Accepted Manuscript Title: Relationship between chest radiographic characteristics, sputum bacterial load, and treatment outcomes in patients with extensively drug-resistant tuberculosis Authors: J.B. te Riele, V Buser, G. Calligaro, A Esmail, G Theron, M Lesosky, K Dheda PII: DOI: Reference:
S1201-9712(18)34574-0 https://doi.org/10.1016/j.ijid.2018.10.026 IJID 3380
To appear in:
International Journal of Infectious Diseases
Received date: Revised date: Accepted date:
18 May 2018 29 October 2018 29 October 2018
Please cite this article as: te Riele JB, Buser V, Calligaro G, Esmail A, Theron G, Lesosky M, Dheda K.Relationship between chest radiographic characteristics, sputum bacterial load, and treatment outcomes in patients with extensively drug-resistant tuberculosis.International Journal of Infectious Diseases (2018), https://doi.org/10.1016/j.ijid.2018.10.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Relationship between chest radiographic characteristics, sputum bacterial load, and treatment outcomes in patients with extensively drug-resistant tuberculosis
JB te Riele1, V Buser2, G. Calligaro2, A Esmail2, G Theron2, M Lesosky1, K Dheda2
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1 Department of Public Health and Family Medicine, University of Cape Town,
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South Africa
2 Division of Pulmonology and UCT Lung Institute, Department of Medicine,
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University of Cape Town, South Africa
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Corresponding Author: Professor Keertan Dheda. Email:
[email protected]
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Contact details of the authors: JB te Riele.
[email protected] V Buser.
[email protected] G Calligaro.
[email protected] A Esmail.
[email protected] G Theron.
[email protected] M Lesosky.
[email protected]
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Keywords: XDR-TB, chest radiography, lung disease extent, cavitary disease
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ABSTRACT
Background: Data about the relationship between chest radiographs and sputum bacillary load, with treatment outcomes, in patients with extensively drug-resistant tuberculosis (XDR-TB) from HIV/TB endemic settings are limited.
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Methods: Available chest radiographs from 97 South African XDR-TB patients, at the
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time of diagnosis, were evaluated by two independent readers using a validated
scoring system. Chest radiograph findings were correlated with baseline sputum bacillary load (smear-grade and culture time-to-positive in MGIT), and prospectively
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ascertained clinical outcomes (culture conversion and all-cause mortality).
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Results: Radiographic bilateral lung disease was present in 75/97 (77%). In the
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multivariate analysis only a higher total radiographic score (95% CI) was associated
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with higher likelihood of death [1.16 (1.05-1.28) p=0.003], and failure to culture
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convert [0.85 (0.74-0.97) p=0.02]. However, when restricting analyses to HIV-infected patients, disease extent, cavitation, and total radiographic scores were not
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associated with mortality or culture-conversion. Finally, cavitary, disease extent, and total radiographic scores all positively correlated with bacterial load (culture time-to-
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positive).
Conclusions: In endemic settings, XDR-TB radiological disease extent scores are
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associated with adverse clinical outcomes, including mortality, in HIV uninfected persons. These data may have implications for clinical and programmatic decisionmaking and for evaluation of new regimens in clinical trials.
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Introduction Tuberculosis (TB) remains a global health problem.1 However, the advent of drugresistant TB (DR-TB) threatens to reverse the gains made by national TB programs and is prohibitively expensive to treat2,3. There is also a growing epidemic of extensively drug-resistant TB (XDR-TB; defined as MDR-TB with resistance to a
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fluoroquinolone and either capreomycin, amikacin, or kanamycin).4 It is estimated
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that ~10% of all MDR-TB patients have XDR-TB.3 Treatment-related outcomes in patients with XDR-TB who did not receive newer or repurposed drugs, like
bedaquiline or linezolid, are extremely poor.5 Indeed, in a long-term prospective
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cohort of 107 XDR-TB patients mortality was 78% and only 11% of patients had a
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favourable outcome at 60 months after diagnosis.6 Even with bedaquiline treatment,
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30 month outcomes were sub-optimal with culture conversion rates of 62%.7
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Chest radiography is currently used for screening, diagnosis, and monitoring of response to anti-TB treatment8. Despite being limited by poor specificity and high
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inter-observer variability it remains a useful adjunct to clinical and microbiological tools. Several quantitative chest radiographic scoring systems have been developed
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and some have shown the potential to limit observer variability and increase the
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clinical value of the chest radiograph in TB.9,10
In drug sensitive TB extent of lung disease and cavities on radiography at diagnosis are known to be associated with an increased sputum bacterial load11, delayed smear and culture conversion10,12, and an increased risk of treatment failure.13,14 There is scanty data about chest radiographic findings in MDR-TB/HIV co-infected 3
patients15,16. Cavities on the baseline chest radiograph in MDR-TB may be an independent predictor of bacterial load, longer conversion times17and poor outcomes.18 However, there are hardly any data about chest radiographic findings in patients with XDR-TB,19and how these relate to outcomes in XDR-TB.18
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We could find no published data that examined the relationship between chest
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radiography and treatment-related outcomes in patients with XDR-TB from HIV and TB endemic settings where several factors including diagnostic delay, strain variability, and immunosuppression could potentially modulate radiographic
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findings. Moreover, the relationship between baseline chest radiography and
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bacterial load in XDR-TB has, hitherto, not been studied before. In this study we
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attempted to discern the relationship between baseline radiographic findings,
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bacterial load and treatment outcomes.
