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1.  Ultrasound findings in cases of extrapulmonary TB in patients with HIV infection in Jeddah, Saudi Arabia 
To report ultrasound (US), laboratory and chest radiograph (CXR) findings of patients with extra-pulmonary tuberculosis (EPTB) and discuss the diagnostic relevance of US in EPTB in high-risk individuals.
In this retrospective study, we described a cohort of 39 patients with a primarily immigrant background diagnosed with HIV and EPTB in Saudi Arabia and evaluated the role of US in their clinical management. All inpatient files of those diagnosed with EPTB who were HIV positive and had at least one US exam and one CXR exam performed were identified; results and outcomes were extracted.
Thirty-nine patients were diagnosed with HIV-associated EPTB between January 2008 and March 2012 and fulfilled the search criteria. Disseminated TB was diagnosed in 32 patients, pleural TB in 15, TB meningitis in 9 and TB pericarditis in 5. Enlarged abdominal lymph nodes were the single most frequent US finding seen in 61%, followed by pleural effusions (38%), liver (36%) and spleen (31%) lesions. CXR were normal in 38% of the patients.
As EPTB infections in HIV positive patients can be treated effectively if diagnosed early, we suggest that US should be integrated in diagnostic algorithms for EPTB.
PMCID: PMC4027353
HIV; Extra-pulmonary tuberculosis; Ultrasound; Diagnosis
2.  Clinical significance of normal chest radiographs among HIV-seropositive patients with suspected tuberculosis in Uganda 
Respirology (Carlton, Vic.)  2011;16(5):836-841.
Background and objectives
The frequency, aetiologies, and outcomes of normal chest radiographs (CXRs) among HIV-seropositive patients with suspected pulmonary tuberculosis (TB) have been infrequently described.
Consecutive HIV-seropositive adults hospitalized for cough of ≥ 2 weeks duration at Mulago Hospital (Kampala, Uganda), between September 2007 and July 2008, were enrolled. Baseline CXRs were obtained on admission. Patients with sputum smears that were negative for acid-fast bacilli (AFB) were referred for bronchoscopy with bronchoalveolar lavage (BAL). BAL fluid was examined for mycobacteria, Pneumocystis jirovecii, and other fungi. Patients were followed for two months after enrolment.
Of the 334 patients, 54 (16%) had normal CXRs. These patients were younger (median age 30 vs. 34 years, P=0.002), had lower counts of CD4+ T lymphocytes (median 13 vs. 57 cells/μL, P<0.001), and were less likely to be smear positive for AFB (17% vs. 39%, P=0.002) than those with abnormal CXRs. Pulmonary TB was the most frequent diagnosis (44%) among those with normal CXRs, followed by unknown diagnoses, pulmonary aspergillosis, and pulmonary cryptococcosis. The frequency of normal CXRs was 12% among pulmonary TB patients. There was a trend towards increased two-month mortality among patients with normal CXRs compared to those with abnormal CXRs (40% vs. 29%, P=0.15).
Normal CXR findings were common among HIV-seropositive patients with suspected TB, especially those who were young, those with low CD4+ T cell counts, and those with sputum smears that were negative for AFB. Mortality was high among those with normal CXRs. Normal CXR findings should not preclude further diagnostic evaluation in this population.
PMCID: PMC3126910  PMID: 21518124
clinical epidemiology; critical care medicine; immunodeficiency; radiology and other imaging; tuberculosis
3.  Chest radiographic findings of pulmonary tuberculosis in severely immunocompromised patients with the human immunodeficiency virus 
The British Journal of Radiology  2012;85(1014):e130-e139.
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.
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.
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.
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.
PMCID: PMC3474111  PMID: 21976629
4.  Screening Strategies for Tuberculosis Prevalence Surveys: The Value of Chest Radiography and Symptoms 
PLoS ONE  2012;7(7):e38691.
We conducted a tuberculosis (TB) prevalence survey and evaluated the screening methods used in our survey, to assess if screening in TB prevalence surveys could be simplified, and to assess the accuracy of screening algorithms that may be applicable for active case finding.
All participants with a positive screen on either a symptom questionnaire, chest radiography (CXR) and/or sputum smear microscopy submitted sputum for culture. HIV status was obtained from prevalent cases. We estimated the accuracy of modified screening strategies with bacteriologically confirmed TB as the gold standard, and compared these with other survey reports. We also assessed whether sequential rather than parallel application of symptom, CXR and HIV screening would substantially reduce the number of participants requiring CXR and/or sputum culture.
