The diagnosis of smear-negative pulmonary tuberculosis: the practice of sputum smear examination in Malawi.

SETTING: Forty hospitals in Malawi (3 central, 22 district and 15 mission) performing smear microscopy and registering tuberculosis patients. OBJECTIVE: To determine, in patients aged 15 years or above, 1) the proportion with smear-negative pulmonary tuberculosis (PTB) who had sputum smears examined, 2) the number of sputum smears examined per patient, and 3) the proportion of patients registered with smear-positive and smear-negative PTB. DESIGN: Data collection during three 6-month periods, from January 1997 to June 1998, using tuberculosis registers, laboratory sputum registers and quarterly reports. RESULTS: Of 6301 smear-negative PTB patients, 84% had sputum smears examined, the rate increasing from 76% in January-June 1997, to 85% in July-December 1997, to 89% in January-June 1998. Of patients who submitted sputum (where the number of smears was recorded), 99% had two or more smears examined and 93% had three smears examined. In district and mission hospitals performance improved over time, while in central hospitals results were more variable. During the same 18-month period 21 422 patients aged 15 years or more were registered with PTB: 59% with smear-positive PTB and 41% with smear-negative PTB; this pattern was similar in each 6-month period. CONCLUSION: The study suggests that it is reasonable to aim for a target of 90% or more of smear-negative PTB patients having sputum smears examined.     

Diagnosis of childhood tuberculosis in Malawi: an audit of hospital practice.

SETTING: All 44 non-private hospitals in Malawi that register and treat children with tuberculosis (TB). OBJECTIVE: To determine 1) clinical features and diagnostic practices in children registered with TB, and 2) the use of the WHO score chart in diagnosis. DESIGN: A cross-sectional study of all children aged 14 years or below in hospital receiving anti-tuberculosis treatment, using reviews of treatment cards, case files and chest X-rays and performing a clinical assessment. RESULTS: There were 150 children, 98 with pulmonary TB (PTB) and 52 with extra-pulmonary TB (EPTB). The median duration of illness was 8 weeks. Most patients had fever, no response to anti-malarial treatment and antibiotics, and 40% had a family history of TB. Nearly 45% had weight for age <60%. Diagnosis was mainly based on clinical features and radiography, with less than 10% having tuberculin skin tests or HIV serology, and very few having other sophisticated investigations. A WHO diagnostic score chart was used in 13 (9%) patients by hospital staff. An independent assessment by the study team found that 61% of patients had a score of 7 or more; this was higher in EPTB than PTB patients. CONCLUSION: Diagnostic practices in children with TB in Malawi are poor, and improvements should be made.     

Clinical diagnosis of smear-negative pulmonary tuberculosis in low-income countries: the current evidence

Sputum smear examination for acid-fast bacilli (AFB) can diagnose up to 50-60% of cases of pulmonary tuberculosis in well-equipped laboratories. In low-income countries, poor access to high-quality microscopy services contributes to even lower rates of AFB detection. Furthermore, in countries with high prevalence of both pulmonary tuberculosis and HIV infection, the detection rate is even lower owing to the paucibacillary nature of pulmonary tuberculosis in patients with HIV infection. In the absence of positive sputum smears for AFB, at primary care level, most cases of pulmonary tuberculosis are diagnosed on the basis of clinical and radiological indicators. This review aims to evaluate various criteria, algorithms, scoring systems, and clinical indicators used in low-income countries in the diagnosis of pulmonary tuberculosis in people with suspected tuberculosis but repeated negative sputum smears. Several algorithms and clinical scoring systems based on local epidemiology have been developed to predict smear-negative tuberculosis. Few of these have been validated within the local context. However, in areas where smear-negative tuberculosis poses a major public-health problem, these algorithms may be useful to national tuberculosis programmes by providing a starting point for development their own context-specific diagnostic guidelines.     

