Backgrounds:

The diagnosis of pulmonary tuberculosis (TB) remains difficult in young children. Rapid biomarker-based tests using non-sputum samples are needed. The role of biomarkers in saliva for diagnosing TB in children has not been fully explored.

Methods

We conducted a review of available studies on the use of host-based salivary biomarkers for diagnosing active pulmonary TB in children and adults.

Results:

We found nine studies on salivary host diagnostic biomarkers, one of which involved children. Three studies evaluated the diagnostic performance of antibodies in saliva to antigens of Mycobacterium tuberculosis, with disappointing results. Six studies measured salivary levels of selected cytokines, growth factors, enzymes and other proteins and found that combinations of these markers showed potential in reaching WHO-endorsed performance criteria for a TB triage test. An eight-marker biosignature comprising of salivary granzyme A, growth differentiation factor 15, serum amyloid A, epithelial-neutrophil activating peptide 78, plasminogen activator inhibitor-1, IL-12(p40), IL-13 and IL-21, was most promising and had a sensitivity of 93% and specificity of 100%.¹

(1) Jacobs et al. Diagnostic Potential of Novel Salivary Host Biomarkers as Candidates for the Immunological Diagnosis of Tuberculosis Disease and Monitoring of Tuberculosis Treatment Response. PLoS One. 2016.

Conclusions/Learning Points:

Saliva could be a valuable diagnostic specimen for diagnosing pulmonary TB in children, however little research in this population exists. Based on adult data, combinations of cytokines and other proteins demonstrate promise as new triage tests for TB. Given the differing TB immune response in children, studies in paediatric populations are now needed. The ready availability of saliva and non-invasive nature of collection is especially appealing for young children. Future directions and suggestions for technologies for salivary biomarker discovery and point-of-care test development are discussed.

Backgrounds:

Despite recent advances in diagnostics, childhood tuberculosis (TB) remains underdiagnosed. The novel lateral flow FujiLAM assay detects lipoarabinomannan (LAM) in urine and its sensitivity for the diagnosis of pulmonary TB was found to be higher compared to AlereLAM in adults. However, data on its performance in children is limited.

Methods

We conducted a systematic review assessing the diagnostic performance of FujiLAM for diagnosing paediatric TB, using AlereLAM as a comparator. The last search was conducted in November 2021.

Results:

We identified three studies with data from 698 children for FujiLAM and 619 for AlereLAM. For FujiLAM, pooled sensitivity and specificity using a microbiological reference standard (MRS) were 51% (95%CI 43-59) and 87% (95%CI 84-90), respectively, and 27% (95%CI 23-32) and 87% (95%CI 82-90) using a composite reference standard (CRS). For AlereLAM, sensitivity and specificity were 41% (95%CI 33-50) and 83% (95%CI 79-86) for MRS, and 32% (95%CI 27-37) and 88% (95%CI 84-92) for CRS. Subgroup analyses for FujiLAM suggested an increased sensitivity in children living with HIV, especially when immunocompromised.

Conclusions/Learning Points:

This is the first systematic review of the diagnostic performance of FujiLAM in children, indicating a moderate but potentially superior sensitivity compared to AlereLAM. Our review emphasizes the points to be addressed in forthcoming evaluations, namely the need for prospective assessments from several geographical regions, rigorous application of reference standards, and specific subgroup analyses in children living with HIV and extrapulmonary TB. As an instrument-free point-of-care test that uses an easy to obtain specimen, FujiLAM has the potential to improve TB diagnosis in children, particularly in low-resource settings.

Backgrounds:

Multisystem inflammatory syndrome in children (MIS-C) is a rare but severe SARS-CoV-2 related disease occurring in children and adolescents. Its pathophysiology is incompletely unraveled, although superantigen-driven hyperinflammation is presumed. Currently approved pediatric vaccines against coronavirus disease 2019 (COVID-19) are mRNA-based and encode the SARS-CoV-2 spike protein. Theoretically, in children with previous MIS-C, re-exposure to the same viral protein could trigger hyperinflammation. However, to date, no specific safety data for COVID-19 vaccination are available for children with a history of MIS-C.

Methods

We conducted an international electronic questionnaire, running from 1 Nov 2021 to 15 Dec 2021.

Results:

We collected data from 83 healthcare professionals involved with MIS-C, originating from 32 countries. Respondents provided information for 5673 MIS-C patients, of which 1750 (30.8%) were eligible for vaccination. Vaccination was documented in 273 (15.6%) children. For 420 additional cases, no contra-indication was in place and, therefore, respondents presumed vaccination without formal registration and vigilance of the procedure.