Presence of any abnormality on CXR had 94% (95%CI 88–98) sensitivity (92% in HIV-infected and 100% in HIV-uninfected) and 73% (95%CI 68–77) specificity. Symptom screening combinations had significantly lower sensitivity than CXR except for ‘any TB symptom’ which had 90% (95%CI 84–95) sensitivity (96% in HIV-infected and 82% in HIV-uninfected) and 32% (95%CI 30–34) specificity. Smear microscopy did not yield additional suspects, thus the combined symptom/CXR screen applied in the survey had 100% (95%CI 97–100) sensitivity. Specificity was 65% (95%CI 61–68). Sequential application of first a symptom screen for ‘any symptom’, followed by CXR-evaluation and different suspect criteria depending on HIV status would result in the largest reduction of the need for CXR and sputum culture, approximately 36%, but would underestimate prevalence by 11%.
CXR screening alone had higher accuracy compared to symptom screening alone. Combined CXR and symptom screening had the highest sensitivity and remains important for suspect identification in TB prevalence surveys in settings where bacteriological sputum examination of all participants is not feasible.
PMCID: PMC3391193  PMID: 22792158
5.  The role and performance of chest X-ray for the diagnosis of tuberculosis: A cost-effectiveness analysis in Nairobi, Kenya 
The objective of this study was to establish 1) the performance of chest X-ray (CXR) in all suspects of tuberculosis (TB), as well as smear-negative TB suspects and 2) to compare the cost-effectiveness of the routine diagnostic pathway using Ziehl-Neelsen (ZN) sputum microscopy followed by CXR if case of negative sputum result (ZN followed by CXR) with an alternative pathway using CXR as a screening tool (CXR followed by ZN).
From TB suspects attending a chest clinic in Nairobi, Kenya, three sputum specimens were examined for ZN and culture (Lowenstein Jensen). Culture was used as gold standard. From each suspect a CXR was made using a four point scoring system: i: no pathology, ii: pathology not consistent for TB, iii: pathology consistent for TB and iv: pathology highly consistent for TB. The combined score i + ii was labeled as "no TB" and the combined score iii + iv was labeled as "TB". Films were re-read by a reference radiologist. HIV test was performed on those who consented. Laboratory and CXR costs were used to compare for cost-effectiveness.
Of the 1,389 suspects enrolled, for 998 (72%) data on smear, culture and CXR was complete. 714 films were re-read, showing a 89% agreement (kappa value = 0.75 s.e.0.037) for the combined scores "TB" or "no-TB". The sensitivity/specificity of the CXR score "TB" among smear-negative suspects was 80%/67%. Using chest CXR as a screening tool in all suspects, sensitivity/specificity of the score "any pathology" was 92%, respectively 63%. The cost per correctly diagnosed case was for the routine process $8.72, compared to $9.27 using CXR as screening tool. When costs of treatment were included, CXR followed by ZN became more cost-effective.
The diagnostic pathway ZN followed by CXR was more cost-effective as compared to CXR followed by ZN. When cost of treatment was also considered CXR followed by ZN became more cost-effective. The low specificity of chest X-ray remains a subject of concern. Depending whether CXR was performed on all suspects or on smear-negative suspects only, 22%–45% of patients labeled as "TB" had a negative culture. The introduction of a well-defined scoring system, clinical conferences and a system of CXR quality control can contribute to improved diagnostic performance.
PMCID: PMC1326228  PMID: 16343340
6.  Utility of Chest Radiography in Emergency Department Patients Presenting with Syncope 
Syncope has myriad etiologies, ranging from benign to immediately life threatening. This frequently leads to over testing. Chest radiographs (CXR) are among these commonly performed tests despite their uncertain diagnostic yield. The objective is to study the distribution of normal and abnormal chest radiographs in patients presenting with syncope, stratified by those who did or did not have an adverse event at 30 days.
We performed a post-hoc analysis of a prospective cohort of consecutive patients presenting to an urban tertiary care academic medical center with a chief complaint of syncope from 2003–2006. The frequency and findings for each CXR were reviewed, as well as emergency department and hospital discharge diagnoses, and 30-day outcome.
There were 575 total subjects, 39.7% were male, and the mean age was 57.2 (SD 24.6). Of the 575 subjects, 403 (70.1%) had CXRs performed, and 116 (20.2%) had an adverse event after their syncope. Of the 116 people who had an adverse event, 15 (12.9%) had a positive CXR, 81 (69.8%) had a normal CXR, and 20 (17.2%) did not have a CXR as part of the initial evaluation. Among the 459 people who did not have an adverse event, 3 (0.7%) had a positive CXR, 304 (66.2%) had a normal CXR, and 152 (33.1%) did not have a CXR performed. Fifteen of the 18 patients (83.4%) with an abnormal CXR had an adverse event. Eighty-one of the 385 patients (21.0%) with a normal CXR had an adverse event. Among those who had a CXR performed, an abnormal CXR was associated with increased odds of adverse event (OR: 18.77 (95% CI= [5.3–66.4])).
Syncope patients with abnormal CXRs are likely to experience an adverse event, though the majority of CXRs performed in the work up of syncope are normal.
PMCID: PMC5102594  PMID: 27833675
7.  Basis for treatment of tuberculosis among HIV-infected patients in Tanzania: the role of chest x-ray and sputum culture 
Active tuberculosis (TB) is common among HIV-infected persons living in tuberculosis endemic countries, and screening for tuberculosis (TB) is recommended routinely. We sought to determine the role of chest x-ray and sputum culture in the decision to treat for presumptive TB using active case finding in a large cohort of HIV-infected patients.
Ambulatory HIV-positive subjects with CD4 counts ≥ 200/mm3 entering a Phase III TB vaccine study in Tanzania were screened for TB with a physical examination, standard interview, CD4 count, chest x-ray (CXR), blood culture for TB, and three sputum samples for acid fast bacillus (AFB) smear and culture.
Among 1176 subjects 136 (12%) were treated for presumptive TB. These patients were more frequently male than those without treatment (34% vs. 25%, respectively; p = 0.049) and had lower median CD4 counts (319/μL vs. 425/μL, respectively; p < .0001). Among the 136 patients treated for TB, 38 (28%) had microbiologic confirmation, including 13 (10%) who had a normal CXR and no symptoms. There were 58 (43%) treated patients in whom the only positive finding was an abnormal CXR. Blood cultures were negative in all patients.
Many ambulatory HIV-infected patients with CD4 counts ≥ 200/mm3 are treated for presumptive TB. Our data suggest that optimal detection requires comprehensive evaluation, including CXR and sputum culture on both symptomatic and asymptomatic subjects.
PMCID: PMC2323005  PMID: 18325120
8.  A Novel Reading Scheme for Assessing the Extent of Radiographic Abnormalities and Its Association with Disease Severity in Sputum Smear-Positive Tuberculosis: An Observational Study in Hyderabad/India 
PLoS ONE  2015;10(9):e0138070.
Existing reading schemes for chest X-ray (CXR) used to grade the extent of disease severity at diagnosis in patients with pulmonary tuberculosis (PTB) are often based on numerical scores that summate specific radiographic features. However, since PTB is known to exhibit a wide heterogeneity in pathology, certain features might be differentially associated with clinical parameters of disease severity.
We aimed to grade disease severity in PTB patients at diagnosis and after completion of DOTS treatment by developing a reading scheme based on five different radiographic manifestations and analyze their association with the clinical parameters of systemic involvement and infectivity.
141 HIV-negative adults with newly diagnosed sputum smear-positive PTB were enrolled in a prospective observational study in Hyderabad, India. The presence and extent on CXRs of five radiographic manifestations, i.e., lung involvement, alveolar infiltration, cavitation, lymphadenopathy and pleural effusion, were classified using the new reading scheme by using a four-quadrant approach. We evaluated the inter-reader reliability of each manifestation, and its association with BMI and sputum smear positivity at diagnosis. The presence and extent of these radiographic manifestations were further compared with CXRs on completion of DOTS treatment.
At diagnosis, an average lung area of 51.7% +/- 23.3% was affected by radiographic abnormalities. 94% of the patients had alveolar infiltrates, with 89.4% located in the upper quadrants, suggesting post primary PTB and in 34.8% of patients cavities were found. We further showed that the extent of affected lung area was a negative predictor of BMI (β value -0.035, p 0.019). No significant association of BMI with any of the other CXR features was found. The extent of alveolar infiltrates, along with the presence of cavitation, were strongly associated with sputum smear positivity. The microbiological cure rate in our cohort after 6 months of DOTS treatment was 95%. The extent of the affected lung area in these patients decreased from 56.0% +/- 21.5% to 31.0 +/- 20% and a decrease was also observed in the extent of alveolar infiltrates from 98.4% to 25.8% in at least one quadrant, presence of cavities from 34.8% to 1.6%, lymphadenopathy from 46.8% to 16.1%, and pleural effusion from 19.4% to 6.5%.
We established a new assessment scheme for grading disease severity in PTB by specifically considering five radiographic manifestations which were differently associated with the BMI and sputum smear positivity, changed to a different extent after 6 months of treatment and exhibited an excellent agreement between radiologists. Our results suggest that this reading scheme might contribute to the estimation of disease severity with respect to differences in disease pathology. Further studies are needed to determine a correlation with short and long-term pulmonary function impairment and whether there would be any benefit in lengthening or modulating therapy based on this CXR severity assessment.
PMCID: PMC4575099  PMID: 26381644
9.  National Guidelines Not Always Followed When Diagnosing Smear-Negative Pulmonary Tuberculosis in Patients with HIV in Botswana 
PLoS ONE  2014;9(2):e88654.
Diagnosis of smear negative pulmonary tuberculosis (SNPTB) is challenging, especially in patients with HIV. The Botswana National Tuberculosis Program (BNTP) guidelines give guidance in diagnosing and treating SNPTB. Patients with chronic cough should be screened for TB by 3 sputum smear investigations. If negative, a chest x-ray (CXR) should be performed. If negative for TB, antimicrobial treatment for other infections should be started. We investigated the clinicians’ use of the guidelines in clinical practice.
Data regarding the medical history (coughing period), requested and conducted investigations concerning tuberculosis diagnosis (sputum smear or culture or CXR) or alternative diagnoses (sputum microscopy or blood or sputum culture for diagnosis of other organisms), in SNPTB HIV-positive patients (outpatients and admitted patients) from 2006–2009 in a district hospital in Botswana were extracted from all available hospital medical records. Additionally, a survey was done in all doctors diagnosing SNPTB in this hospital using a self-administered questionnaire with questions regarding the application of the BNTP guidelines in practice. Descriptive analyses of collected data were performed to test the compliance to the guidelines.
Data from medical records showed that in 47.0% (132/281) of patients, TB treatment was started without microbiological results from sputum smears. Other methods to rule out or confirm PTB were used in 2.1% (6/281); and 99.6% (280/281) of SNPTB patients had received a CXR. The survey in 7 clinicians found that all always used CXR, and all clinicians requested three sputum results only sometimes. Six out of 7 clinicians started antibiotics before starting TB treatment. Reasons clinicians gave for difficulties in following the guidelines included inability of patients to produce sputum; and laboratory delays in releasing sputum results.
Between 2006 and 2009 a high proportion of SNPTB diagnoses in a district hospital in Botswana were not supported by laboratory investigation.
PMCID: PMC3925109  PMID: 24551128
10.  The Sensitivity and Specificity of Using a Computer Aided Diagnosis Program for Automatically Scoring Chest X-Rays of Presumptive TB Patients Compared with Xpert MTB/RIF in Lusaka Zambia 
PLoS ONE  2014;9(4):e93757.
To determine the sensitivity and specificity of a Computer Aided Diagnosis (CAD) program for scoring chest x-rays (CXRs) of presumptive tuberculosis (TB) patients compared to Xpert MTB/RIF (Xpert).
Consecutive presumptive TB patients with a cough of any duration were offered digital CXR, and opt out HIV testing. CXRs were electronically scored as normal (CAD score ≤60) or abnormal (CAD score>60) using a CAD program. All patients regardless of CAD score were requested to submit a spot sputum sample for testing with Xpert and a spot and morning sample for testing with LED Fluorescence Microscopy-(FM).
Of 350 patients with evaluable data, 291 (83.1%) had an abnormal CXR score by CAD. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CXR compared to Xpert were 100% (95%CI 96.2–100), 23.2% (95%CI 18.2–28.9), 33.0% (95%CI 27.6–38.7) and 100% (95% 93.9–100), respectively. The area under the receiver operator curve (AUC) for CAD was 0.71 (95%CI 0.66–0.77). CXR abnormality correlated with smear grade (r = 0.30, p<0.0001) and with Xpert CT(r = 0.37, p<0.0001).
To our knowledge this is the first time that a CAD program for TB has been successfully tested in a real world setting. The study shows that the CAD program had high sensitivity but low specificity and PPV. The use of CAD with digital CXR has the potential to increase the use and availability of chest radiography in screening for TB where trained human resources are scarce.
PMCID: PMC3976315  PMID: 24705629
11.  Predictors for MTB Culture-Positivity among HIV-Infected Smear-Negative Presumptive Tuberculosis Patients in Uganda: Application of New Tuberculosis Diagnostic Technology 
PLoS ONE  2015;10(7):e0133756.
The existing World Health Organization diagnostic algorithms for smear-negative TB perform poorly in HIV-infected individuals. New TB diagnostics such as urine TB lipoarabinomannan (LAM) could improve the accuracy and reduce delays in TB diagnosis in HIV-infected smear-negative presumptive TB. We sought to determine predictors for MTB culture-positivity among these patients.
This study was nested into a prospective evaluation of HIV-infected outpatients and inpatients clinically suspected to have TB who were screened by smear-microscopy on two spot sputum samples. Data on socio-demographics, clinical symptoms, antiretroviral therapy, CXR, CD4 count, mycobacterial sputum and blood cultures and TB-LAM were collected. Logistic regression and conditional inference tree analysis were used to determine the most predictive indicators for MTB culture-positivity.