Efficacy of an unsupervised ambulatory treatment regimen for smear-negative pulmonary tuberculosis and tuberculous pleural effusion in Malawi.

SETTING: Queen Elizabeth Central Hospital, Blantyre, and Zomba Central Hospital, Zomba, Malawi. OBJECTIVE: To evaluate treatment outcome of unsupervised ambulatory treatment (2R3H3Z3/2TH[EH]/4H) in Blantyre and 'standard' treatment (1STH[SEH]/11TH[EH]) in Zomba in human immunodeficiency virus (HIV) seropositive and seronegative patients with smear-negative pulmonary tuberculosis (PTB) and pleural TB. DESIGN: All patients with smear-negative and pleural TB registered between 1 April and 31 December 1995 were assessed for enrolment in the study. Study patients were followed up and 12-month treatment outcomes were recorded. RESULTS: A total of 434 patients, 296 with smear-negative PTB and 138 with pleural TB, were enrolled: 366 (84%) of patients were HIV-positive; 220 (51%) completed treatment, and 144 (33%) died by 12 months. In patients from Blantyre and Zomba, baseline characteristics were similar, apart from older age in those from Zomba, and the proportion of patients who completed treatment and who died were similar. In both sites, significantly higher case fatality rates were found in older patients, HIV-positive patients and patients with pulmonary parenchymal lung disease. CONCLUSION: Unsupervised ambulatory treatment evaluated in this study had an efficacy similar to that of 'standard' treatment. For operational reasons, however, it will not be recommended for widespread use in Malawi's National Tuberculosis Control Programme.     

The rapid diagnosis of smear-negative pulmonary tuberculosis: a cost-effectiveness analysis

OBJECTIVE: The prompt diagnosis of smear-negative pulmonary tuberculosis (PTB) is a clinical challenge. It may be achieved by a number of tests which have varying accuracies, costs and degrees of invasiveness. The objective of this study was to compare the cost-effectiveness of clinical judgement (empirical), the Roche Cobas amplicor assay for Mycobacterium tuberculosis (amplicor), acid-fast staining of bronchoalveolar lavage specimens (BAL), nucleic acid amplification tests of bronchoalveloar lavage specimens for M. tuberculosis (BAL + NAA), computed tomography (CT) and amplicor assay followed by BAL. METHODOLOGY: The range of predictive values of the various strategies were derived from published data and a new study of 441 consecutive adult patients with suspected smear-negative PTB prospectively stratified into three pretest risk groups: low, intermediate and high. The cost-effectiveness was evaluated with a decision tree model (DATA software). RESULTS: The incidence of PTB was 5.7% (4% culture positive) for the whole group, 95% in the high-risk group, 0.9% in the low-risk group and 3.4% in the intermediate-risk group. The sensitivity of the empirical approach was 49% and of the amplicor assay was 44%. Patient outcomes were expressed as life expectancy for the base case of a 58-year-old man with a pretest probability of 5.7%. At this low pretest risk the differences in life expectancies between tests was < 0.1 years and the empirical approach incurred the lowest cost. Sensitivity analysis at increasing pretest risks showed better life expectancies (approximately 1 years) for CT scan and test combinations than empirical and amplicor for additional costs of US$243-US$309. Bronchoalveolar lavage had the worst overall cost-effectiveness. CONCLUSIONS: We conclude that the pretest risk of active PTB was a key determinant of test utility; that the AMPLICOR assay was comparable to clinical judgement; that BAL was the least useful test; and that with increasing risks, CT scan and test combinations performed better. Further studies are needed to better define patients with intermediate risk for PTB and to directly compare the cost-effectiveness of more sensitive nucleic acid amplification tests such as the enhanced Gen Probe, CT scan and test combinations/sequences in these patients.     

