Eyuboglu, F., Fishman, J.A., Goletti, D.,
Ison, M.G., Jones, C.E., Kampmann, B., et al. (2012). The
risk of tuberculosis in transplant candidates and recipients: A TBNET
consensus statement. Eur Respir J., 40 (4), 990-1013. DOI.
 Stop TB Partnership: http://stoptb.org/news/stories/2013/ns13_060.asp
1st November 2013.
TB Register and the contact tracing module are now utilised by other
international organisations and settings. Archived
on 1st November 2013.
 Use of interferon-03b3 release assays (IGRAs) in tuberculosis control
in low and middle income settings:http://www.who.int/tb/features_archive/igra_egm_report_oct2011.pdf.
on 1st November 2013.
 Recommendations for investigating contacts of persons with infectious
tuberculosis in low- and middle-income Countries
 Graham, S.M., Ahmed, T., Amanullah, F., Browning, R., Cardenas, V.,
Casenghi, M., Cuevas, L.E., Gale, M., Gie, R.P., Grzemska, M., Handelsman,
E., Hatherill, M., Hesseling, A.C., Jean- Philippe, P., Kampmann, B., et
al. (2012). Evaluation
of tuberculosis diagnostics in children: 1. Proposed clinical case
definitions for classification of intrathoracic tuberculosis disease.
Consensus from an expert panel. J Infect Dis., 205 (Suppl
2), S199-208. DOI.
 ECDC guidance: http://www.ecdc.europa.eu/en/publications/publications/1103_gui_igra.pdf.
 Educational texts: