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: