Matthijs Backx

SUMMARY: BACKGROUND: TB cohort review is a structured clinical audit of case management and epidemiological data. In 2012, Wales (UK) implemented a national cohort review programme to improve clinical outcomes and enhance public health surveillance. METHODS: Retrospective population-based cohort analysis of care quality outcomes for all notified TB cases in Wales (2012–2022). Adjusted regression modelling assessed temporal trends post-implementation and compared outcomes of cases presented at TB cohort review with those not presented. RESULTS: Of the 1,175 notified TB cases over the study period, 985 (83.1%) were presented at cohort review. Many case management outcomes achieved near-target thresholds. Adherence support was increasingly targeted at index cases with social complexity and higher transmission risk, alongside substantial improvements in the completeness of surveillance data. Persistent programmatic challenges in contact identification and assessment were identified. CONCLUSION: As countries approach pre-elimination thresholds, TB services must ensure rigorous surveillance data collection and targeting of limited resources to populations at greatest risk of transmission and non-completion of treatment. Since implementing a national TB cohort review in Wales, there have been significant post-implementation improvements in care outcomes. This provides a robust, resource-efficient framework for TB control that could be applied to other similarly resourced low-incidence countries.

Background: The presence of (1→3)-β-D-Glucan (BDG) in serum may be indicative of invasive fungal disease (IFD), but even without IFD, elevated BDG can be associated with adverse patient outcomes. Methods: COVID-19-infected patients (n = 125) who were screened for IFD with fungal biomarkers were evaluated to assess the prognostic value of BDG. BDG was correlated with patients’ mortality, considering the influences of IFD and anti-fungal therapy (AFT). Results: A BDG concentration > 31 pg/mL was associated with significant mortality in the absence of documented IFD and without subsequent antifungal therapy (≤31 pg/mL: 28% vs. >31 pg/mL: 91%; p = 0.0001). In patients without IFD but with BDG > 31 pg/mL, mortality dropped to 50% when AFT was administered. In patients with BDG > 31 pg/mL and neither IFD nor AFT, the average probability of death was 3.38-fold greater. Conclusions: Elevated serum BDG is associated with significant mortality in COVID-19-infected patients without IFD, irrespective of AFT. A BDG-associated proinflammatory response might be driving the high mortality. BDG serves as a prognostic marker in COVID-19-infected patients with or without IFD. When BDG is very low (≤31 pg/mL) the likelihood of death remains consistent with the background mortality rates for COVID-19 within the ICU.

Background: The presence of (1→3)-β-D-Glucan (BDG) in serum may be indicative of in-vasive fungal disease (IFD), but even without IFD elevated BDG can be associated with adverse patient outcomes. Methods: COVID-19 infected patients (n=125) who were screened for IFD with fungal biomarkers were evaluated to assess the prognostic value of BDG. BDG was correlated with patients’ mortality, while considering the influences of IFD and anti-fungal therapy (AFT). Results: A BDG concentration >31pg/mL was associated with significant mortality in the absence of documented IFD and without subsequent an-tifungal therapy (≤31pg/mL: 28% vs >31pg/mL: 91%; P = 0.0001). In patients without IFD but with a BDG >31pg/mL, mortality dropped to 50% when AFT was administered. In pa-tients with a BDG >31pg/mL, no IFD nor AFT then the average probability of death is 3.38-fold greater. Conclusions: Elevated serum BDG is associated with significant mortal-ity in COVID -19 infected patients without IFD, irrespective of AFT. A BDG associated proinflammatory response might be driving the high mortality. BDG serves as a prognos-tic marker in COVID -19 infected patients with or without IFD. When BDG is very low (≤31pg/mL) the likelihood of death remains consistent with the background morality rates for COVID-19 within the ICU.

Objectives: Chest X-ray (CXR) is recommended by the World Health Organization as a TB screening tool on admission to prison. We piloted the offer of CXR on admission to prison to understand if it was acceptable to residents, feasible to deliver within 48 hours of admission, and to inform TB epidemiology. Study Design: Cross-sectional Method: Between 1 September 2023 and 31 March 2024, CXRs were offered to new prison admissions. We measured the numbers accepting, numbers completed and the results. For each person accepting the CXR we undertook an assessment of clinical and social TB risks. We measured the time taken to deliver the CXR and receive results. Results: CXR was acceptable to those in prison with 61% (n=310) of new admissions accepting the offer. Of those accepting the offer, 226 (73%) went on to receive a CXR, equating to 44% of all new arrivals within the pilot period. A quarter of those accepting the CXR offer did not attend their first appointment and needed further appointment offers. We observed that as the number of rearranged appointments increased the number of men attending decreased. The total median number of days from arrival at the prison to completion of CXR was 17 [IQR 13-20 days]. We did not identify any respiratory TB, however nine (4%) CXRs were abnormal.. Conclusion: CXR screening was acceptable to prison residents but we could not achieve delivery within 48 hours of arrival to prison. We identified other respiratory abnormalities suggesting CXR screening could be used as a wider respiratory health screen of which TB would be included. What this study adds: CXR screening for TB on admission to prison is recommended despite a low certainty of evidence for this approach. Our findings contribute to the evidence and demonstrate the complexity of implementing this in practice The offer of CXR on admission to prison was acceptable to new arrivals although delivery within 48 hours of arrival to prison could not be achieved within the existing service model Whilst we did not identify any TB, we identified other respiratory abnormalities suggesting CXR screening on arrival could be used as a wider respiratory health screen. Implications for policy and practice: To achieve CXR within 48 hours of admission to prison would require a bespoke service model in addition to existing prison radiography provision Policies should consider CXR TB screening as part of a wider respiratory health screen, offering the opportunity to address multiple health issues at the same time The frequent movement of people through the criminal justice system presents a challenge to continuity of care and should be considered when designing interventions

