Valeriu Crudu - Academia.edu (original) (raw)

Papers by Valeriu Crudu

Nature communications, Jan 26, 2024

There is still incomplete knowledge of which Mycobacterium tuberculosis (Mtb) antigens can trigge... more There is still incomplete knowledge of which Mycobacterium tuberculosis (Mtb) antigens can trigger distinct T cell responses at different stages of infection. Here, a proteome-wide screen of 20,610 Mtb-derived peptides in 21 patients mid-treatment for active tuberculosis (ATB) reveals IFNγ-specific T cell responses against 137 unique epitopes. Of these, 16% are recognized by two or more participants and predominantly derived from cell wall and cell processes antigens. There is differential recognition of antigens, including TB vaccine candidate antigens, between ATB participants and interferon-gamma release assay (IGRA + /−) individuals. We developed an ATB-specific peptide pool (ATB116) consisting of epitopes exclusively recognized by ATB participants. This pool can distinguish patients with pulmonary ATB from IGRA + /− individuals from various geographical locations, with a sensitivity of over 60% and a specificity exceeding 80%. This proteome-wide screen of T cell reactivity identified infection stage-specific epitopes and antigens for potential use in diagnostics and measuring Mtb-specific immune responses. Tuberculosis is the ninth leading cause of death worldwide and the leading cause from a single infectious agent, ranking above HIV/AIDS. The World Health Organization (WHO) estimates that approximately one-quarter of the world's population (1.7 billion total) is infected with Mycobacterium tuberculosis (Mtb). In 2021 Mtb was responsible for 1.6 million deaths and~10 million new infections 1 Infection with Mtb manifests as a spectrum of diseases ranging from asymptomatic subclinical infection (latent infection, LTBI) to active disease (ATB) 2,3. To date, tuberculin skin test (TST) and interferon-gamma release assays (IGRA), which detect an immunological response against Mtb, are diagnostic tests for latent infection 4,5. Importantly, the classically used tuberculin skin test can be positive in both LTBI and BCG vaccinated participants and thus cannot distinguish them 6,7. A major advance in the diagnosis of Mtb infection was represented by the introduction of IGRA tests that consist of ex vivo analysis of peripheral blood cells for a cytokine (IFNγ) response to peptide pools spanning the ESAT-6 and CFP10 antigens recognized by T cells 8. As these antigens are absent from M. bovis BCG and most nontuberculous mycobacteria (NTMs), such responses can distinguish prior or current Mtb infection from BCG vaccination and NTM

Journal of the American Medical Informatics Association, Feb 9, 2022

ObjectiveThis study aims to establish an informative dynamic prediction model of treatment outcom... more ObjectiveThis study aims to establish an informative dynamic prediction model of treatment outcomes using follow-up records of tuberculosis (TB) patients, which can timely detect cases when the current treatment plan may not be effective.Materials and MethodsWe used 122 267 follow-up records from 17 958 new cases of pulmonary TB in the Republic of Moldova. A dynamic prediction framework integrating landmark modeling and machine learning algorithms was designed to predict patient outcomes during the course of treatment. Sensitivity and positive predictive value (PPV) were calculated to evaluate performance of the model at critical time points. New measures were defined to determine when follow-up laboratory tests should be conducted to obtain most informative results.ResultsThe random-forest algorithm performed better than support vector machine and penalized multinomial logistic regression models for predicting TB treatment outcomes. For all 3 outcome classes (ie, cured, not cured, and died after 24 months following treatment initiation), sensitivity and PPV of prediction models improved as more follow-up information was collected. Specifically, sensitivity and PPV increased from 0.55 to 0.84 and from 0.32 to 0.88, respectively, for the not cured class.ConclusionThe dynamic prediction framework utilizes longitudinal laboratory test results to predict patient outcomes at various landmarks. Sputum culture and smear results are among the important variables for prediction; however, the most recent sputum result is not always the most informative one. This framework can potentially facilitate a more effective treatment monitoring program and provide insights for policymakers toward improved guidelines on follow-up tests.

arXiv (Cornell University), Sep 28, 2021

Understanding factors that contribute to the increased likelihood of disease transmission between... more Understanding factors that contribute to the increased likelihood of disease transmission between two individuals is important for infection control. However, analyzing measures of genetic relatedness is complicated due to correlation arising from the presence of the same individual across multiple dyadic outcomes, potential spatial correlation caused by unmeasured transmission dynamics, and the distinctive distributional characteristics of some of the outcomes. We develop two novel hierarchical Bayesian spatial methods for analyzing dyadic genetic relatedness data, in the form of patristic distances and transmission probabilities, that simultaneously address each of these complications. Using individual-level spatially correlated random effect parameters, we account for multiple sources of correlation between the outcomes as well as other important features of their distribution. Through simulation, we show the limitations of existing approaches in terms of estimating key associations of interest, and the ability of the new methodology to correct for these issues across datasets with different levels of correlation. All methods are applied to Mycobacterium tuberculosis data from the Republic of Moldova where we identify previously unknown factors associated with disease transmission and, through analysis of the random effect parameters, key individuals and areas with increased transmission activity. Model comparisons show the importance of the new methodology in this setting. The methods are implemented in the R package GenePair.