Fiberoptic bronchoscopy for the rapid diagnosis of smear-negative pulmonary tuberculosis

ABSTRACT: BACKGROUND: This study was aimed to investigate the diagnostic value of fiberoptic bronchoscopy (FOB) with chest high-resolution computed tomography (HRCT) for the rapid diagnosis of active pulmonary tuberculosis (PTB) in patients suspected of PTB but found to have a negative sputum acid-fast bacilli (AFB) smear. METHODS: We evaluated the diagnostic accuracy of results from FOB and HRCT in 126 patients at Gangnam Severance Hospital (Seoul, Korea) who were suspected of having PTB. RESULTS: Of 126 patients who had negative sputum AFB smears but were suspected of having PTB, 54 patients were confirmed as having active PTB. Hemoptysis was negatively correlated with active PTB. Tree-in-bud appearance on HRCT was significantly associated with active PTB. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FOB alone was 75.9%, 97.2%, 95.3%, and 84.3%, respectively, for the rapid diagnosis of active PTB. The combination of FOB and HRCT improved the sensitivity to 96.3% and the NPV to 96.2%. CONCLUSIONS: FOB is a useful tool in the rapid diagnosis of active PTB with a high sensitivity, specificity, PPV and NPV in sputum smear-negative PTB-suspected patients. HRCT improves the sensitivity of FOB when used in combination with FOB in sputum smear-negative patients suspected of having PTB.     

Fibreoptic bronchoscopy in the diagnosis of sputum smear-negative pulmonary tuberculosis: current status

Sputum smear-negative pulmonary tuberculosis (SSN-PTB) is a common problem faced by clinicians. Performing fibreoptic bronchoscopy (FOB), and subjecting the bronchoscopic secretions/transbronchial lung biopsy (TBLB) material to conventional diagnostic methods of smear, mycobacterial culture and histopathology appears to be helpful in the diagnosis of SSN-PTB. Application of polymerase chain reaction (PCR) may be helpful as an adjunctive method in the appropriate clinical setting. The FOB facilitates rapid diagnosis and offers the additional advantage of the diagnosis of several conditions that may mimic PTB. However, FOB is an invasive procedure, and is associated with the risk of transmission of tuberculosis (TB) and other infections. It is costly, and is not widely available in the developing countries. In developed countries with no limitations on resources, early FOB seems to be the best course of action in a patient with suspected SSN-PTB. In resource-poor settings, where transmission of TB is high, sputum induction with hypertonic saline can be useful in adding to the diagnostic yield. If the TB suspect still remains induced sputum smear-negative, and if the pre-test probability of the patient having PTB is high, starting antituberculosis treatment (ATT) and closely monitoring the patient and reserving FOB to those patients who do not seem to improve/deteriorate or those who have a negative spontaneously expectorated/induced sputum culture (if performed and available) seems to be a practically useful approach. Proper precautions must be followed to disinfect the bronchoscope in between use so as to minimise the risk of nosocomial transmission of infection.     

Clinical utility of a commercial ligase chain reaction kit for the diagnosis of smear-negative pulmonary tuberculosis.

SETTING: In paucibacillary forms of smear-negative tuberculosis it is very difficult to establish a correct and rapid diagnosis, as several weeks are usually required to obtain positive results from culture. In the last few years new rapid techniques based on molecular biology for the detection of Mycobacterium tuberculosis have been introduced. OBJECTIVE: The aim of this study was to evaluate the utility of the ligase chain reaction method (LCx, Abbott) for the diagnosis of smear-negative pulmonary tuberculosis. DESIGN: Thirty smear-negative patients with radiographic changes and clinical signs consistent with TB participated in the study. Sputum and bronchial aspirate were assessed according to traditional methods on L?wenstein-Jensen medium, and bronchoalveolar lavage (BAL) was assessed by the LCx test and the Bactec 460 system. Another 30 patients with non-tuberculous infections were included in the study as controls. RESULTS: Of the 30 patients suspected of tuberculosis, 19 had active disease on clinical, bacteriological and radiographic grounds, nine inactive tuberculosis and two had lung cancer. Bacteriological confirmation was obtained in 12 of the 19 (63.2%) patients with active tuberculosis. The sensitivity of sputum culture was 42.1% and bronchial aspirate culture 47.4%. BAL fluid revealed positive results in 57.9% using both LCx and Bactec. The results of the LCx assay can be obtained in 5 hours as opposed to several weeks using other methods. CONCLUSION: The LCx test may be useful in the diagnosis of smear-negative pulmonary tuberculosis and may be recommended in these clinical situations.     

Fibreoptic bronchoscopy in smear-negative pulmonary tuberculosis

Fifty smear-negative pulmonary tuberculosis patients underwent fibreoptic bronchoscopy. Bronchial aspirate smears of twelve patients and post-bronchoscopic sputum smears of fourteen patients were positive for acid-fast bacilli (AFB). Bronchial biopsy provided the diagnosis in 9 out of 30 patients. Brush smears were positive in 28 patients, being the only positive sample in ten cases. A high yield from brush smears was obtained due to their preparation from caseous material wherever visible in the bronchi. With these results a rapid diagnosis was established in 36 of the 50 patients. When culture results were available, a definite diagnosis of tuberculosis was made in 45 of the patients. The yield from brush smears was found to be significantly better when compared to bronchial aspirate smears (p less than 0.01) and post-bronchoscopic sputum smears (p less than 0.01).     

两种试验对菌阴肺结核诊断价值的比较

目的比较酶联免疫斑点试验(T-SPOT.TB)与结核菌素试验(PPD)在菌阴结核诊断中的诊断效果和价值。方法我院收治的菌阴肺结核患者60例为菌阴肺结核组,同期收治经相关检查及治疗后排除结核感染的肺炎患者52例为肺炎组,两组患者年龄、性别构成等一般资料无显著性差异。分别采用T-SPOT.TB试验与PPD试验检测比较诊断效果。结果 60例菌阴肺结核患者采用T-SPOT.TB检测,阳性56例,敏感性为93.33%(56/60),与采用PPD检测(敏感性为71.67%,43/60)比较,P0.01。52例肺炎患者TSPOT.TB检测4例阳性,特异性为92.31%(48/52),与PPD检测(特异性67.31%,35/52)比较,P0.01。结论 T-SPOT.TB检测在菌阴肺结核临床辅助诊断中具有较高的灵敏度及阴性预测值,其应用价值显著高于结核菌素试验检测。     

痰与支气管肺泡灌洗液结核分枝杆菌FQ-PCR检测对涂阴肺结核诊断价值的比较

目的 探讨呼吸道痰标本和支气管肺泡灌洗液(BALF)Mtb-DNA检测对涂阴肺结核的诊断价值。方法 选择福州肺科医院2009年7月至2009年12月胸部影像学疑为肺结核但至少3份痰涂片镜检Mtb阴性,或胸部影像学无法排除肺结核需进一步检查的患者共51例,所有入选患者初诊根据临床症状、体征、胸部影像学结果分为疑似结核组（24例）和待排结核组（27例）。均行抗结核抗体、红细胞沉降率检测及PPD试验,应用实时荧光定量聚合酶链反应（FQ-PCR）定性及定量检测两组患者痰和BALF中的Mtb-DNA。结果 疑似结核组和待排结核组各有22例和2例确诊肺结核,确诊的24例中痰FQ-PCR敏感度为45.8%（11/24）,特异度为96.3%（26/27）,Youden指数42.1%;BALF FQ-PCR的敏感度为75.0%（18/24）,特异度96.3%（26/27）,Youden指数71.3%。结论 FQ-PCR检测BALF Mtb较痰更为敏感,对影像学疑诊但痰涂片阴性的结核患者有很高的实用价值,尤其适用于无痰的患者。     