Background: The use of the PCR to aid in the diagnosis of Pneumocystis pneumonia (PcP) has demonstrated excellent clinical performance, as evidenced through various systematic reviews and meta-analyses, yet there are concerns over the interpretation of positive results due to the potential presence of Pneumocystis colonization of the airways. While this can be overcome by applying designated positivity thresholds to PCR testing, the shear number of assays described limits the development of a universal threshold. Commercial assays provide the opportunity to overcome this problem, provided satisfactory performance is determined through large-scale, multi-centre evaluations. Methods: Retrospective case/control and consecutive cohort performance evaluations of the OLM PneumID real-time PCR assay were performed on DNA eluates from a range of samples sent from patients where “in-house” PCR had been performed as part of routine diagnostic testing. The clinical performance of the PneumID assay was determined before including it in a diagnostic algorithm to provide the probability of PcP (dependent on diagnostic evidence). Results: After being used to test 317 patients (32 with PcP), the overall performance of the PneumID assay was found to be excellent (Sensitivity/Specificity: 96.9%/95.1%). False positivity could be removed by applying a threshold specific to sample type (PneumID assay into diagnostic algorithms alongside (1-3)-β-D-Glucan testing provided high probabilities of PcP (up to 85.2%) when both were positive and very low probabilities (PneumID qPCR provides a commercial option for the accurate diagnosis of PcP, generating excellent sensitivity and specificity, particularly when testing respiratory specimens. The combination of PcP PCR with serum (1-3)-β-D-Glucan provides excellent clinical utility for diagnosing PcP.

Pneumocystis pneumonia (PcP) is a serious complication of many significant immunocompromising conditions. Prior incidence estimates in Wales are based on PcP’s presentation in the HIV and transplant populations. The objectives were to describe the incidence of PcP in Wales using laboratory reporting measures and assess the impact of underlying immunosuppression cause on mortality. All positive PCR results for PcP between 2015 and 2018 were identified. The total number of unique positives with clinical and radiological correlation was 159 patients, a mean of 39.75 annually. The healthcare records of these patients were reviewed. The mortality at one month was 35.2% and 49.1% at one year. HIV remains the commonest cause of immunosuppression but has lower mortality than non-HIV conditions (12% vs. 59% at one year, p < 0.00001). Non-HIV conditions were categorised as life-threatening and non-life threatening but had a non-significant mortality (66% vs. 54%; p = 0.149), highlighting the negative impact of PcP. An incidence of PcP in Wales of 1.23–1.26 cases per 100,000 has been identified, 32–35% greater than the upper limit previously estimated. There is high mortality in non-HIV patients regardless of immunosuppression cause. A heightened awareness of PcP in these groups will hasten diagnosis and potentially improve mortality.

Aspergillus fumigatus is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to A. fumigatus are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered A. fumigatus –specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of A. fumigatus hyphae. T cells expressing the Af-CAR recognized A. fumigatus strains and clinical isolates and exerted a direct antifungal effect against A. fumigatus hyphae. In particular, CD8 ⁺ Af-CAR T cells released perforin and granzyme B and damaged A. fumigatus hyphae. CD8 ⁺ and CD4 ⁺ Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8 ⁺ Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8 ⁺ Af-CAR T cells conferred greater antifungal efficacy compared to CD4 ⁺ Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.

Background: Treatment for invasive candidiasis (IC) is time-critical, and culture-based tests can limit clinical utility. Nonculture-based methods such as Candida PCR represent a promising approach to improving patient management but require further evaluation to understand their optimal role and incorporation into clinical algorithms. This study determined the performance of the commercially available OLM CandID real-time PCR when testing serum and developed a diagnostic algorithm for IC. Methods: The study comprised a retrospective performance evaluation of the CandID real-time PCR assay when testing surplus serum (n = 83 patients, 38 with IC), followed by a prospective consecutive cohort evaluation (n = 103 patients, 24 with IC) post incorporation into routine service. A combined diagnostic algorithm, also including (1-3)-β-D-Glucan testing, was generated. Results: Prospective CandID testing generated a sensitivity/specificity of 88%/82%, respectively. Specificity was improved (>95%) when both PCR replicates were positive and/or the patient had multiple positive samples. When combining CandID with (1-3)-β-D-Glucan testing, the probability of IC when both were positive or negative was >69% or CandID provides excellent performance and a rapid time-to-result using methods widely available in generic molecular diagnostic laboratories. By combining nonculture diagnostics, it may be possible to accurately confirm or exclude IC.