Diagnosis of smear-negative or sputum-scarce tuberculosis in adults in HIV--论文代写范文精选

在HIV环境性条件下，虽然有更高的感染艾滋病毒,五分之一的患者无法提供样品。但微生物在50%的患者诊断仅仅是可能的。下面的report代写范文进行详述。

Abstract
Sputum induction can aid tuberculosis (TB) diagnosis, but adult data from HIV-endemic environments are limited, and it is unclear how performance varies depending on the clinical context (in-patient versus outpatient), HIV status and whether patients are smear-negative or sputum-scarce.696 adults with suspected smear-negative or sputum-scarce TB from Cape Town (South Africa) were referred for routine sputum induction. Liquid culture for Mycobacterium tuberculosis served as the reference standard.

82% (573 out of 696) of patients provided a specimen ≥1 mL, 83% (231 out of 278) of which were of adequate quality. 15% (96 out of 652) of sputum induction specimens were culture-positive, and this yield was higher among inpatients versus outpatients (17% (71 out of 408) versus 10% (25 out of 244), p=0.01) and HIV-infected versus uninfected patients (17% (51 out of 294) versus 9% (16 out of 173), p=0.02), but similar for CD4 (>200 versus ≤200 cells•μL−1) and patient (smear-negative versus sputum-scarce) subcategories. Overall sensitivity (95% CI) of smear-microscopy was 49% (39–59%), higher among in-patients versus outpatients (55% (43–67%) versus 32% (14–50%), p=0.05), but unaffected by HIV co-infection, CD4 count or patient type. 29% (203 out of 696) of patients commenced anti-TB treatment and sputum induction offered microbiological confirmation and susceptibility testing in only 47% (96 out of 203).

Under programmatic conditions in an HIV-endemic environment although the yield of culture was approximately two-fold higher amongst HIV-infected patients and inpatients, a fifth of all patients were unable to provide a specimen following sputum induction. Same-day microbiological diagnosis was only possible in ∼50% of patients.

Introduction
The diagnosis of patients suspected of tuberculosis (TB) who are sputum smear-negative for acid-fast bacilli or who are unable to produce sputum (sputum scarce) is a daily challenge for clinicians in HIV-endemic settings [1]. In developing countries facing the dual epidemics of TB and HIV, the burden of smear-negative or sputum-scarce TB is large and accounts for approximately every second notified TB case [2]. Failure to confirm a TB diagnosis negatively impacts both patients and TB control by: 1) increasing morbidity and mortality [3–5]; 2) fuelling the transmission of multidrug resistant (MDR)-TB by ineffectively treating undiagnosed disease [6, 7]; and 3) exposing patients that are inappropriately given empiric TB treatment to unnecessary, toxic and prolonged drug therapy [8]. Strategies to improve and decentralise the diagnosis of adults with suspected smear-negative and sputum-scarce TB are needed, with focus not only on improved diagnostic test efficacy but also on the optimisation of sputum specimen acquisition methods [9]. The World Health Organization endorsement [10] and roll-out of the novel MTB/RIF (Mycobacterium tuberculosis/rifampicin) assay (Cepheid, Sunnyvale, CA, USA) looks set to offer rapid diagnostic yields close to those of solid culture techniques, even in primary care settings [11–14], thus making the need to address the diagnostic bottleneck of sputum specimen acquisition urgent.

Sputum induction, performed using the ultrasonic nebulisation of hypertonic saline, is a relatively simple and safe procedure suitable for use in resource-limited decentralised settings [15–20]. Induction has been shown to offer similar TB case detection rates to more invasive techiques such as bronchoscopy as an aid to TB diagnosis [21, 22]. It has shown particular utility for diagnostic sampling in children [23, 24] and for TB screening in asymptomatic patients prior to the initiation of antiretrovirals [25]. Consequently, advocacy for the roll-out and widespread use of sputum induction in HIV-endemic, resource-limited primary care settings is increasing. However, data are limited for smear-negative or sputum-scarce adult TB suspects in HIV-endemic settings [15–18]. Available studies are small with large variability in diagnostic performance measures and wide confidence intervals [15–18]. 

Studies are heterogenous due to differences that include: 1) the clinical context of patients undergoing sputum induction (e.g. hospital inpatient versus respiratory clinic outpatient) [19]; 2) the preceding diagnostic workup of patients prior to sampling (e.g. chest radiography versus none) [19]; 3) HIV prevalence [19]; 4) sputum induction procedure (e.g. 3% versus 5% hypertonic saline concentration) [20]; and 5) type of diagnostic testing on induced specimens (e.g. conventional light versus fluoresence microscopy) [15–18]. These differences prevent useful meta-analysis [19, 20] and limit generalisability. Larger studies that provide a more robust evidence base to guide national TB programme policy are overdue. Furthermore, the absence of direct comparative performance data between HIV-infected and uninfected (and stratified by CD4 cell count), outpatients and inpatients, and smear-negative and sputum-scarce TB suspects from a single study is a major research gap, and we hypothesised that between-group differences would be lower than could be expected from a simple comparison of pre-sampling TB prevalences.