酶联免疫斑点试验在菌阴肺结核诊断中的价值

目的探讨酶联免疫斑点检测技术(enzyme-linked immunospot assay,ELISPOT)(T-SPOT.TB)在菌阴肺结核诊断中的应用价值。方法应用T-SPOT.TB试剂盒对55例菌阴肺结核(A组)和36例其他肺部疾病(B组)患者的外周血中Mtb特异性T淋巴细胞进行检测,同时对两组患者进行PPD试验、血清结核抗体(Mtb-AB)检测。结果A组T-SPOT.TB的阳性率为89.1%(49/55),要明显高于B组的19.4%(7/36)(χ2=44.59,P<0.001)。在A组,T-SPOT.TB的阳性率要明显高于PPD试验[36.4%(20/55)]、Mtb-AB[52.7%(29/55)]及PPD试验+Mtb-AB的阳性率[23.6%(13/55)],(χ2=12.13,χ2=7.08,χ2=21.54,P值均<0.01)。T-SPOT.TB在B组中的阴性率为80.6%(29/36),较PPD试验[86.1%(31/36)]及Mtb-AB阴性(63.9%,23/36)和PPD+Mtb-AB检测方法的阴性率[88.9%(32/36)]经检验,差异无统计学意义(χ2=0.39,χ2=2.69,χ2=0.41,P值均>0.05)。结论T-SPOT.TB检测特异度和敏感度要优于PPD试验及Mtb-AB的检测,可用于菌阴肺结核的辅助诊断,具有一定的临床推广使用的价值。     

支气管肺泡灌洗液RNA恒温扩增检测涂阴肺结核的诊断价值

目的评价支气管肺泡灌洗液结核分枝杆菌RNA恒温扩增检测(simultaneous amplification and testing for Mycobacterium tuberculosis,SAT-TB)对涂阴肺结核的诊断价值。方法选取涂阴肺结核组(观察组)95例和非结核病组(对照组)67例共计162例,两组患者均行纤维支气管镜检查,留取支气管肺泡灌洗液行荧光定量PCR(FQ-PCR),RNA恒温扩增检测(SAT-TB),结核菌快速培养,计算BALF的SAT-TB对涂阴肺结核诊断的敏感度,特异度,阳性预测值,阴性预测值。结果 SAT-TB检测BALF对诊断涂阴肺结核的敏感度为53.7%,特异度为98.5%,阳性预测值为98.1%,阴性预测值为60.0%,BALF的SAT-TB检测在敏感度,特异度,阳性预测值,阴性预测值与FQ-PCR法相比较均无显著性差异(χ~2值分别为3.572,0.341,0.679,1.603,P值均0.05)。结论 BALF中SAT-TB检测在涂阴肺结核中的敏感度,特异度均较高,且检测快速,对涂阴肺结核的快速诊断具有较大的应用价值。     

Bronchoscopic aspiration and bronchoalveolar lavage in the diagnosis of sputum smear-negative pulmonary tuberculosis

The ability to make a definitive diagnosis in sputum smear-negative pulmonary tuberculosis by bronchoscopic aspiration, bronchoalveolar lavage (BAL), and examination of postbronchoscopy sputum were compared. Thirty-four patients with lesions on chest x-rays suspected of being pulmonary tuberculosis were entered into the study. The diagnosis of pulmonary tuberculosis was subsequently confirmed in 28 patients and the method of arriving at the final diagnosis was analyzed. A positive acid-fast bacilli (AFB) smear result was obtained in 4/28 (14%) of cases by a combination of bronchoscopic techniques and postbronchoscopy sputum examination. Prebronchoscopy sputum culture was positive in 12/28 (43%). Combined with bronchoscopy specimens, a positive AFB culture result was obtained in 26/28 (93%). Sputum examination, bronchoscopic aspiration, and BAL are complementary techniques and together they give a high yield of definitive diagnosis of pulmonary tuberculosis.     

