Shah S, Demissie M, Lambert L, et al. Intensified tuberculosis case finding among HIV-infected persons from a voluntary counseling and testing center in Addis Ababa, Ethiopia. J Acquir Immune Defic Syndr. 2009 Apr 15;50(5):537-45.
To evaluate commonly available screening tests for pulmonary tuberculosis (TB), using sputum bacteriology as a gold standard, in HIV-infected patients in Addis Ababa, Ethiopia
Prospective observational study of HIV-infected patients, all of whom underwent TB screening, regardless of symptoms
This study was conducted at Zewditu Memorial Hospital from November 2005 to June 2006. Zewditu Memorial Hospital is a large referral hospital in Addis Ababa that serves more than 40,000 patients a year and provides inpatient and outpatient services, including care and treatment for TB and HIV/AIDS with antiretroviral therapy (ART) and isoniazid preventive therapy (IPT), if appropriate. The voluntary counseling and testing (VCT) service has five full-time counselors and provides rapid, anonymous HIV counseling and testing services. Approximately 50-60 clients are seen each day, of whom about 20% are HIV infected. An ART program was started at this site in July 2003. Patients being evaluated for ART initiation undergo a routine medical examination, including symptom screening for TB disease and other opportunistic infections, and determination of eligibility for IPT for those without clinical TB, to prevent immune reconstitution syndrome.
All newly diagnosed HIV-infected patients diagnosed in the VCT clinic were offered enrollment in the TB screening study. Inclusion criteria were all persons with documented HIV infection diagnosed at the VCT clinic who were 18 years of age or older (based on age of consent for HIV testing in Ethiopia) and who agreed to participate in the study and the required follow-up. Exclusion criteria included being unable or unwilling to complete the full diagnostic evaluation, pregnant, in jail or prison, taking medications with antimycobacterial activity (e.g., flouroquinolones, macrolides, or aminoglycosides) within the prior 2 weeks, and currently receiving anti-TB treatment. A total of 438 HIV-infected persons were enrolled in the study. Sixty-one percent were female and the median age was 34 years (range, 18-65 years). Few subjects reported TB risk factors, such as exposure to a known TB case (n = 30, 7%), history of incarceration (n = 31, 7%), or prior history of TB diagnosis (n = 59, 13%). The median CD4 cell count was 181 cells/mm3, and 273 (62%) subjects had CD4 cell counts of <250 cells/mm3.
A trained physician conducted a standardized symptom screening and physical examination in a private consultation room within the VCT clinic. Patients were asked in their native language about the presence and duration of cough, hemoptysis, fever, weight loss, night sweats, shortness of breath, chest pain, diarrhea, appetite loss, and fatigue. Additional data were collected on basic demographics and risk factors for TB. All patients provided three sputum samples for smear examinations ("spot-early morning-spot"), had blood drawn for CD4 cell count, and underwent a single full-size, posterior-anterior view CXR. The early morning sputum was split for direct smear and a portion was sent to the national TB reference laboratory for concentrated smear and mycobacterial culture. CXR findings were recorded using a standardized form that included specific radiographic patterns suspicious for active TB, such as tuberculoma, miliary pattern, cavity in any lobe, upper or lower lobe infiltrate with hilar adenopathy, interstitial pattern, upper lobe fibrosis with nodular change, intrathoracic mass with lymphadenopathy (noncalcified), pleural effusion, and/or pleural thickening (unilateral, >1/2 thoracic cavity).
The primary outcome measure was the performance of routinely available TB diagnostic tests (e.g., symptom screening, physical examination, direct mycobacterial smear for AFB, and chest radiography). Each symptom was evaluated alone and in combination with other symptoms at varying durations for each symptom. Test performance was measured by calculating the sensitivity, specificity, positive predictive value, and negative predictive value of each test. The secondary outcome measures were as follows: (1) "TB risk factors": comparison of demographic and clinical factors among confirmed TB cases with those without confirmed disease. Factors examined included sex, age, body mass index, TB history, contact with a TB case, history of incarceration, modified Karnofsky performance scale, and CD4 cell count; (2) "CXR reliability": compared the final interpretation (based on categories above) of each radiologist to determine the reliability of CXR readings (i.e., inter-rater agreement); and (3) "simulated performance and cost of diagnostic algorithms": comparison of the performance and direct costs of the current Ethiopian TB screening guidelines with this alternative approach.