Journal of Microbiology, Immunology and Infection

ABSTRACTBackgroundEmerging evidence suggests that shortened, simplified treatment regimens for ri... more ABSTRACTBackgroundEmerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) is detected on Drug Susceptibility Testing (DST).Methods and FindingsGenomic and associated demographic data were used to parameterize a mathematical model estimating long-term health outcomes and costs (2022 USD) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. In this model individuals were followed over their lifetime, simulating the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB d...

To study the adaptation of multi-drug resistantMycobacterium tuberculosis(MDR-TB) during treatmen... more To study the adaptation of multi-drug resistantMycobacterium tuberculosis(MDR-TB) during treatment patients diagnosed with MDR-TB were recruited into an observational study. Clinical data andM. tuberculosisDNA at diagnosis and between seven days and two months of MDR-TB treatment were collected. The drugs prescribed were recorded. Interpretable WGS data from 118 isolates from 54 participants was obtained (11 in Belarus and 43 in Moldova) and screened for the presence of unfixed single nucleotide polymorphisms (mixed SNPs / loci).This study was performed shortly after the publication of the 2019 WHO consolidated guidelines on drug-resistant tuberculosis treatment. Existing drug supplies and procurement in one country after the switch to the all oral MDR-TB regimen in addition to patient factors, influenced the selection of and exposure to drugs.Confidently mixed SNPs were identified in samples from multiple participants in only five genes (gyrA, pncA, Rv1129c, Rv1148c, andsugI). All ...

Emerging Infectious Diseases, May 1, 2023

Tuberculosis caused by Mycobacterium tuberculosis is one of the leading causes of death from a si... more Tuberculosis caused by Mycobacterium tuberculosis is one of the leading causes of death from a single infectious agent. Identifying dominant epitopes and comparing their reactivity in different tuberculosis (TB) infection states can help design diagnostics and vaccines. We performed a proteome-wide screen of 20,610 Mtb derived peptides in 21 Active TB (ATB) patients 3-4 months post-diagnosis of pulmonary TB (mid-treatment) using an IFNgamma and IL-17 Fluorospot assay. Responses were mediated exclusively by IFNgamma and identified a total of 137 unique epitopes, with each patient recognizing, on average, 8 individual epitopes and 22 epitopes (16%) recognized by 2 or more participants. Responses were predominantly directed against antigens part of the cell wall and cell processes category. Testing 517 peptides spanning TB vaccine candidates and ESAT-6 and CFP10 antigens also revealed differential recognition between ATB participants mid-treatment and healthy IGRA+ participants of seve...

Bulletin of the Academy of Sciences of Moldova. Medical Sciences

Tuberculosis, one of the ancient infections that especially affects humans, the main target organ... more Tuberculosis, one of the ancient infections that especially affects humans, the main target organ of this disease being the lung, is caused by M. tuberculosis and remains one of the most important public health problems, especially in developing countries. The emergence of multidrug-resistant and extensively drug-resistant tuberculosis is considered a serious threat to tuberculosis control worldwide. The burden of drug-resistant tuberculosis remains increasing in countries endemic for this infection. The risk factors that influence this situation and that are elucidated more frequently in the specialized literature are the abusive use of drugs, the failure of the therapeutic regimen, the relapse of tuberculosis, the difficulty of obtaining drug sensitivity testing in a fast time. In Moldova, but also in other regions of Eastern Europe, drug resistance represents a serious obstacle in the effective control of this disease. There is evidence that the transmission of resistant strains,...

Open Forum Infectious Diseases, Dec 1, 2022

BackgroundAs part of its End TB strategy, the WHO has identified the need for non-sputum-based di... more BackgroundAs part of its End TB strategy, the WHO has identified the need for non-sputum-based diagnostics that meet target product profiles (TPP) of 90% sensitivity and 70% specificity for diagnosis of Active TB (ATB) and 75% sensitivity and specificity for predicting progression from Latent TB (LTB) to ATB. The successful translation of a 3-gene blood-based signature, identified using diverse datasets, into a prototype point-of-care diagnostic, that meets the WHO TPPs, has demonstrated the power of integrating large amounts of heterogeneous data to identify generalizable disease signatures. We hypothesized that integration of more diverse datasets, comprising patients with ATB or other inflammatory lung diseases, would identify novel, robust signatures, for diagnosing ATB and predicting progression from LTB to ATB, that meet the WHO TPPs.MethodsUsing multi-cohort analyses, we integrated and analyzed data from 3,615 peripheral blood samples, in 49 publicly available transcriptomic datasets (discovery cohorts), from healthy controls and patients with LTB, ATB, and other diseases (COPD, viral infections, sarcoidosis, etc.). We used data from (1) 3,836 blood samples in 28 retrospective datasets and (2) 360 prospectively collected blood samples, from a household contact study in Moldova, as validation cohorts.ResultsUsing the discovery cohorts we identified a 9-gene signature for diagnosing ATB patients from healthy controls, or individuals with LTB or other diseases. The signature achieved 90% sensitivity and 82% specificity in retrospective validation (Figure 1A) and 90% sensitivity and 69% specificity in the prospective cohort from Moldova (Figure 1B). In a longitudinal cohort of adolescents, the 9-gene signature predicted progression from LTB to ATB up to 1 year prior to sputum conversion with 76% sensitivity and 83% specificity (Figure 1C). Finally, the signature predicted prolonged lung inflammation post-treatment in the Catalysis Treatment Response Cohort (Figure 1D).9-gene TB signature validates in independent retrospective and prospective cohorts.Open in a separate window(A) ROC curves for comparing ATB vs. all other samples (All), or individually comparing ATB vs. Healthy, LTBI or Other Disease (OD) samples in independent retrospective validation and (B) a prospective Moldova cohort. (C) ROC curves comparing progressor and non-progressor samples collected at different time points in the Adolescent Cohort Study (ACS), for the 9-gene signature in solid lines and a previous 3-gene signature in dashed lines, (D) Distribution of the 9-gene score at different time points post-treatment in the Catalysis Treatment Response Cohort Study, for individuals with persistent lung inflammation at 24 weeks compared with those who had clear lungs at 24 weeks.ConclusionOverall, the 9-gene signature meets the WHO TPPs required for the End TB strategy.Disclosures Purvesh Khatri, PhD, Cepheid, Inc.: Advisor/Consultant|Inflammatix, Inc.: Advisor/Consultant|Inflammatix, Inc.: Inflammatix is in negotiations to license the 9-gene signature discussed here.|Inflammatix, Inc.: Stocks/Bonds.

Journal of Clinical Microbiology

While the goal of universal drug susceptibility testing has been a key component of the WHO End T... more While the goal of universal drug susceptibility testing has been a key component of the WHO End TB Strategy, in practice, this remains inaccessible to many. Rapid molecular tests for tuberculosis (TB) and antituberculosis drug resistance could significantly improve access to testing.

Journal of Microbial & Biochemical Technology, Nov 29, 2013

Background: Drug resistance represents a serious obstacle to effective tuberculosis (TB) control ... more Background: Drug resistance represents a serious obstacle to effective tuberculosis (TB) control in Moldova. The results of drug resistance surveillance (DRS) can reflect the indicators of TB control program efficacy. Multidrug resistance (MDR) is one of the main causes of ineffective treatment of new TB cases. The aim of the study: To estimate the trends of TB drug resistance in Moldova during the period of 2006-2011. The results of DRS to I line TB drugs among new and previously treated TB cases were studied. Methods: DRS included all isolates from new patients diagnosed with pulmonary TB during the last 7 years. The DST was performed in the National TB Reference Laboratory and three regional tuberculosis reference laboratories. Results: The prevalence of TB resistance increased considerably during the last period. In the performed study, the results of DRS from 7240 TB new cases and 6997 previously treated TB cases were analyzed. The level of primary drug resistance has been increased from 42.0% to 49.2% during this period, and MDR TB from 19.4% to 29.2%. Among previously treated patients the level of MDRTB increased from 50.8% up to 63.4%. Though the patients with MDRTB, detected in 2011, 13.8% were identified with extensively drug resistance. Conclusion: At the current stage TB drug resistance is a serious problem in the Republic of Moldova, having serious impact on public health and economic consequences. The increased number of resistant cases influences the treatment results. The accumulation of a greater number of resistant strains in the society can lead to infection and increases the number of TB resistant cases.

PLOS Digital Health

Background Limited access to drug-susceptibility tests (DSTs) and delays in receiving DST results... more Background Limited access to drug-susceptibility tests (DSTs) and delays in receiving DST results are challenges for timely and appropriate treatment of multi-drug resistant tuberculosis (TB) in many low-resource settings. We investigated whether data collected as part of routine, national TB surveillance could be used to develop predictive models to identify additional resistance to fluoroquinolones (FLQs), a critical second-line class of anti-TB agents, at the time of diagnosis with rifampin-resistant TB. Methods and findings We assessed three machine learning-based models (logistic regression, neural network, and random forest) using information from 540 patients with rifampicin-resistant TB, diagnosed using Xpert MTB/RIF and notified in the Republic of Moldova between January 2018 and December 2019. The models were trained to predict the resistance to FLQs based on demographic and TB clinical information of patients and the estimated district-level prevalence of resistance to FL...

Ministerul Sănătății, Muncii și Protecţiei Sociale al Republicii Moldova, 2017