MIS-C was declared as a contra-indication for COVID-19 vaccination in multiple regions (Belgium/France/Italy/India/Mexico/Pakistan/Turkey/USA), accounting for 1144 patients (20.2% of the cohort). Reasons for contra-indication included national/regional guidelines (9/14 regions) and safety concerns (9/14).

In those vaccinated, mild/moderate adverse events (AE) were reported similarly to those published in healthy controls. Besides one patient experiencing Bell’s palsy, no severe/serious AE were described. In particular, no relapse MIS-C or other similar inflammatory conditions were reported.

Conclusions/Learning Points:

MIS-C is not regarded as a universal contra-indication for COVID-19 vaccination in most countries. In those vaccinated, no particular AE and no relapse MIS-C was reported. At the time of the survey, less than one-third of MIS-C patients were eligible for vaccination and at most 40 percent of those eligible were vaccinated. Further follow-up is warranted.

Backgrounds:

The diagnosis of tuberculosis (TB) in children remains the biggest hurdle in overcoming the epidemic. The blood-based T cell marker for TB assay (TAM TB) characterizes TB-specific CD4+ T cells based on the expression of surface markers. This approach allows a differentiation between latently and actively infected TB patients.

Methods

RaPaed-TB is a diagnostic validation study conducted in five countries enrolling children suspected of having TB. Alongside a thorough clinical and microbiological workup, a number of new tests are being evaluated including the TAM TB. The latter is a flow-cytometry based assay using a standardized kit which gives a result within 16-24h. Data cleaning is underway; presented data are preliminary and totals differ.

Results:

In total, 974 participants were enrolled with an overall microbiological confirmation rate (PCR/culture) of 24.2% (236/974), sufficient information for clinical case definition was available for 732 children. Overall, more than 890 TAM TBs were performed at enrolment. Using culture as reference standard, early analyses show a modest sensitivity of 60.8% (95%CI 48.8-72.0) and specificity of 83.5% (95%CI 77.0-88.9) in the overall cohort, with superior performance in children <1 year with a sensitivity of 80.0% (95%CI 51.9-95.7) and specificity of 85.0% (95%CI 62.1-96.8). Logistic regression was performed to explore determinants of TAM TB accuracy, generating strong evidence of TST-positivity increasing the odds for true-positivity in reference standard positive children by 5.06 (95%CI 1.83-13.99, p=0.0018). Further analyses are ongoing, and results are to be presented.

Conclusions/Learning Points:

RaPaed-TB is one of the largest TB diagnostic validation studies comparing several new tests ever performed in children. Presented data indicate a promising performance of TAM-TB, especially in the very young children.

Backgrounds:

The diagnosis of tuberculosis (TB) in children remains the biggest hurdle in overcoming the epidemic. The blood-based T cell marker for TB assay (TAM TB) characterizes TB-specific CD4+ T cells based on the expression of surface markers. This approach allows a differentiation between latently and actively infected TB patients.

Methods

RaPaed-TB is a diagnostic validation study conducted in five countries enrolling children suspected of having TB. Alongside a thorough clinical and microbiological workup, a number of new tests are being evaluated including the TAM TB. The latter is a flow-cytometry based assay using a standardized kit which gives a result within 16-24h. Data cleaning is underway; presented data are preliminary and totals differ.

Results:

In total, 974 participants were enrolled with an overall microbiological confirmation rate (PCR/culture) of 24.2% (236/974), sufficient information for clinical case definition was available for 732 children. Overall, more than 890 TAM TBs were performed at enrolment. Using culture as reference standard, early analyses show a modest sensitivity of 60.8% (95%CI 48.8-72.0) and specificity of 83.5% (95%CI 77.0-88.9) in the overall cohort, with superior performance in children <1 year with a sensitivity of 80.0% (95%CI 51.9-95.7) and specificity of 85.0% (95%CI 62.1-96.8). Logistic regression was performed to explore determinants of TAM TB accuracy, generating strong evidence of TST-positivity increasing the odds for true-positivity in reference standard positive children by 5.06 (95%CI 1.83-13.99, p=0.0018). Further analyses are ongoing, and results are to be presented.

Conclusions/Learning Points:

RaPaed-TB is one of the largest TB diagnostic validation studies comparing several new tests ever performed in children. Presented data indicate a promising performance of TAM-TB, especially in the very young children.