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      Complications of miliary tuberculosis: low mortality and predictive biomarkers from a UK cohort

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          Abstract

          Background

          Untreated, miliary tuberculosis (TB) has a mortality approaching 100%. As it is uncommon there is little specific data to guide its management. We report detailed data from a UK cohort of patients with miliary tuberculosis and the associations and predictive ability of admission blood tests with clinical outcomes.

          Methods

          Routinely collected demographic, clinical, blood, imaging, histopathological and microbiological data were assessed for all patients with miliary TB identified from the London TB register from 2008 to 2012 from Northwest London Hospitals NHS Trust. Multivariable logistic regression was used to assess factors independently associated with the need for critical care intervention. Receiver operator characteristics (ROC) were calculated to assess the discriminatory ability of admission blood tests to predict clinical outcomes.

          Results

          Fifty-two patients were identified with miliary tuberculosis, of whom 29% had confirmed central nervous system (CNS) involvement. Magnetic resonance imaging (MRI) was more sensitive than computed tomography (CT) or lumbar puncture for detecting CNS disease. Severe complications were frequent, with 15% requiring critical care intervention with mechanical ventilation. This was independently associated with admission hyponatraemia and elevated alanine aminotransferase (ALT). Having an admission sodium ≥125 mmol/L and an ALT <180 IU/L had 82% sensitivity and 100% specificity for predicting a favourable outcome with an area under the ROC curve (AUC) of 0.91. Despite the frequency of severe complications, one-year mortality was low at 2%.

          Conclusions

          Although severe complications of miliary tuberculosis were frequent, mortality was low with timely access to critical care intervention, anti-tuberculous therapy and possibly corticosteroid use. Clinical outcomes could accurately be predicted using routinely collected biochemistry data.

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          Most cited references9

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          Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study.

          Prevention and control of disease and injury require information about the leading medical causes of illness and exposures or risk factors. The assessment of the public-health importance of these has been hampered by the lack of common methods to investigate the overall, worldwide burden. The Global Burden of Disease Study (GBD) provides a standardised approach to epidemiological assessment and uses a standard unit, the disability-adjusted life year (DALY), to aid comparisons. DALYs for each age-sex group in each GBD region for 107 disorders were calculated, based on the estimates of mortality by cause, incidence, average age of onset, duration, and disability severity. Estimates of the burden and prevalence of exposure in different regions of disorders attributable to malnutrition, poor water supply, sanitation and personal and domestic hygiene, unsafe sex, tobacco use, alcohol, occupation, hypertension, physical inactivity, use of illicit drugs, and air pollution were developed. Developed regions account for 11.6% of the worldwide burden from all causes of death and disability, and account for 90.2% of health expenditure worldwide. Communicable, maternal, perinatal, and nutritional disorders explain 43.9%; non-communicable causes 40.9%; injuries 15.1%; malignant neoplasms 5.1%; neuropsychiatric conditions 10.5%; and cardiovascular conditions 9.7% of DALYs worldwide. The ten leading specific causes of global DALYs are, in descending order, lower respiratory infections, diarrhoeal diseases, perinatal disorders, unipolar major depression, ischaemic heart disease, cerebrovascular disease, tuberculosis, measles, road-traffic accidents, and congenital anomalies. 15.9% of DALYs worldwide are attributable to childhood malnutrition and 6.8% to poor water, and sanitation and personal and domestic hygiene. The three leading contributors to the burden of disease are communicable and perinatal disorders affecting children. The substantial burdens of neuropsychiatric disorders and injuries are under-recognised. The epidemiological transition in terms of DALYs has progressed substantially in China, Latin America and the Caribbean, other Asia and islands, and the middle eastern crescent. If the burdens of disability and death are taken into account, our list differs substantially from other lists of the leading causes of death. DALYs provide a common metric to aid meaningful comparison of the burden of risk factors, diseases, and injuries.
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            Miliary tuberculosis: new insights into an old disease.

