Mixed Mycobacterium tuberculosis–Strain Infections Are Associated With Poor Treatment Outcomes Among Patients With Newly Diagnosed Tuberculosis, Independent of Pretreatment Heteroresistance

Shin, Sanghyuk S.; Modongo, Chawangwa; Baik, Yeonsoo; Allender, Christopher John; Lemmer, Darrin; Colman, Rebecca E.; Engelthaler, David M.; Warren, Robin M.; Zetola, Nicola M.

doi:10.1093/infdis/jiy480

Cited by 42 publications

(56 citation statements)

References 43 publications

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“…However, as very few of the emergent RAVs were identified even among the multiple low-frequency variants that may represent standing variation or sequencing error(2), it suggests that weekly or more frequent sampling in addition to effective exclusion of sequencing error would be required to identify low-frequency RAVs that were likely to be clinically significant. This is in agreement with another study of treatment failures that found that only variants at >19% frequency were likely to become fixed (14) and that very low-frequency variants did not affect outcome of patients with DS-TB (5).…”

Section: Discussionsupporting

confidence: 92%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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Section: Discussionsupporting

confidence: 92%

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Nimmo

Brien

Millard

et al. 2020

Preprint

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“…However, more recent applications of advanced molecular tools suggest mixed infection might occur more frequently than initially expected (6,7). This possibility led to many research studies of mixed infection, which found that mixed infection is associated with poor treatment outcomes (6,8), including acquisition of multidrug-resistant TB (7,8). Mixed infection research contributed to the discovery that exogenous reinfection was responsible for a substantial portion of incident TB, implying incomplete protection from a primary infection in subsequent infections (9,10).…”

mentioning

confidence: 99%

Possible Transmission Mechanisms of Mixed Mycobacterium tuberculosis Infection in High HIV Prevalence Country, Botswana

Baik¹,

Modongo²,

Moonan³

et al. 2020

Emerg. Infect. Dis.

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“…Examining the bases mapped to each site using per-base binomial testing (see Methods) shows sample-C from patient-1 contains multiple mixed positions (M-sites) at the sites differing between A and B. This kind of within-patient heterogeneity, which is reported to be associated with impaired treatment response, 10, 13, 14 is not evident using standard methods of consensus base calling, using which C appears identical to (that is, has a zero pairwise SNV distance from) sample A. Consequently, we decided to develop automated methods detecting mixed TB infection using our routinely sequenced data.…”

Section: Resultsmentioning

confidence: 99%

“…Such infections are currently of clinical interest since response to treatment is known to be delayed in individuals with mixed infection. 10, 13, 14 Mixed infection may reflect either the development of intra-host diversity during chronic infection 6 , or co-infection by more than one strain circulating in the community in which the affected individual resides. 15, 16 Co-circulating strains are commonly closely related, 15 and co-circulation is ongoing in hyperendemic settings, in which mixed isolates are reported in 10-30% of cases.…”

Section: Introductionmentioning

confidence: 99%

M. tuberculosis microvariation is common and is associated with transmission: analysis of three years prospective universal sequencing in England

Wyllie

Nikolayevskyy

et al. 2019

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BackgroundThe prevalence, association with disease status, and public health impact of infection with mixtures of M. tuberculosis strains is unclear, in part due to limitations of existing methods for detecting mixed infections.MethodsWe developed an algorithm to identify mixtures of M. tuberculosis strains using next generation sequencing data, assessing performance using simulated sequences. We identified mixed M. tuberculosis strains when there was at least one mixed nucleotide position, and where both the mixture’s components were present in similar isolates from other individuals. We determined risk factors for mixed infection among isolations of M. tuberculosis in England using logistic regression. We used survival analyses to assess the association between mixed infection and putative transmission.Findings6,560 isolations of TB were successfully sequenced in England 2016-2018. Of 3,691 (56%) specimens for which similar sequences had been isolated from at least two other individuals, 341 (9.2%) were mixed. Infection with lineages other than Lineage 4 were associated with mixed infection. Among the 1,823 individuals with pulmonary infection with Lineage 4 M. tuberculosis, mixed infection was associated with significantly increased risk of subsequent isolation of closely related organisms from a different individual (HR 1.43, 95% CI 1.05,1.94), indicative of transmission.InterpretationMixtures of transmissible strains occur in at least 5% of tuberculosis infections in England; when present in pulmonary disease, such mixtures are associated with an increased risk of tuberculosis transmission.FundingPublic Health England; NIHR Health Protection Research Unit Oxford; European Union.Research in ContextEvidence Before This StudyWe searched Pubmed using the search terms ‘tuberculosis’ and ‘mixed’ or ‘mixture’ for English Language articles published up to 1 April 2019. Studies, most performed without the benefit of genomic sequencing, report mixed TB infection from a range of medium and high prevalence areas and show it to be associated with delayed treatment response. Modelling suggests detection and treatment of mixed TB infection is an important goal for TB eradication campaigns. Although routine DNA sequencing of M. tuberculosis isolates is becoming widespread, efficient methods for detecting mixed infection from such data are underdeveloped, and the true prevalence of mixed infection and its association with transmission is unclear.Added Value of This StudyThis study investigated a large series of TB isolations obtained as part of a routine Mycobacterial sequencing program by two reference laboratories, in a low incidence area, England. We developed an efficient generalisable approach to identify transmitted mixed M. tuberculosis infection; our approach is capable of sensitive and specific detection of a single mixed nucleotide position. We identified mixed infection of similar strains (‘microvariation’) in about 9.2% of the M. tuberculosis samples which we were able to assess, and found evidence of increased transmission from individuals with mixed infection.Implications of All the Available EvidenceTB microvariation is a risk factor for TB transmission, even in the low incidence area studied. Although an efficient and highly specific technique identifying microvariation exists, it relies on comparison with similar sequences isolated from other patients. Sharing of sequence data from the many TB sequencing programs being deployed globally will increase the sensitivity of microvariation detection, and may assist targeted public health interventions.

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Mixed Mycobacterium tuberculosis–Strain Infections Are Associated With Poor Treatment Outcomes Among Patients With Newly Diagnosed Tuberculosis, Independent of Pretreatment Heteroresistance

Abstract: Among patients starting first-line tuberculosis therapy in Botswana, mixed infections were associated with poor tuberculosis treatment outcomes, independent of heteroresistance.

Cited by 42 publications

References 43 publications

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Dynamics of within-hostMycobacterium tuberculosisdiversity and heteroresistance during treatment

Possible Transmission Mechanisms of Mixed Mycobacterium tuberculosis Infection in High HIV Prevalence Country, Botswana

M. tuberculosis microvariation is common and is associated with transmission: analysis of three years prospective universal sequencing in England

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