Of the 418 smear-negative participants [female, 64%; median age (IQR) 32 (28-39) years, median CD4 106 (IQR 22 - 298) cells/mm3], 96/418 (23%) were sputum and/ or blood culture-positive for Mycobacterium tuberculosis (MTB) complex. Abnormal CXR (aOR 3.68, 95% CI 1.76- 7.71, p=0.001) and positive urine TB-LAM (aOR 6.21, 95% CI 3.14-12.27, p< 0.001) were significantly associated with MTB culture-positivity. Previous TB treatment (aOR 0.41, 95% CI 0.17-0.99, p=0.049) reduced the likelihood of a positive MTB culture. A conditional inference tree analysis showed that positive urine TB-LAM and abnormal CXR were the most predictive indicators of MTB culture-positivity. A combination of urine TB-LAM test and CXR had sensitivity and specificity of 50% and 86.1% respectively overall, and 70.8% and 84.1% respectively among those with CD4<100 cells/mm3.
A positive urine TB-LAM test and an abnormal CXR significantly predict MTB culture-positivity among smear-negative HIV-infected presumptive TB patients while previous TB treatment reduces the likelihood of a positive MTB culture. Validation studies to assess the performance of diagnostic algorithms that include urine TB-LAM in the diagnosis of smear-negative TB in HIV-infected individuals are warranted.
PMCID: PMC4519276  PMID: 26222142
12.  Symptom screen: diagnostic usefulness in detecting pulmonary tuberculosis in HIV-infected pregnant women in Kenya 
Public Health Action  2011;1(2):30-33.
To determine the diagnostic usefulness of tuberculosis (TB) symptom screening to detect active pulmonary TB among human immunodeficiency virus (HIV) infected pregnant women in two PMTCT (prevention of mother-to-child transmission) clinics in western Kenya that are supported by the United States Agency for International Development–Academic Model Providing Access to Healthcare partnership.
Cross-sectional study. Participants were interviewed for TB symptoms with a standardized questionnaire (cough >2 weeks, fever, night sweats, weight loss or failure to gain weight). Those with cough submitted sputum specimens for smear microscopy for acid-fast bacilli and mycobacterial culture. Women at >14 weeks gestation underwent shielded chest radiography (CXR).
Of 187 HIV-infected women, 38 (20%) were symptom screen-positive. Of these, 21 had a cough for >2 weeks, but all had negative sputum smears and mycobacterial cultures. CXRs were performed in 26 symptomatic women: three were suggestive of TB (1 miliary, 1 infiltrates and 1 cavitary). Of 149 women with a negative symptom screen, 100 had a CXR and seven had a CXR suggestive of TB (1 cavitary, 2 miliary and 4 infiltrates).
This study did not support the utility of isolated symptom screening in identification of TB disease in our PMTCT setting. CXR was useful in identification of TB suspects in both symptomatic and asymptomatic women.
PMCID: PMC4463033  PMID: 26392933
symptom screening; tuberculosis; HIV-infected; pregnant
13.  High Tuberculosis Prevalence in a South African Prison: The Need for Routine Tuberculosis Screening 
PLoS ONE  2014;9(1):e87262.
Tuberculosis is a major health concern in prisons, particularly where HIV prevalence is high. Our objective was to determine the undiagnosed pulmonary tuberculosis (“undiagnosed tuberculosis”) prevalence in a representative sample of prisoners in a South African prison. In addition we investigated risk factors for undiagnosed tuberculosis, to explore if screening strategies could be targeted to high risk groups, and, the performance of screening tools for tuberculosis.
Methods and Findings
In this cross-sectional survey, male prisoners were screened for tuberculosis using symptoms, chest radiograph (CXR) and two spot sputum specimens for microscopy and culture. Anonymised HIV antibody testing was performed on urine specimens. The sensitivity, specificity and predictive values of symptoms and investigations were calculated, using Mycobacterium tuberculosis isolated on sputum culture as the gold standard.
From September 2009 to October 2010, 1046 male prisoners were offered enrolment to the study. A total of 981 (93.8%) consented (median age was 32 years; interquartile range [IQR] 27–37 years) and were screened for tuberculosis. Among 968 not taking tuberculosis treatment and with sputum culture results, 34 (3.5%; 95% confidence interval [CI] 2.4–4.9%) were culture positive for Mycobacterium tuberculosis. HIV prevalence was 25.3% (242/957; 95% CI 22.6–28.2%). Positive HIV status (adjusted odds ratio [aOR] 2.0; 95% CI 1.0–4.2) and being an ex-smoker (aOR 2.6; 95% CI 1.2–5.9) were independently associated with undiagnosed tuberculosis. Compared to the gold standard of positive sputum culture, cough of any duration had a sensitivity of 35.3% and specificity of 79.6%. CXR was the most sensitive single screening modality (sensitivity 70.6%, specificity 92.2%). Adding CXR to cough of any duration gave a tool with sensitivity of 79.4% and specificity of 73.8%.