            Miliary tuberculosis is a potentially lethal form of tuberculosis resulting from massive lymphohaematogeneous dissemination of Mycobacterium tuberculosis bacilli. The emergence of the HIV/AIDS pandemic and widespread use of immunosuppressive drugs has changed the epidemiology of miliary tuberculosis. Impaired cell-mediated immunity underlies the disease's development. Clinical manifestations are non-specific and typical chest radiographic findings may not be seen until late in the course of the disease. Atypical presentations--eg, cryptic miliary tuberculosis and acute respiratory distress syndrome--often delay the diagnosis. Several laboratory abnormalities with prognostic and therapeutic implications have been described, including pulmonary function and gas exchange impairment. Isolation of M tuberculosis from sputum, body fluids, or biopsy specimens, application of molecular methods such as PCR, and histopathological examination of tissue biopsy specimens are useful for the confirmation of diagnosis. Although response to first-line antituberculosis drugs is good, evidence regarding optimum duration of treatment is lacking and the role of adjunctive corticosteroid treatment is unclear.
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              Corticosteroids for prevention of mortality in people with tuberculosis: a systematic review and meta-analysis.

              The effects of corticosteroids are systemic, but their benefits in tuberculosis are thought to be organ specific, with clinicians using them routinely to treat some forms of tuberculosis (such as meningitis), but not others. We aimed to assess the effects of steroids on mortality attributable to all forms of tuberculosis across organ systems. We did a systematic review and meta-analysis to estimate the efficacy of steroids for the prevention of mortality in all forms of tuberculosis, and to quantify heterogeneity in this outcome between affected organ systems. We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Central Register of Controlled Trials, Medline, Embase, and Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) for studies published up to Sept 6, 2012, and checked reference lists of included studies and relevant reviews. We included all trials in people with tuberculosis in any organ system, with tuberculosis defined clinically or microbiologically. There were no restrictions by age, comorbidity, publication language, or type, dose, or duration of steroid treatment. We used the Mantel-Haenszel method to summarise mortality across trials. We identified 41 eligible trials, 18 of which assessed pulmonary tuberculosis. 20 of the 41 trials (including 13 of those for pulmonary tuberculosis) were done before the introduction of modern rifampicin-containing antituberculosis chemotherapy. Meta-analysis stratified by affected organ systems identified no heterogeneity; steroids reduced mortality by 17% (risk ratio [RR] 0·83, 95% CI 0·74-0·92; I(2) 0%), consistent across all organ groups. In a sensitivity analysis that only included trials that used rifampicin-containing regimens, the results were similar (RR 0·85, 95% CI 0·74-0·98; I(2) 21%). A sensitivity analysis in pulmonary tuberculosis that excluded trials with high potential risks of bias suggested a slight benefit, but the point estimate was closer to no effect and the difference was not significant (RR 0·93, 95% CI 0·60-1·44). Steroids could be effective in reducing mortality for all forms of tuberculosis, including pulmonary tuberculosis. However, further evidence is needed since few recent trials have assessed the effectiveness of corticosteroids in patients with pulmonary tuberculosis. UK Department for International Development. Copyright © 2013 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                jonathan.underwood@imperial.ac.uk
                fionacresswell@doctors.org.uk
                alexsalam@doctors.org.uk
                alex.keeley@gmail.com
                crcleland87@gmail.com
                laurence.john@nhs.net
                r.n.davidson@imperial.ac.uk
                Journal
                BMC Infect Dis
                BMC Infect. Dis
                BMC Infectious Diseases
                BioMed Central (London )
                1471-2334
                20 April 2017
                20 April 2017
                2017
                : 17
                : 295
                Affiliations
                [1 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Division of Infectious Diseases, , Imperial College London, ; London, UK
                [2 ]GRID grid.410725.5, Lawson Unit, , Brighton and Sussex University Hospitals NHS Trust, ; Brighton, UK
                [3 ]ISNI 0000 0001 2322 6764, GRID grid.13097.3c, , King’s College London, ; London, UK
                [4 ]Department of Medicine, Western Sussex Hospitals Trust, Worthing, UK
                [5 ]ISNI 0000 0004 0417 012X, GRID grid.426108.9, , Royal Free Hospital, ; London, UK
                [6 ]ISNI 0000 0004 0398 9627, GRID grid.416568.8, Department of Infectious Diseases, , Northwick Park Hospital, Northwest London Teaching Hospitals NHS Trust, ; London, UK
                Author information
                http://orcid.org/0000-0001-6963-2821
                Article
                2397
                10.1186/s12879-017-2397-6
                5399311
                28427368
                0124223a-fd87-4a3c-9501-cca8532112c4
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 6 August 2016
                : 11 April 2017
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Infectious disease & Microbiology
                tuberculosis,miliary tuberculosis,central nervous system infection,mortality,biomarkers

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