To address these gaps and evaluate our hypothesis, we conducted a large, cross-sectional study of sputum induction to evaluate the procedural side-effects, sampling efficacy, specimen quality, culture-based diagnostic yield and diagnostic accuracy of smear microscopy stratified by clinical context (inpatient versus outpatient), HIV status and CD4 count, and TB suspect reason for induction (sputum scarce versus smear negative). In addition, we evaluated the ability of sputum induction sampling to allow for microbiological TB confirmation and susceptibility in all patients commencing anti-TB treatment.

Study population
The study was conducted at the Groote Schuur Hospital respiratory clinic in Cape Town, South Africa. Routine sputum induction facilities are available to hospital inpatients (including ward and emergency room admissions) and outpatients (including specialist and general medical clinics) on doctors’ request. Patients (≥16 years old) referred for induction between February 12, 2008 and May 30, 2009 were eligible for inclusion in the study. Basic demographics, HIV status and reason for referral for induction were recorded by nursing staff. Only patients referred for induction with suspected smear-negative or sputum-scarce TB were included, and patients referred for any other indications, e.g. possible Pneumocystis jiroveci infection or malignancy were excluded. The study was approved by the University of Cape Town human research ethics committee.

Diagnostic workup and treatment
As per routine practice, all patients referred for induction with suspected smear-negative or sputum-scarce TB had received a doctor’s assessment and chest radiography, as well as an attempted collection of a self-expectorated early morning sputum sample prior to referral. Patients with two smear-negative sputum samples within 4 weeks of referral for induction were considered smear-negative. Data on the exact timing between attempted self-expectoration and induction was not documented for all patients; however, for sputum-scarce inpatients, self-expectoration was attempted on admission. Using the laboratory and hospital pharmacy record systems, the commencement of anti-TB treatment for study patients within a month of enrolment was noted. Any patient commencing treatment without a positive TB culture result on a recent (±4 weeks from enrolment) specimen (induced sputum or other) was considered to have received empiric treatment.

Sputum induction procedure
Sputum induction was performed by respiratory clinic nursing staff in an enclosed negative-pressure induction booth as previously described [26]. Briefly, ∼20 mL of sterile 5% hypertonic saline (Sabax; Adcock Ingram, Midrand, South Africa) was delivered via a Wilson’s 402A ultrasonic nebuliser (Medimark, Cape Town, South Africa) over 15–20 min or until 2–4 mL of induced sputm could be collected. No pro-expectorating manoeuvres were employed. Research nurses monitored for side-effects and induction was terminated if side-effects developed.

Laboratory methods
Induced sputa were processed by the National Health Laboratory Service reference laboratory (Groote Schuur Hospital, Cape Town, South Africa). Specimens were decontaminated with N-acetyl-L-cysteine/sodium hydroxide and then centrifuged. Thereafter, an auramine O-stained smear underwent fluoresence microscopy and 0.5 mL of the deposit was inoculated into a Mycobacterial Growth Indicator Tube 960 (Becton Dickinson Diagnostics, Franklin Lakes, NJ, USA). Approximately half of samples received Gram staining prior to decontamination and sputum quality was determined using the Bartlett score [27]. Culture-positive acid-fast bacilli were identified as M. tuberculosis complex using either an in-house PCR method [28] or the GenoType MTBDRplus assay (version 1; Hain LifeSciences, Nehren, Germany) if drug susceptibility testing had been requested. MTBDRplus assay testing was introduced for routine drug susceptibility testing only in the latter part of the study period (fig. 1).

Statistical analysis
All patients (or patients in a subgroup) referred for induction with suspected smear-negative or sputum-scarce TB were used as the denominator when calculating the culture-based TB case detection rates of sputum induction. M. tuberculosis culture was used as the reference standard for evaluating the diagnostic accuracy of induced sputum smear microscopy and only included patients with a valid culture result. Sensitivity, specificity, and positive and negative predictive values are presented with 95% confidence intervals. Univariate and multivariate logistic regression analysis was used to investigate the predictors of induced sputum: sputum sampling, culture positivity and smear positivity. Basic demographic and sputum induction characteristics, as well as diagnostic accuracy measures, of different patient groups were compared using the Chi-squared, Wilcoxon rank-sum and Kruskal–Wallis tests, as appropriate, and all statistical tests were two-sided at α=0.05. Stata IC (version 10; Stata Corp., College Station, TX, USA) was used for all statistical analyses.

Results
Demographics, patient setting and indication for sputum induction Of the patients referred for sputum induction during the 15-month study period, 696 patients had suspected smear-negative or sputum-scarce TB (fig. 1). 62% (434 out of 696) and 74% (517 out of 696) of patients referred for induction were inpatients and had suspected sputum-scarce TB, respectively. table 1 shows basic patient demographics and the reason for sputum induction referral stratifed by patient setting and HIV status. A greater proportion (95% CI) of outpatients compared to inpatients were sputum scarce (79% (74–84%) versus 71% (67–74%), p=0.02). The median (interquartile range (IQR)) age of patients was 40 (32–53) years, with a younger median age among inpatients versus outpatients (38 (29–48) years versus 45 (34–57) years, p<0.001), and HIV-infected versus -uninfected patients (35 (30–42) years versus 46 (36–56) years, p<0.001). Among HIV-infected patients, the median (IQR) CD4 cell count was 155 (65–269) cells•μL−1, with no difference in median CD4 cell count noted between inpatients and outpatients. 24% (74 out of 308) of HIV-infected patients had missing CD4 cell count data.

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