Relapse or reinfection: Classification of malaria infection using transition likelihoods.
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ABSTRACT:
SUBMITTER: Lin FC
PROVIDER: S-EPMC8711853 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Our study sought to compare the strain types of Clostridium difficile causing initial and recurrent episodes of C. difficile infection (CDI) in adult patients with a first episode of CDI or 1 prior episode of CDI within the previous 90 days. Strains originated from patients who had been entered into two phase 3 randomized clinical trials of fidaxomicin versus vancomycin. Isolates of C. difficile from the initial and recurrent episodes within 28 (± 2) days of cure of CDI were compared using restriction endonuclease analysis (REA) typing. Paired isolates were available from 90 of 194 (46%) patients with recurrent CDI. Patients with isolates available were significantly younger (P = .008) and more likely to be from Canadian sites (P = .0001), compared with patients without isolates. In 75 of 90 subjects (83.3%), the identical REA type strain was identified at recurrence and the initial episode (putative relapse). Early recurrences (0-14 days after treatment completion) were relapses in 86.7% and a new strain (reinfection) in 13.3%. Later recurrences (15-31 days after treatment) were relapses in 76.7% and reinfections in 23.3%. Mean time (± standard deviation) to recurrence was 12.2 (± 6.4) days for relapses and 14.7 (± 6.8) days for reinfections (P = .177). The most common BI/NAP1/027 group and the previous US epidemic REA group J/NAP2/001 had a significantly higher combined rate of recurrence with the same strain (relapse), compared with the other REA groups (39 of 42 [93%] vs 36 of 48 [75%], respectively; P = .023). We found a higher than historic rate of recurrent CDI caused by the same isolate as the original episode, a finding that may be related to the relatively short observation period in this study and the high frequency of isolation of epidemic strains, such as groups BI and J, for which relapse rates may be higher than for other REA groups. Caution in generalizing these observations is required, because the patients studied were younger and more likely to be from Canadian sites than were patients with recurrence who did not provide isolates.
| S-EPMC3388025 | biostudies-literature
Project description:Background:Plasmodium vivax resistance to chloroquine (CQ) has been reported worldwide, although the World Health Organization clinical drug efficacy studies protocol does not permit classification of patient outcomes. Methods:We enrolled 40 patients with P. vivax malaria in northeastern Cambodia, where >17% treatment failures were previously reported. Patients were treated with CQ (30 mg/kg) and followed for 2 months, with frequent clinical examination and capillary blood sample collection for microscopy, molecular parasite detection and genotyping, and drug concentration measurements. Reinfections were prevented by relocating patients to a transmission-free area. Results:P. vivax parasites were eliminated in all patients by day 3. Genomic analyses revealed that all clones in polyclonal infections were cleared at the same rate, indicating their equal susceptibility to CQ. CQ blood concentrations were below the therapeutic level in all recurrent infections (24 of 40 patients), which were efficiently cleared by a second course of CQ treatment. Genotyping (128 SNPs barcode) and sequences of entire parasite genome (Whole-Genome Sequencing, Illumina) indicated that two thirds (6 of 8) of the recurrent parasites resulted from heterologous relapses whose 50% are from by sibling/recombinant clones. Conclusions:No evidence of CQ resistance was observed. Our data suggest that P. vivax antimalarial drug resistance is likely overestimated and that the current guidelines for clinical drug studies of P. vivax malaria need to be revised.
