IP-10 for the diagnosis and treatment monitoring of
tuberculosis in children.
Agnieszka M. Strzelak MD1 (ORCID:
0000-0002-8313-1924), Anna O. Komorowska-Piotrowska
MD1 (ORCID: 0000-0001-5034-538X), Agnieszka Borowa
MD2, Maria Krasińska MD2, Wojciech
K. Feleszko PhD1 (ORCID: 0000-0001-6613-2012), Marek
K. Kulus PhD1 (ORCID: 0000-0002-5360-4372).
1 Department of Pediatric Pulmonology and Allergy,
Medical University of Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw,
Poland
2 Department of Lung Diseases and Tuberculosis for
Children and Adolescents, Mazovian Center for Treatment of Lung Diseases
and Tuberculosis, Reymonta 83/91 Street, 05-400 Otwock, Poland
Corresponding Author: Anna Komorowska-Piotrowska MD,
Department of Pediatric Pulmonology and Allergy, Medical University of
Warsaw, 63A Zwirki i Wigury Street, 02-091 Warsaw, Poland. Tel:
(+)482231794-19; Fax: (+)48223179542;
E-mail: anna.komorowskapiotrowska@gmail.com
Words: 3482
Running Head: IP-10 in childhood tuberculosis.
ABSTRACT:
Purpose: To determine the utility of
interferon-gamma-inducible protein 10 (IP-10) for identifying active
tuberculosis (TB) and latent TB infection (LTBI) in children in
BCG-vaccinated population, establish its diagnostic performance
characteristics, and evaluate changes in IP-10 level during
anti-TB-chemotherapy.
Methods: Concentrations of IP-10 and IFN-γ were measured
in QuantiFERON-TB Gold (QFT) supernatants in children with suspected TB
or due to a recent TB contact. A total of 225 children were
investigated: 33 with active TB, 48 with LTBI, 83 TB contacts, 20 with
suspected TB but other final diagnosis, and 41 controls. In 60 children
cytokine responses were evaluated on follow-up visit after 2 months of
anti-TB-treatment.
Results: IP-10 expression was significantly higher in
infected children (active TB and LTBI cases) than in uninfected
individuals. IP-10 proved effective in identifying TB infection at its
optimal cut-off (>1084.5 pg/ml), but was incapable of
differentiating between children with active TB and LTBI. Combining
IP-10 and IFN-γ increased QFT sensitivity. IP-10 but not IFN-γ decreased
significantly during anti-TB-treatment in children with active TB (p =
0.003).
Conclusion: IP-10 identifies TB infection and declines
during anti-TB-chemotherapy in children. Incorporating IP-10 into new
immunodiagnostic assays could improve TB diagnosis and allow treatment
monitoring.
KEY WORDS:
Latent Tuberculosis, Chemokine CXCL10, Mycobacterium
tuberculosis, LTBI, TB contact
INTRODUCTION:
Childhood tuberculosis (TB), caused by Mycobacterium tuberculosis(Mtb .), is still an urgent global health issue. The COVID-19
pandemic had a negative impact on TB disease in terms of access to
diagnosis and treatment, therefore community transmission of infection
is expected to increase in all age groups 1.
Epidemiological estimates of global childhood TB burden have been long
underestimated. Firstly, childhood active TB (ATB) is very difficult to
diagnose due to diverse clinical presentations, difficulties in
obtaining specimens for microbiological evaluation, and paucibacillary
disease 2,3. Secondly, the diagnostic work-up for
latent tuberculous infection (LTBI) lacks the gold standard and
routinely used immunological tests, namely tuberculin skin test (TST)
and Interferon gamma (IFN-γ) release assays (IGRAs), have considerable
limitations in pediatric population.
TST shows cross-reactivity with bacillus Calmette-Guérin (BCG) and
majority of non-tuberculous mycobacteria (NTMs) and has therefore low
specificity in BCG vaccinated and NTM infected children4,5. Commercially available IGRAs, ELISA-based
QuantiFERON –TB Gold In-Tube (QFT) and ELISPOT-based T SPOT.TB have
comparable sensitivity and higher specificity than TST in identifyingMtb. Infection. However, they perform less reliable in human
immune virus (HIV)-infected and young children, albeit with inconsistent
results 6-9. Neither test discriminates ATB from LTBI,
nor are they licensed for ATB diagnosis. Yet, they are widely used to
facilitate the diagnosis of ATB with sensitivity reaching 77-85%10. The new version of QFT test, QuantiFERON-TB Gold
Plus, has so far exhibited similar properties to previous-generation
IGRAs in children in both ATB and LTBI 10.
It is plausible that additional cytokine biomarkers may improve IGRAs’
performance 11. One of the most promising surrogate
biomarker is the interferon-gamma-inducible protein 10 (IP-10), a
chemokine expressed primarily by antigen-presenting cells upon
stimulation by IFN-γ 12. In the TB field, IP-10-based
assays have emerged as alternatives to IGRAs with IP-10 being released
in 100-fold higher concentrations than IFN-γ. IP-10 has comparable
accuracy to IGRAs in identifying Mtb. infection in adults and
children and may even perform better in HIV-infected and the young11-19. Additionally, IP-10 has been suggested a
potential biomarker for treatment monitoring, but studies in pediatric
populations are scarce 20,21.
The aim of the present study was to assess IP-10 responses in children
with symptoms of ATB and in TB contact referrals in a low TB-incidence
country where BCG vaccination is routinely administered at birth. We
intended to examine the potential of IP-10 to differentiate between
different stages of Mtb . infection, to compare IP-10 with QFT and
TST results, and to explore the influence of age and antituberculous
treatment on IP-10 level.
METHODS: