Accuracy of Tongue Swab Testing Using Xpert MTB-RIF Ultra for Tuberculosis Diagnosis.

Tongue dorsum swabs have shown promise as alternatives to sputum for detecting Mycobacterium tuberculosis (MTB) in patients with pulmonary tuberculosis (TB). Some of the most encouraging results have come from studies that used manual quantitative PCR (qPCR) to analyze swabs. Studies using the automated Cepheid Xpert MTB/RIF Ultra qPCR test (Xpert Ultra) have exhibited less sensitivity with tongue swabs, possibly because Xpert Ultra is optimized for testing sputum, not tongue swab samples. Using two new sample preprocessing methods that demonstrated good sensitivity in preliminary experiments, we assessed diagnostic accuracy and semi-quantitative signals of Xpert Ultra performed on tongue swabs collected from 183 adults with presumed TB in Kampala, Uganda. Relative to a sputum Xpert Ultra reference standard, the sensitivity of tongue swab Xpert Ultra was 77.8% (95% confidence interval [CI] 64.4-88.0) and specificity was 100.0% (95% CI, 97.2-100.0). When compared to a microbiological reference standard (MRS) incorporating both sputum Xpert Ultra and sputum mycobacterial culture, sensitivity was 72.4% (95% CI, 59.1-83.3) and specificity remained the same. Semi-quantitative Xpert Ultra results were generally lower with tongue swabs than with sputum, and cycle threshold values were higher. None of the eight sputum Xpert Ultra "trace" or "very low" results were detected using tongue swabs. Tongue swabs should be considered when sputum cannot be collected for Xpert Ultra testing, or in certain mass-screening settings. Further optimization of tongue swab analysis is needed to achieve parity with sputum-based molecular testing for TB.

The transition to Xpert MTB/RIF ultra: diagnostic accuracy for pulmonary tuberculosis in Kampala, Uganda.

BACKGROUND: The World Health Organization (WHO) has endorsed the next-generation Xpert MTB/RIF Ultra (Ultra) cartridge, and Uganda is currently transitioning from the older generation Xpert MTB/RIF (Xpert) cartridge to Ultra as the initial diagnostic test for pulmonary tuberculosis (TB). We assessed the diagnostic accuracy of Ultra for pulmonary TB among adults in Kampala, Uganda. METHODS: We sampled adults referred for Xpert testing at two hospitals and a health center over a 12-month period. We enrolled adults with positive Xpert and a random 1:1 sample with negative Xpert results. Expectorated sputum was collected for Ultra, and for solid and liquid culture testing for Xpert-negative patients. We measured sensitivity and specificity of Ultra overall and by HIV status, prior history of TB, and hospitalization, in reference to Xpert and culture results. We also assessed how classification of results in the new "trace" category affects Ultra accuracy. RESULTS: Among 698 participants included, 211 (30%) were HIV-positive and 336 (48%) had TB. The sensitivity of Ultra was 90.5% (95% CI 86.8-93.4) and specificity was 98.1% (95% CI 96.1-99.2). There were no significant differences in sensitivity and specificity by HIV status, prior history of TB or hospitalization. Xpert and Ultra results were concordant in 670 (96%) participants, with Ultra having a small reduction in specificity (difference 1.9, 95% CI 0.2 to 3.6, p=0.01). When "trace" results were considered positive for all patients, sensitivity increased by 2.1% (95% CI 0.3 to 3.9, p=0.01) without a significant reduction in specificity (- 0.8, 95% CI - 0.3 to 2.0, p=0.08). CONCLUSIONS: After 1 year of implementation, Ultra had similar performance to Xpert. Considering "trace" results to be positive in all patients increased case detection without significant loss of specificity. Longitudinal studies are needed to compare the benefit of greater diagnoses to the cost of overtreatment.

Lung function and health-related quality of life among adult patients following pulmonary TB treatment.