| S-EPMC6306015 | biostudies-literature
Project description:In the present study, we propose and analyze an epidemic mathematical model for malaria dynamics, considering multiple recurrent phenomena: relapse, reinfection, and recrudescence. A limitation in hospital bed capacity, which can affect the treatment rate, is modeled using a saturated treatment function. The qualitative behavior of the model, covering the existence and stability criteria of the endemic equilibrium, is investigated rigorously. The concept of the basic reproduction number of the proposed model is obtained using the concept of the next-generation matrix. We find that the malaria-free equilibrium point is locally asymptotically stable if the basic reproduction number is less than one and unstable if it is larger than one. Our observation on the malaria-endemic equilibrium of the proposed model shows possible multiple endemic equilibria when the basic reproduction number is larger or smaller than one. Hence, we conclude that a condition of a basic reproduction number less than one is not sufficient to guarantee the extinction of malaria from the population. To test our model in a real-life situation, we fit our model parameters using the monthly incidence data from districts in Central Sumba, Indonesia called Wee Luri, which were collected from the Wee Luri Health Center. Using the first twenty months' data from Wee Luri district, we show that our model can fit the data with a confidence interval of 95%. Both analytical and numerical experiments show that a limitation in hospital bed capacity and reinfection can trigger a more substantial possibility of the appearance of backward bifurcation. On the other hand, we find that an increase in relapse can reduce the chance of the appearance of backward bifurcation. A non-trivial result appears in that a higher probability of recrudescence (treatment failure) does not always result in the appearance of backward bifurcation. From the global sensitivity analysis using a combination of Latin hypercube sampling and partial rank correlation coefficient, we found that the initial infection rate in humans and the mosquito infection rate are the most influential parameters in determining the increase in total new human infections. We expand our model as an optimal control problem by including three types of malaria interventions, namely the use of bed net, hospitalization, and fumigation as a time-dependent variable. Using the Pontryagin maximum principle, we characterize our optimal control problem. Results from our cost-effectiveness analysis suggest that hospitalization only is the most cost-effective strategy required to control malaria disease.
| S-EPMC9609641 | biostudies-literature
Project description:Relapse and Reinfection in Tuberculosis
| PRJEB2777 | ENA
Project description:PSEUDOMARKER is a software package that performs joint linkage and linkage disequilibrium analysis between a marker and a putative disease locus. A key feature of PSEUDOMARKER is that it can combine case-controls and pedigrees of varying structure into a single unified analysis. Thus it maximizes the full likelihood of the data over marker allele frequencies or conditional allele frequencies on disease and recombination fraction.The new version 2.0 uses the software package NOMAD to maximize likelihoods, resulting in generally comparable or better optima with many fewer evaluations of the likelihood functions.After being modified substantially to use modern optimization methods, PSEUDOMARKER version 2.0 is more robust and substantially faster than version 1.0. NOMAD may be useful in other bioinformatics problems where complex likelihood functions are optimized.
| S-EPMC3932042 | biostudies-literature
Project description:Multilevel linear models allow flexible statistical modelling of complex data with different levels of stratification. Identifying the most appropriate model from the large set of possible candidates is a challenging problem. In the Bayesian setting, the standard approach is a comparison of models using the model evidence or the Bayes factor. Explicit expressions for these quantities are available for the simplest linear models with unrealistic priors, but in most cases, direct computation is impossible. In practice, Markov Chain Monte Carlo approaches are widely used, such as sequential Monte Carlo, but it is not always clear how well such techniques perform. We present a method for estimation of the log model evidence, by an intermediate marginalisation over non-variance parameters. This reduces the dimensionality of any Monte Carlo sampling algorithm, which in turn yields more consistent estimates. The aim of this paper is to show how this framework fits together and works in practice, particularly on data with hierarchical structure. We illustrate this method on simulated multilevel data and on a popular dataset containing levels of radon in homes in the US state of Minnesota.
| S-EPMC9931113 | biostudies-literature
Project description:Whole-genome sequencing was used to determine whether the reductions in recurrence of Clostridium difficile infection observed with fidaxomicin in pivotal phase 3 trials occurred by preventing relapse of the same infection, by preventing reinfection with a new strain, or by preventing both outcomes. Paired isolates of C. difficile were available from 93 of 199 participants with recurrences (28 were treated with fidaxomicin, and 65 were treated with vancomycin). Given C. difficile evolutionary rates, paired samples ≤2 single-nucleotide variants (SNVs) apart were considered relapses, paired samples >10 SNVs apart were considered reinfection, and those 3-10 SNVs apart (or without whole-genome sequences) were considered indeterminate in a competing risks survival analysis. Fidaxomicin reduced the risk of both relapse (competing risks hazard ratio [HR], 0.40 [95% confidence interval {CI}, .25-.66]; P = .0003) and reinfection (competing risks HR, 0.33 [95% CI, 0.11-1.01]; P = .05).