Undiagnosed tuberculosis and HIV prevalence was high in this prison, justifying routine screening for tuberculosis at entry into the prison, and intensified case finding among existing prisoners.
PMCID: PMC3907552  PMID: 24498059
14.  Exploring the Sociodemographic and Clinical Features of Extrapulmonary Tuberculosis in Saudi Arabia 
PLoS ONE  2015;10(2):e0101667.
Saudi Arabia annually reports a relatively higher proportion (28–32%) of extrapulmonary tuberculosis (EPTB) cases in comparison to other global regions. However, there were few studies conducted so far to determine the sociodemographic factors and clinical manifestations associated with EPTB at a nationwide level.
A retrospective analysis on culture positive EPTB isolates collected from all the provinces of the country were conducted for a period of 12 months to determine the spectrum of diversity in EPTB infection sites and the confounding factors. A detailed clinical and demographical data analysis was carried out along with first line drug susceptibility testing.
Principal Findings
Intra-thoracic and extra-thoracic lymph nodes (44.6%) were the most common sites of infection followed by gastrointestinal (17.3%) and central nervous systems (11.8%). Male patients were mostly infected (58.8%), in contrary to the global trend. Any drug resistance was observed in 23.1% isolates with a 2.1% of multi-drug resistance. HIV reactivity was found only in 2.2% cases. A higher proportion of Saudi nationals (58.8%) were infected compared to the immigrants, descending mostly from South Asia (34.4%) and South East Asia (31.2%). The Saudi population predominated with all forms of EPTB while immigrants showed no significant variations.
Saudi Arabia faces a serious threat from EPTB, particularly to the central nervous system and gastrointestinal systems. More effective diagnostic strategies and control measures must be implemented to reduce the high rate of EPTB in the country. In addition, these findings warrant further detailed research to explore all related comorbid conditions of EPTB development, particularly the host-related factors.
PMCID: PMC4315397  PMID: 25647300
15.  Blood Absolute T Cell Counts may Predict 2-Month Treatment Response in Patients with Pulmonary Tuberculosis 
Disease markers  2010;28(6):343-352.
Background and objective: Little is known about the usefulness of lymphocyte subsets as early predictors of anti-tuberculosis (TB) treatment response in immuno-competent patients.
Methods:Among a total of 64 patients with culture positive pulmonary TB, 29 remained sputum smear/culture positive or had delayed resolution on CXR (slow responders (SR)), and 35 had sputum culture conversion to negative and rapid resolution on CXR (fast responders (FR)) after two months of anti-tuberculosis treatment. Clinical parameters and lymphocyte subsets were investigated.
Results: A larger proportion of patients in the SR group had cavities on CXR, bilateral lung involvement, positive acid-fast bacilli stains, and complaint of cough at diagnosis than those in the FR group. Absolute counts of CD3+ T cells (p = 0.016) and CD8+ T cells (p = 0.012) at diagnosis were both significantly higher in the SR group. This trend was present throughout the 6-month treatment course. Absolute T cell counts (odds ratio (OR) 1.002, 95% confidence interval (CI) 1.0–1.004), positive sputum acid fast bacilli stain (OR 6.69, 95% CI 1.37–32.77) and bilateral lung involvemment on CXR (OR 13.114, 95% CI 1.87–92.14) at diagnosis were independent predictors for a slow response. Combining these three predictors, a prediction score (PS) could be calculated to display an optimal discrimination for slow response (area under the curve (AUC) = 0.855, p < 0.001) whereas absolute T cell counts yielded the highest discriminative value on an individual level (AUC = 0.676, p = 0.015).
Conclusions: A higher T cell count at diagnosis in patients with TB may predict a slow response to two months of treatment. The calculation of a PS further increased predictive accuracy and performance.
PMCID: PMC3833334  PMID: 20683148
Pulmonary tuberculosis; slow responders; absolute T cell counts; prediction score
16.  Implementation Research to Inform the Use of Xpert MTB/RIF in Primary Health Care Facilities in High TB and HIV Settings in Resource Constrained Settings 
PLoS ONE  2015;10(6):e0126376.
The current cost of Xpert MTB RIF (Xpert) consumables is such that algorithms are needed to select which patients to prioritise for testing with Xpert.
To evaluate two algorithms for prioritisation of Xpert in primary health care settings in a high TB and HIV burden setting.