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Methods Setting
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In this prospective outcomes-based cohort study available baseline chest radiographs (at the time of XDR-TB diagnosis) from patients admitted to Brooklyn Chest Hospital
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(BCH), Cape Town, South Africa, between October 2008 and June 2012 were evaluated. At the time of evaluation a limited number of radiographs were available
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at the study site because of transfer of patients to peripheral clinics where CXRs were not accessible and could not be removed from outlying health facilities. Patients were managed as in-patients for at least the duration of the intensive phase of treatment and discharged to clinic treatment and follow up after four consecutive negative cultures. 4
Study Population 222 patients with XDR-TB admitted to BCH during the period October 2008 to June 2012 were followed up. 97/222 available chest radiographs (CXR), dated within 3 months of XDR-TB diagnosis, were independently scored by two non-specialist
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medical doctors. In total, 125 CXRs were unavailable for study (13/125 were more
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than 3 months from the date of XDR-TB diagnosis, 109/125 unavailable as patients transferred out to peripheral clinics with their CXRs, and 3/125 were unreadable
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according to Chest Radiograph Recording and Reporting (CRRS) criteria.20
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XDR-TB treatment regimen and outcomes
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Patients received a WHO approved, directly observed, regimen21. Bedaquiline and
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linezolid were not available. Treatment outcomes were assigned at censor date (31st
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October 2013) and regarded as favourable (cure or treatment completion) or unfavourable (default, treatment failure and death). Treatment-related outcome
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definitions used were based on Laserson’s classifications.22
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Ethics Statement
Ethics approval was obtained from the University of Cape Town human research
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ethics committee.
Scoring of chest radiographs The two experienced primary care medical doctors attended a two day CRRS20 chest radiology teaching course prior to the scoring of CXRs. To further establish consensus 5
scoring both readers, pilot read consisting of 20 CXRs was done together with two specialist pulmonologists experienced in TB. Thus, criteria for calling cavities and disease extent were agreed on before independent scoring of the CXRs.
The scoring systems applied in this study (Figure 1) include two horizontal lines that
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were measured at the lower border of the 2nd and 5th anterior costochondral
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junctions resulting in 6 zones. Each of the 6 zones was given a numerical score for the extent of disease (disease extent score) and for the number and size of the cavities (cavity score) present. Any parenchymal or pleural abnormalities were regarded as
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diseased and the area involved was estimated as more than or less than 50% of the
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total area. Cavities were declared where there was clear visible ring like opacity of
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greater than 50% of the total circumference. Cavities less than 1 cm were not
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considered and scored as ‘no cavitation’. A “total score” was derived by the sum of
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Statistical analysis
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the total disease extent and total cavitation scores for all 6 zones.
Factors (history of previous multi-drug-resistant, total number of drugs the organism
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was resistant to, weight under 50kg, HIV status, and CD4 count) known to be associated with treatment outcomes (mortality and culture conversion) were tested
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for association using Wilcoxon-rank sum (for continuous variables) and Fisher’s exact test (for discrete variables). Anti-retroviral therapy was not considered as all but 2 HIV-infected patients were on ARV treatment at the time of XDR-TB diagnosis. A univariate and multivariate Cox proportional hazards regression model was used to identify outcome predictors. Selected variables in the multivariate analysis included 6
those with a p-value