The sensitivity, specificity, and predictive value of each of the 8 symptoms, if screened individually, are presented in Table 1. Overall, 32 (7%) HIV-infected patients were diagnosed with confirmed TB disease: of those, nine (28%) were smear positive and culture positive (sm+cx+), 18 (56%) were smear negative but culture positive (sm-cx+), and five (16%) were smear positive but culture negative (sm+cx-). Direct smear microscopy by Ziehl-Neelson method detected three (9%) of 32 TB cases; when combined with the sputum concentration method, 14 (44%) cases were AFB smear positive. If HIV-infected persons in this study were evaluated according to the current TB screening guidelines for Ethiopia (adapted from WHO guidelines), five (16%) of 32 confirmed TB cases would have been missed from the outset because they were asymptomatic. Three (9%) of 32 would have been detected by symptom screening and sputum smear microscopy (using direct Ziehl-Neelson smear only), with an additional nine (28%) detected if concentrated sputum smear methods were used. With chest radiography, an additional 86 persons would have been considered as "clinical" TB cases and thus initiated on TB treatment. However, only 17 (20%) of 86 were proven cases of TB, whereas the remaining 69 (80%) were not. With the current algorithm, seven (22%) of 27 symptomatic TB cases would not have been detected. Overall, this algorithm based on routinely available diagnostic tests has a sensitivity of 63% and specificity of 83%. An alternate strategy, whereby all HIV-positive patients undergo screening first by chest radiography, followed by sputum smear only for those with negative CXRs, was evaluated. With this approach, sputum smear would be performed for 350 clients, 24 (7%) more than the 326 clients tested with sputum smear using the current Ethiopian guidelines. Overall, 22 (69% sensitivity) of 32 TB cases would be detected. Specificity of this strategy is similar to the current Ethiopian guidelines. Comparing costs of strategy A (Ethiopian national guidelines) versus strategy B reveals a 10% increase in case detection (22 cases vs. 20 cases) with strategy B for a 17% greater cost per case detected ($42.16 vs. $36.10). More sputum smears and CXRs would be done using strategy B.
|Individual symptoms (of any duration)|
|Fever (missing 4 non-TB cases)||121||20||101||62.5||74.9||16.5||96.2|
|Night sweats (missing 1 TB case; 14 non-TB)||122||16||106||51.6||73.0||13.1||95.0|
|Weight loss (missing 4 TB cases; 53 non-TB)||211||19||192||67.9||45.6||9.0||94.7|
|Fatigue (missing 4 non-TB cases)||201||20||181||62.5||55||10.0||94.8|
|Loss of appetite (missing 6 non-TB cases)||141||14||127||43.8||68.3||9.9||93.8|
|Shortness of breath (missing 4 TB cases; 14 non-TB)||43||4||39||14.3||90.1||9.3||93.6|
|Chest Pain (missing 2 TB cases; 17 non-TB)||20||2||18||6.7||95.4||10.0||93.0|
|Combination of symptoms (of any duration)§|
|Cough or fever (missing 1 TB case; 4 non-TB)||170||24||146||75.0||64.0||14.1||97.0|
|Cough or night sweats (missing 1 TB case; 6 non-TB)||177||20||157||64.5||60.8||11.3||95.7|
|Cough or weight loss (missing 2 TB cases; 43 non-TB)||249||24||225||80.0||38.0||9.6||95.8|
|Cough or fatigue (missing 2 non-TB cases)||242||23||219||71.9||45.8||9.5||95.4|
|Fever or night sweats (missing 11 non-TB cases)||168||24||144||75.0||63.5||14.3||96.9|
|Fever or weight loss (missing 3 TB cases; 41 non-TB)||247||23||224||79.3||38.6||9.3||95.9|
|Fever or fatigue (missing 4 non-TB cases)||245||25||220||78.1||45.3||10.2||96.3|
|Cough or fever or night sweats (missing 7 non-TB cases)||202||25||177||78.1||55.6||12.4||96.9|
|Cough or fever or weight loss (missing 2 TB cases; 34 non-TB)||272||26||246||86.7||33.9||9.6||96.9|
|Cough or fever or fatigue (missing 3 non-TB cases)||263||26||237||81.3||41.2||9.9||96.5|
|Any 1 symptom present||326||27||299||84.4||26.4||8.3||95.5|
|At least 3 symptoms present||172||22||150||68.8||63.1||12.8||96.2|
|Suspicious for TB (missing 2 TB; 6 non-TB)||88||19||69||59.4||83.0||21.6||96.3|
The authors conclude that traditional symptom screening is insufficient for detecting TB disease among HIV-infected persons but may serve to exclude TB disease. More sensitive, rapid, and low-cost diagnostic tests are needed to meet the demand of resource-limited settings.
There is no widely accepted quality rating system for diagnostic evaluation studies such as this. However, some limitations were noted: 1) patients with symptoms, who were smear negative and culture negative, were not followed longitudinally or reevaluated for subsequent development of TB disease. These patients may be true TB cases that were undetected using solid media culture but that may have been detected with a more sensitive technique (e.g., liquid culture). This may lead to an underestimate of TB prevalence in this study and reduce the calculated sensitivity of symptom screening; 2) although liquid culture is known to be a more sensitive diagnostic method, it was not available in Ethiopia at the time of the study. HIV-infected patients are known to develop disseminated TB disease at a higher rate than HIV-uninfected persons, but an evaluation of an algorithm for extrapulmonary TB was beyond the scope of the present study; and 3) symptom screening may vary by provider and health care setting, so performance of this tool may differ across settings.
The 7% predictive value in this study is similar to that found in other studies evaluating TB screening algorithms among HIV-infected persons.(1,2,3) Also, 15% of confirmed cases reported no TB symptoms and had negative sputum smear for AFB. These rates are similar to results from other recent studies that identified cases of subclinical TB only detected by sputum mycobacterial culture.(4,5)
The limited availability of more sensitive diagnostic tests for TB must be addressed. Without investing in better diagnostic modalities, patients with TB and HIV co-infection are at high risk of misdiagnosis, delayed diagnosis with poor treatment outcomes, TB drug resistance, and community spread of their disease.
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