Consecutive, presumptive TB patients with a cough of any duration were offered either Xpert or Fluorescence microscopy (FM) test depending on their CXR score or HIV status. In one facility, sputa from patients with an abnormal CXR were tested with Xpert and those with a normal CXR were tested with FM (“CXR algorithm”). CXR was scored automatically using a Computer Aided Diagnosis (CAD) program. In the other facility, patients who were HIV positive were tested using Xpert and those who were HIV negative were tested with FM (“HIV algorithm”).
Of 9482 individuals pre-screened with CXR, Xpert detected TB in 2090/6568 (31.8%) with an abnormal CXR, and FM was AFB positive in 8/2455 (0.3%) with a normal CXR. Of 4444 pre-screened with HIV, Xpert detected TB in 508/2265 (22.4%) HIV positive and FM was AFB positive in 212/1920 (11.0%) in HIV negative individuals. The notification rate of new bacteriologically confirmed TB increased; from 366 to 620/ 100,000/yr and from 145 to 261/100,000/yr at the CXR and HIV algorithm sites respectively. The median time to starting TB treatment at the CXR site compared to the HIV algorithm site was; 1(IQR 1-3 days) and 3 (2-5 days) (p<0.0001) respectively.
Use of Xpert in a resource-limited setting at primary care level in conjunction with pre-screening tests reduced the number of Xpert tests performed. The routine use of Xpert resulted in additional cases of confirmed TB patients starting treatment. However, there was no increase in absolute numbers of patients starting TB treatment. Same day diagnosis and treatment commencement was achieved for both bacteriologically confirmed and empirically diagnosed patients where Xpert was used in conjunction with CXR.
PMCID: PMC4451006  PMID: 26030301
17.  The clinical value of daily routine chest radiographs in a mixed medical–surgical intensive care unit is low 
Critical Care  2005;10(1):R11.
The clinical value of daily routine chest radiographs (CXRs) in critically ill patients is unknown. We conducted this study to evaluate how frequently unexpected predefined major abnormalities are identified with daily routine CXRs, and how often these findings lead to a change in care for intensive care unit (ICU) patients.
This was a prospective observational study conducted in a 28-bed, mixed medical–surgical ICU of a university hospital.
Over a 5-month period, 2,457 daily routine CXRs were done in 754 consecutive ICU patients. The majority of these CXRs did not reveal any new predefined major finding. In only 5.8% of daily routine CXRs (14.3% of patients) was one or more new and unexpected abnormality encountered, including large atelectases (24 times in 20 patients), large infiltrates (23 in 22), severe pulmonary congestion (29 in 25), severe pleural effusion (13 in 13), pneumothorax/pneumomediastinum (14 in 13), and malposition of the orotracheal tube (32 in 26). Fewer than half of the CXRs with a new and unexpected finding were ultimately clinically relevant; in only 2.2% of all daily routine CXRs (6.4% of patients) did these radiologic abnormalities result in a change to therapy. Subgroup analysis revealed no differences between medical and surgical patients with regard to the incidence of new and unexpected findings on daily routine CXRs and the effect of new and unexpected CXR findings on daily care.
In the ICU, daily routine CXRs seldom reveal unexpected, clinically relevant abnormalities, and they rarely prompt action. We propose that this diagnostic examination be abandoned in ICU patients.
PMCID: PMC1550788  PMID: 16420655
18.  Mycobacterium tuberculosis Complex and HIV Co-Infection among Extrapulmonary Tuberculosis Suspected Cases at the University of Gondar Hospital, Northwestern Ethiopia 
PLoS ONE  2016;11(3):e0150646.
Extrapulmonary Tuberculosis (EPTB) and Human Immunodeficiency Virus (HIV) infection are interrelated as a result of immune depression. The aim of this study was to determine the prevalence of Mycobacterium tuberculosis complex isolates and the burden of HIV co-infection among EPTB suspected patients.
An institution based cross-sectional study was conducted among EPTB suspected patients at the University of Gondar Hospital. Socio-demographic characteristics and other clinical data were collected using a pretested questionnaire. GeneXpert MTB/RIF assay was performed to diagnosis Mycobacterium tuberculosis complex and Rifampicin resistance. All samples were also investigated by cytology and culture. The HIV statuses of all patients were screened initially by KHB, and all positive cases were further re-tested by STAT-pack. Data was analyzed using SPSS version 20 computer software and a P-value of < 0.05 was taken as statistically significant.