Pulmonary TB (PTB) increases the risk of chronic lung complications, which are associated with increased morbidity and mortality. We determined the prevalence and predictors of post-TB lung disease and persistent symptoms in a resource-limited setting.Adults who completed PTB treatment underwent spirometry and completed the St. George's Respiratory Questionnaire (SGRQ), a questionnaire that assesses quality of life on symptom, activity, and impact. We performed multivariate analyses to calculate the X-adjusted prevalence ratio (PRadj) of abnormal spirometry and identify associated risk factors.Among the 162 participants, 89 (54.9%) were male. The median age was 32 years, and 65 (40.1%) had HIV. Overall, 65 participants (40.1%) had abnormal lung function, with spirometric restriction seen in 29.0%, obstruction in 4.9%, and a mixed pattern in 6.2%. Smoking (PRadj 1.88, 95% CI 1.11-3.16; P = 0.02) and female sex (PRadj 1.81, 95% Cl 1.15-2.84; P = 0.01) were independent risk factors for abnormal lung function. The median SGRQ scores were higher in participants with cavitation (P < 0.001) or bilateral consolidation on initial chest X-ray (P = 0.01).Lung function abnormalities, particularly spirometric restriction, are common in patients completing PTB treatment. Female sex and smoking status were associated with lung function abnormalities; therefore, additional studies to understand the underlying mechanistic pathways are warranted..

Accuracy and incremental yield of urine Xpert MTB/RIF Ultra versus Determine TB-LAM for diagnosis of pulmonary tuberculosis.

The performance of urine Xpert MTB/RIF Ultra (Xpert Ultra) for pulmonary TB diagnosis is unknown. HIV-positive and HIV-negative adults were enrolled at two health facilities in Kampala, Uganda. We compared the accuracy of urine Xpert Ultra and Determine TB-LAM in reference to sputum-based testing (positive Xpert MTB/RIF or culture), and assessed incremental yield. Urine Xpert Ultra had low sensitivity (17.2%, 95% CI 12.3-23.2) but high specificity (98.1%, 95% CI 94.4-99.6). Sensitivity reached 50.0% (95% CI 28.2-71.8) among HIV-positive patients with CD4 <100 cells/µL. Compared to Determine TB-LAM, urine Xpert Ultra was 9.4% (95% CI 3.8-14.9, P = 0.01) more sensitive, and 17.2% (95% CI 4.5-29.8, P = 0.01) more sensitive among HIV-positive patients. However, the incremental sensitivity of urine Xpert Ultra relative to sputum Xpert MTB/RIF was only 1% (95% CI -0.9 to 2.8). Urine Xpert Ultra could be an alternative for patients with advanced HIV infection unable to produce sputum.

Drug-resistant TB and HIV in resource-limited settings: what TB/HIV programmes can learn from each other.

Although management of drug resistance in tuberculosis (TB) and HIV in poor settings is in its infancy, lessons learned from TB may be relevant to HIV and vice versa. The experience with HIV has shown that rapid scale-up and lower drug pricing are achievable goals. The current prerequisites for obtaining drugs to treat multidrug-resistant TB (MDR-TB) may be too stringent given the immediacy of the MDR-TB problem. We call for a more rapid roll-out of treatment for MDR-TB with fewer administrative encumbrances and a greater sense of urgency in national TB control programmes. On the other hand, antiretroviral roll-out programmes should learn from the genesis of the MDR-TB problem; laboratory monitoring should be enhanced and compliance optimized to avoid the acquisition of additional drug resistance in HIV.

Patients who return to care after tracking remain at high risk of attrition: experience from a large HIV clinic, Uganda.

We determined the retention rate of patients infected with HIV who resumed care after being tracked at the Infectious Diseases Clinic (IDC) in Kampala, Uganda. Between April 2011 and September 2013, patients who missed their clinic appointment for 8-90 days were tracked, and those who returned to the clinic within 120 days were followed up. The proportion of patients retained among tracked patients, and those who resumed care before tracking started was compared. At 18 months of follow up, 33 (39%) of the tracked patients and 72 (61%) of those who had resumed care before tracking started were retained in care. The most important cause of attrition among the traceable was self-transfer to another clinic (38 [73%] patients), whereas among those who resumed care before tracking was loss to follow up (LTFU) (32 [71%] patients). Tracked patients who resume care following a missed appointment are at high risk of attrition. To increase retention, antiretroviral therapy clinics need to adopt a chronic care model which takes into consideration patients' changing needs and their preference for self-management.

Causes of lower respiratory infection in HIV-infected Ugandan adults who are sputum AFB smear-negative.

SETTING: Mulago national referral and teaching hospital. OBJECTIVE: To assess the etiology of lower respiratory infections in HIV-infected Ugandan adults who are sputum acid-fast bacilli (AFB) smear-negative. DESIGN: A descriptive cross-sectional study. Participants included consecutive adult patients admitted to medical wards with respiratory symptoms of at least 3 weeks and infiltrates on chest radiograph. Those who were sputum AFB smear-negative and HIV-positive underwent bronchoscopy and bronchoalveolar lavage (BAL). BAL fluid was obtained and stained for AFB and Pneumocystis carinii, and cultured for bacteria and fungi. RESULTS: Of 198 patients screened, 48 were sputum smear-positive for AFB. Sixty-seven were excluded for various reasons, leaving 83 patients who met the inclusion criteria and underwent bronchoscopy: 32 (38.6%) patients had P. carinii infection, 20 (24%) had pulmonary tuberculosis, nine (11%) had pulmonary Kaposi's sarcoma and pyogenic bacteria were identified in seven (8%). No aetiological diagnosis was found in 24 (30%) patients. CONCLUSION: P. carinii and Mycobacterium tuberculosis were the commonest causes of disease among sputum AFB smear-negative, HIV-positive adults presenting to Mulago Hospital. Pulmonary Kaposi's sarcoma and pyogenic bacteria occurred with less frequency.

Evaluation of asthma control using Global Initiative for Asthma criteria and the Asthma Control Test in Uganda.

SETTING: Chest clinic of a national referral hospital in a resource-limited country. OBJECTIVES: To determine the level of asthma control, factors influencing asthma control and the accuracy of the Asthma Control Test (ACT). DESIGN: We collected demographic and clinical data and administered the Global Initiative for Asthma (GINA) criteria test and the ACT. The proportions of patients in each of the GINA and ACT control categories (uncontrolled, partly controlled and well controlled) were calculated. Multivariate analysis was performed to identify factors associated with asthma control. Diagnostic test parameters for the ACT using GINA criteria as gold standard were calculated. RESULTS: Of 88 asthma patients enrolled, 67% were female. The median age was 34 years (range 12-85). Using GINA criteria, respectively 59 (67%), 17 (19%) and 12 (14%) patients had uncontrolled, partly controlled and well controlled asthma; per ACT, the corresponding figures were respectively 40% (35/88), 43% (38/88) and 17% (15/88). ACT sensitivity, specificity, positive predictive and negative predictive value were respectively 95%, 92%, 99% and 73%. Nasal congestion was associated with uncontrolled asthma (P = 0.031). CONCLUSION: The majority of the patients at the Mulago Hospital have inadequately controlled asthma, and this is associated with nasal congestion. A simple symptom questionnaire, the ACT, can correctly classify asthma control.

Tuberculin skin test conversion among HIV patients on antiretroviral therapy in Uganda.

SETTING: A human immunodeficiency virus (HIV) clinic in a setting of high tuberculosis (TB) and HIV prevalence. OBJECTIVE: To study the incidence of and factors associated with tuberculin skin test (TST) conversion in HIV patients on antiretroviral therapy (ART). DESIGN: Prospective cohort study of TST-negative, ART-naïve HIV patients (CD4 cell count < 250 cells/l) without active TB. TST was repeated at 2 months and, if negative, at 6 months. TST positivity was defined as an induration of ≥5 mm. Clinical examination, chest X-ray and CD4 cell counts were performed at baseline and follow-up. Proportions and incidence of TST conversion were calculated, and logistic regression analyses were performed. RESULTS: Of the 142 patients, 105 (75.5%) were females. The mean age was 35.9 years (standard deviation 8.1) and the median CD4 cell count was 119 cells/l (interquartile range 42168). The incidence of TST conversion was 30.2/100 person years (95%CI 19.546.8). Conversion was not associated with clinical, CD4 cell count or chest radiography findings. CONCLUSIONS: A high incidence of TST conversion was observed, supporting the World Health Organization recommendation to provide isoniazid preventive therapy (IPT) to all HIV patients in high TB prevalence settings. If case-control programmes choose to provide IPT only to TST-positive patients, repeat TST should be considered following initiation of ART.

Chest radiographic findings of pulmonary tuberculosis in severely immunocompromised patients with the human immunodeficiency virus.