Bronchoscopic aspiration and bronchoalveolar lavage in the diagnosis of sputum smear-negative pulmonary tuberculosis

The ability to make a definitive diagnosis in sputum smear-negative pulmonary tuberculosis by bronchoscopic aspiration, bronchoalveolar lavage (BAL), and examination of postbronchoscopy sputum were compared. Thirty-four patients with lesions on chest x-rays suspected of being pulmonary tuberculosis were entered into the study. The diagnosis of pulmonary tuberculosis was subsequently confirmed in 28 patients and the method of arriving at the final diagnosis was analyzed. A positive acid-fast bacilli (AFB) smear result was obtained in 4/28 (14%) of cases by a combination of bronchoscopic techniques and postbronchoscopy sputum examination. Prebronchoscopy sputum culture was positive in 12/28 (43%). Combined with bronchoscopy specimens, a positive AFB culture result was obtained in 26/28 (93%). Sputum examination, bronchoscopic aspiration, and BAL are complementary techniques and together they give a high yield of definitive diagnosis of pulmonary tuberculosis.     

Combined bronchoalveolar lavage and polymerase chain reaction in the diagnosis of pulmonary tuberculosis in smear-negative patients.

SETTING: The polymerase chain reaction (PCR) may be sensitive and specific for the diagnosis of tuberculosis, but most reports are of studies conducted in well-controlled laboratories. A study to evaluate the clinical value of bronchoalveolar lavage (BAL) combined with PCR was necessary. OBJECTIVE: One hundred and thirty one patients were recruited into the study from March 1994 to February 1997. DESIGN: Patients with a positive acid-fast stain on sputum smear were recruited into group A as positive controls, patients with lung cancer and a negative acid-fast stain on sputum smear were put into group B as negative controls, and patients who had clinical symptoms of pulmonary TB without sputum or with negative smear results were the investigating group. PCR was performed on the sputum samples from group A and B patients and on the BAL fluid from those in group C. RESULTS: The sensitivity of PCR was 96% in group A, and the specificity was 100% in group B. The sensitivity of PCR in the BAL fluid from the group C patients was 36% and the specificity was 96%; the positive predictive value was 94% and the negative predictive value was 45%. CONCLUSION: BAL plus PCR is useful in the rapid diagnosis of pulmonary TB in non-productive or smear-negative patients.     

Care seeking behaviour and diagnostic processes in patients with smear-positive pulmonary tuberculosis in Malawi.

SETTING: Government hospitals in five districts in Malawi. OBJECTIVE: To determine care seeking behaviour and diagnostic processes in patients newly diagnosed with smear-positive pulmonary tuberculosis (PTB). DESIGN: Structured questionnaires completed by interview between January to September 1998. RESULTS: During the study period 1,518 patients were registered with PTB, of whom 1,099 (72%) were interviewed. The median delay between onset of cough and diagnosis was 8 weeks. There was a variable pattern of care seeking behaviour, with 70% of patients initially visiting a place of orthodox medical care and 30% visiting traditional healers, grocery shops, etc. Of these, 867 (79%) patients had one or more subsequent contacts for help, with these visits targeted more to orthodox medical care. At all stages, antibiotics resulted in symptomatic improvement in up to 40% of cases. There was a median time of 7 weeks between cough and first submission of sputum specimens. Almost all patients received sputum smear results after a median length of 4 days; 474 (43%) of patients were only aware of their diagnosis at the time of receiving smear results, this observation being significantly associated with lack of schooling and not knowing another person with TB. CONCLUSION: More needs to be done to educate communities and non-orthodox care providers about the diagnosis and treatment of TB.     

菌阴肺结核在结核病控制中的重要性

菌阴肺结核是指经痰涂片抗酸杆菌（AFB）和痰培养分枝杆菌检查均为阴性的活动性肺结核类型，大约占全部肺结核的40％～60％，是结核病控制工作中不可忽视的群体。