| S-EPMC3982846 | biostudies-literature
Project description:Background:Chronic asymptomatic Plasmodium falciparum infections are common in endemic areas and are thought to contribute to the maintenance of malaria immunity. Whether treatment of these infections increases the subsequent risk of clinical episodes of malaria is unclear. Methods:In a 3-year study in Mali, asymptomatic individuals with or without P. falciparum infection at the end of the 6-month dry season were identified by polymerase chain reaction (PCR), and clinical malaria risk was compared during the ensuing 6-month malaria transmission season. At the end of the second dry season, 3 groups of asymptomatic children were identified: (1) children infected with P. falciparum as detected by rapid diagnostic testing (RDT) who were treated with antimalarials (n = 104), (2) RDT-negative children whose untreated P. falciparum infections were detected retrospectively by PCR (n = 55), and (3) uninfected children (RDT/PCR negative) (n = 434). Clinical malaria risk during 2 subsequent malaria seasons was compared. Plasmodium falciparum-specific antibody kinetics during the dry season were compared in children who did or did not harbor asymptomatic P. falciparum infections. Results:Chronic asymptomatic P. falciparum infection predicted decreased clinical malaria risk during the subsequent malaria season(s); treatment of these infections did not alter this reduced risk. Plasmodium falciparum-specific antibodies declined similarly in children who did or did not harbor chronic asymptomatic P. falciparum infection during the dry season. Conclusions:These findings challenge the notion that chronic asymptomatic P. falciparum infection maintains malaria immunity and suggest that mass drug administration during the dry season should not increase the subsequent risk of clinical malaria.
| S-EPMC6075513 | biostudies-literature
Project description:BackgroundSince leprosy is both treated and controlled by multidrug therapy (MDT) it is important to monitor recurrent cases for drug resistance and to distinguish between relapse and reinfection as a means of assessing therapeutic efficacy. All three objectives can be reached with single nucleotide resolution using next generation sequencing and bioinformatics analysis of Mycobacterium leprae DNA present in human skin.MethodologyDNA was isolated by means of optimized extraction and enrichment methods from samples from three recurrent cases in leprosy patients participating in an open-label, randomized, controlled clinical trial of uniform MDT in Brazil (U-MDT/CT-BR). Genome-wide sequencing of M. leprae was performed and the resultant sequence assemblies analyzed in silico.Principal findingsIn all three cases, no mutations responsible for resistance to rifampicin, dapsone and ofloxacin were found, thus eliminating drug resistance as a possible cause of disease recurrence. However, sequence differences were detected between the strains from the first and second disease episodes in all three patients. In one case, clear evidence was obtained for reinfection with an unrelated strain whereas in the other two cases, relapse appeared more probable.Conclusions/significanceThis is the first report of using M. leprae whole genome sequencing to reveal that treated and cured leprosy patients who remain in endemic areas can be reinfected by another strain. Next generation sequencing can be applied reliably to M. leprae DNA extracted from biopsies to discriminate between cases of relapse and reinfection, thereby providing a powerful tool for evaluating different outcomes of therapeutic regimens and for following disease transmission.
| S-EPMC5498066 | biostudies-literature
Project description:Recurrent tuberculosis is an important indicator of the effectiveness of tuberculosis control and can occur by relapse or exogenous reinfection. We conducted a retrospective cohort study on all bacteriologically confirmed tuberculosis cases that were successfully treated between 2000 and 2012 in Shanghai, an urban area with a high number but a low prevalence rate of tuberculosis cases and a low prevalence of HIV infection. Genotyping the Mycobacterium tuberculosis from clinical isolates was used to distinguish between relapse and reinfection. In total, 5.3% (710/13,417) of successfully treated cases had a recurrence, a rate of 7.55 (95% CI 7.01-8.13) episodes per 1000 person-years, more than 18 times the rate of tuberculosis in the general population. Patients who were male, age 30-59, retreatment cases, had cavitation, diabetes, drug-resistant or multidrug-resistant tuberculosis in their initial episode of tuberculosis, were at high risk for a recurrence. Among 141 recurrent cases that had paired isolates, 59 (41.8%) had different genotypes, indicating reinfection with a different strain. Patients who completed treatment were still at high risk of another episode of tuberculosis and exogenous reinfection contributed a significant proportion of the recurrent tuberculosis cases. Targeted control strategies are needed to prevent new tuberculosis infections in this setting.
| S-EPMC5638046 | biostudies-literature