OBJECTIVE: We describe chest radiograph (CXR) findings in a population with a high prevalence of human immunodeficiency virus (HIV) and tuberculosis (TB) in order to identify radiological features associated with TB; to compare CXR features between HIV-seronegative and HIV-seropositive patients with TB; and to correlate CXR findings with CD4 T-cell count. METHODS: Consecutive adult patients admitted to a national referral hospital with a cough of duration of 2 weeks or longer underwent diagnostic evaluation for TB and other pneumonias, including sputum examination and mycobacterial culture, bronchoscopy and CXR. Two radiologists blindly reviewed CXRs using a standardised interpretation form. RESULTS: Smear or culture-positive TB was diagnosed in 214 of 403 (53%) patients. Median CD4+ T-cell count was 50 cells mm(-3) [interquartile range (IQR) 14-150]. TB patients were less likely than non-TB patients to have a normal CXR (12% vs 20%, p = 0.04), and more likely than non-TB patients to have a diffuse pattern of opacities (75% vs 60%, p = 0.003), reticulonodular opacities (45% vs 12%, p < 0.001), nodules (14% vs 6%, p = 0.008) or cavities (18% vs 7%, p = 0.001). HIV-seronegative TB patients more often had consolidation (70% vs 42%, p = 0.007) and cavities (48% vs 13%, p < 0.001) than HIV-seropositive TB patients. TB patients with a CD4+ T-cell count of ≤ 50 cells mm(-3) less often had consolidation (33% vs 54%, p = 0.006) and more often had hilar lymphadenopathy (30% vs 16%, p = 0.03) compared with patients with CD4 51-200 cells mm(-3). CONCLUSION: Although different CXR patterns can be seen in TB and non-TB pneumonias there is considerable overlap in features, especially among HIV-seropositive and severely immunosuppressed patients. Providing clinical and immunological information to the radiologist might improve the accuracy of radiographic diagnosis of TB.

Low prevalence of vitamin D deficiency in Ugandan HIV-infected patients with and without tuberculosis.

OBJECTIVE: To examine whether hypovitaminosis D is a risk factor for the development of tuberculosis (TB) associated immune reconstitution inflammatory syndrome (IRIS). METHODS: We measured serum 25-hydroxyvitamin D (25D) concentrations in four groups of patients at Mulago Hospital, Kampala, Uganda: 1) patients co-infected with TB and the human immunodeficiency virus (HIV) receiving anti-tuberculosis treatment (HIV+TB+; n = 92) who did and did not develop TB-IRIS after starting antiretroviral treatment (ART), 2) HIV-infected patients without TB (HIV+TB-; n = 20) starting ART, 3) non-HIV-infected individuals with TB (HIV-TB+; n = 27), and 4) those without TB (HIV-TB-; n = 23). RESULTS: The prevalence of optimal 25D levels (>75 nmol/l) was as follows: 59% in HIV+TB+, 65% in HIV+TB-, 63% in HIV-TB+ and 35% in HIV-TB- patients. 25D concentrations decreased during the first 3 months of ART in HIV+TB+ individuals who developed IRIS (P = 0.005) and those who did not (P = 0.002), and in HIV+TB- individuals (P = 0.015); however, 25D concentration in patients who did or did not develop TB-IRIS did not differ. CONCLUSION: The prevalence of optimal vitamin D status was relatively high in HIV-infected patients with and without TB living near the equator. No difference in 25D concentrations was observed between TB-IRIS and non-IRIS. However, 25D concentrations decreased during ART.

Sensitivity and specificity of fluorescence microscopy for diagnosing pulmonary tuberculosis in a high HIV prevalence setting.

SETTING: Mulago Hospital, Kampala, Uganda. OBJECTIVE: To evaluate the diagnostic performance of fluorescence microscopy (FM) for diagnosing pulmonary tuberculosis (TB) in a high human immunodeficiency virus (HIV) prevalence setting. DESIGN: Consecutive in-patients with cough for >2 weeks submitted two sputum specimens for smear microscopy. Smears were examined by conventional light microscopy (CM) and FM. The performance of the two methods was compared using mycobacterial culture as a reference standard. RESULTS: A total of 426 patients (82% HIV-infected) were evaluated. FM identified 11% more smear-positive patients than CM (49% vs. 38%, P < 0.001). However, positive FM results were less likely than positive CM results to be confirmed by culture when smears were read as either 'scanty' (54% vs. 90%, P < 0.001) or 1+ (82% vs. 91%, P = 0.02). Compared to CM, the sensitivity of FM was higher (72% vs. 64%, P = 0.005), and the specificity lower (81% vs. 96%, P < 0.001). In receiver operating characteristic analysis, maximum area under the curve for FM was obtained at a threshold of >4 acid-fast bacilli/100 fields (sensitivity 68%, specificity 90%). CONCLUSION: Although FM increases the sensitivity of sputum smear microscopy, additional data on FM specificity and on the clinical consequences associated with false-positive FM results are needed to guide implementation of this technology in high HIV prevalence settings.