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Morten Ruhwald

Publications and source records attributed to Morten Ruhwald.

6 recordsLinked to original sources
PubMed2025

Targeted next-generation sequencing for drug-resistant tuberculosis diagnosis: implementation considerations for bacterial load, regimen selection and diagnostic algorithm placement.

INTRODUCTION: Early and accurate diagnosis of drug-resistant tuberculosis (DR-TB) is essential for improving treatment outcomes. Phenotypic drug susceptibility testing (pDST) is comprehensive but slow, while rapid molecular assays provide resistance information for a limited number of drugs. Targeted next-generation sequencing (tNGS) offers the potential for broad and rapid resistance detection, but its integration into diagnostic algorithms has been hindered by uncertainty about its placement within existing workflows. METHODS: This study evaluated the extent to which two tNGS solutions-Deeplex Myc-TB (GenoScreen) and TB Drug Resistance Test (Oxford Nanopore Technologies, ONT)-provided interpretable drug resistance results that could inform regimen design, in comparison to other WHO-recommended molecular assays and pDST. Data were collected from three high-burden DR-TB settings under the Seq&Treat study. Sequencing success rates and drug resistance detection were analysed based on: (1) the initial Xpert MTB/RIF result (very low, low, medium, high), (2) resistance results for drugs in WHO-recommended regimens and (3) performance relative to other WHO-endorsed assays. The potential impact of different algorithms on the estimates was also considered. Key factors influencing successful tNGS adoption within diagnostic pathways were identified, leveraging insights from the Seq&Treat diagnostic accuracy study. RESULTS: Sequencing success rates were 88.5% (GenoScreen) and 93.1% (ONT) across 763 samples. While tNGS provided complete resistance data for 73%-86% of drugs in recommended regimens, pDST achieved 92%-93%. Both tNGS solutions matched or exceeded the sensitivity of WHO-recommended molecular assays. CONCLUSIONS: This study highlights the critical role of tNGS as a centralised tool for comprehensive drug resistance testing to inform DR-TB treatment decisions following initial screening assays. By complementing existing molecular tests with tNGS, diagnostic workflows can be optimised to ensure timely and comprehensive resistance detection. These findings support policy updates to integrate tNGS into global TB diagnostic algorithms. TRIAL REGISTRATION NUMBER: NCT04239326.

Humans↗
PubMed2025

Future-proofing tuberculosis therapy: framework for concurrent drug and resistance testing development.

The rapid emergence of resistance to novel tuberculosis drugs, such as bedaquiline, is a key threat to the long-term effectiveness of novel regimens. Given that the introduction of these agents has enabled the introduction of an all-oral regimen for rifampicin-resistant and multidrug-resistant tuberculosis, the rise of resistance underscores the urgent need to safeguard their efficacy and responsible use. A major barrier is the delay in developing reliable tools to detect resistance to novel compounds, which limits clinical decision-making and surveillance efforts. Herein, we outline a framework for integrating the development of drug susceptibility testing alongside tuberculosis drug development, including early stage resistance profiling and defining appropriate epidemiological cutoff values. We highlight key gaps, including the need for structured partnerships between drug developers, diagnostic manufacturers, regulators, research institutions, funders, and policy makers. We propose a roadmap to accelerate drug susceptibility testing and development of new tuberculosis regimens, ensuring that resistance detection maintains pace with the introduction of novel drugs. Establishing collaborative platforms for data sharing, genomic analysis, and diagnostic innovation will help ensure that resistance detection evolves in step with drug development, thereby preserving novel treatments and improving global tuberculosis care.

Humans↗
PubMed2006

Latent tuberculosis in HIV positive, diagnosed by the M. tuberculosis specific interferon-gamma test.

BACKGROUND: Although tuberculosis (TB) is a minor problem in Denmark, severe and complicated cases occur in HIV positive. Since the new M. tuberculosis specific test for latent TB, the QuantiFERON-TB In-Tube test (QFT-IT) became available the patients in our clinic have been screened for the presence of latent TB using the QFT-IT test. We here report the results from the first patients screened. METHODS: On a routine basis the QFT-IT test was performed and the results from 590 HIV positive individuals consecutively tested are presented here. CD4 cell count and TB risk-factors were recorded from patient files. MAIN FINDINGS: 27/590(4.6%) of the individuals were QFT-IT test positive, indicating the presence of latent TB infection. Among QFT-IT positive patients, 78% had risk factors such as long-term residency in a TB high endemic area (OR:5.7), known TB exposure (OR:4.9) or previous TB disease (OR:4.9). The prevalence of latent TB in these groups were 13%, 16% and 19% respectively. There was a strong correlation between low CD4 T-cell count and a low mitogen response (P < 0.001;Spearman) and more patients with low CD4 cell count had indeterminate results. CONCLUSION: We found an overall prevalence of latent TB infection of 4.6% among the HIV positive individuals and a much higher prevalence of latent infection among those with a history of exposure (16%) and long term residency in a high endemic country (13%). The QFT-IT test may indeed be a useful test for HIV positive individuals, but in severely immunocompromised, the test may be impaired by T-cell anergy.

AIDS-Related Opportunistic Infections↗
PubMed2003

Tumor-associated antigens identified by mRNA expression profiling as tumor rejection epitopes.

Thirteen H-2b-binding peptides derived from six potentially overexpressed proteins in p53-/- thymoma (SM7) cells were studied for immunogenecity and vaccine-induced prevention of tumor growth in mice inoculated with SM7 tumor cells. Six of the peptides generated specific CTL responses after immunization, but only two of these peptides (RAD23-31 and RAD24-31) were capable of generating a weak vaccination-induced protection against adoptive tumor growth. SM7 inoculated mice treated with a blocking antibody against the inhibitory T cell signal transducing molecule CTLA4 appeared to delay tumor take, suggesting that SM7 thymoma cells are recognized by the adaptive immune system of the host. However, prophylactic vaccination with RAD23-31 and RAD24-31 peptides combined with anti-CTLA4 Ab treatment and did not improve tumor resistance. Our data would indicate that vaccination with immunogenic peptides derived from potentially overexpressed tumor proteins, as identified by mRNA expression profiling of p53-/- thymoma cells, at best results in a weak tumor protection thus questioning this way of detection of new tumor rejection epitopes.

Journal Article↗