A total of 141 extrapulmonary suspected patients were enrolled in this study. The overall prevalence of culture confirmed extrapulmonary tuberculosis infection was 29.8%, but the GeneXpert result showed a 26.2% prevalence of Mycobacterium tuberculosis complex infection. The 78.4% prevalence of extrapulmonary tuberculosis infection was found to be higher among the adult population. The prevalence of HIV infection among EPTB suspected patients was 14.1%, while it was 32.4% among GeneXpert-confirmed extrapulmonary TB cases (12/37). Tuberculosis lymphadenitis was the predominant (78.4%) type of EPTB infection followed by tuberculosis cold abscess (10.7%). Adult hood, previous history of contact with known pulmonary tuberculosis patients, and HIV co-infection showed a statistically significant association with extrapulmonary tuberculosis infection (P<0.013).
The prevalence of culture confirmed-EPTB infection was high, and a higher EPTB-HIV co-infection was also observed.
PMCID: PMC4780813  PMID: 26950547
19.  Pulmonary edema following generalized tonic clonic seizures is directly associated with seizure duration 
Seizure  2015;27:19-24.
Postictal pulmonary edema (PPE) is almost invariably present in human and animal cases of sudden unexpected death in epilepsy (SUDEP) coming to autopsy. PPE may be a contributing factor in SUDEP. The incidence of postictal PPE is unknown. We retrospectively investigated PPE following generalized tonic clonic seizures (GTCS) in the epilepsy monitoring unit.
Chest X-Rays (CXR) following each GTCS were obtained in 24 consecutive patients. Relationship of CXR abnormality to seizure duration, ictal/postictal oxygen desaturation (SpO2), apnea and presence of postictal generalized EEG suppression (PGES) was investigated using logistic regression.
Eleven of 24 patients had CXR abnormalities following a GTCS. In these 11 patients, 22 CXR were obtained and abnormalities were present in 15 CXR. Abnormalities included PPE in 7 patients, of which 2 also had focal infiltrates. In 4 patients focal infiltrates were present without PPE. There was no significant difference in mean time to CXR (225 min) following GTCS in the abnormal CXR group versus the normal group of patients (196 min).
Mean preceding seizure duration was longer (p=0.002) in GTCS with abnormal CXR (259.7 sec) versus GTCS with normal CXR (101.2 sec). Odds-ratio for CXR abnormality was 20.46 (p=0.006) with seizure duration greater than 100 sec versus less than 100 sec. On multivariable analysis, only the seizure duration was a significant predictor of CXR abnormality (p=0.015).
Radiographic abnormalities are not uncommon following GTCS. The presence of CXR abnormality is significantly associated with the duration of the preceding GTCS. Severe, untreated PPE may be relevant to the pathophysiology of SUDEP.
PMCID: PMC4383169  PMID: 25844030
Pulmonary Edema; Seizure; Convulsion; SUDEP
20.  Diagnostic management and outcomes of pulmonary tuberculosis suspects admitted to a central hospital in Malawi 
Public Health Action  2011;1(1):2-5.
Zomba Central Hospital, Malawi.
To determine diagnostic management and outcomes of pulmonary tuberculosis (PTB) suspects admitted to adult wards.
A retrospective, cross-sectional review of medical records of patients admitted to hospital between July and September 2010.
There were 141 PTB suspects. Sputum examination was requested and performed in 67 (48%) suspects, but none were smear-positive. Chest X-ray (CXR) was requested and performed in 26 (39%) suspects whose sputum smears were negative. Eleven suspects had a CXR suggestive of PTB: two were started on TB treatment and eight died before treatment started. Human immunodeficiency virus (HIV) status was known for 50 patients (35% of all suspects) on admission, all of whom were HIV-positive. HIV testing was requested for 37 patients, but was only performed in 12, five of whom were HIV-positive. Only one patient was referred for antiretroviral treatment. There were 41 (29%) deaths, eight of whom had probable TB and were not treated. In the remaining 33 patients who died, only nine (27%) had sputum smears examined and four (12%) had a CXR.
The study shows inadequacies in the diagnostic management of PTB suspects in the Zomba Central Hospital, but suggests opportunities for improvement.
PMCID: PMC4547185  PMID: 26392925
PTB suspects; diagnosis; management; outcomes; Malawi
21.  Performance of Clinical Algorithms for Smear-Negative Tuberculosis in HIV-Infected Persons in Ho Chi Minh City, Vietnam 
Background. Tuberculosis (TB) disease diagnosis in Vietnam relies on symptom screening, chest radiography (CXR), and acid fast bacilli (AFB) sputum smear which have a poor sensitivity in HIV patients. We evaluated the performance of clinical algorithms in screening and diagnosing AFB smear-negative TB in HIV patients. Methods. We enrolled 399 HIV-positive patients seeking care at a HIV clinic in Ho Chi Minh City (HCMC), Vietnam. Participants' demographics, medical history, common TB symptoms, CXR, and laboratory tests were collected. Results. Of 399 HIV patients, 390 had initial AFB-negative smears and 22/390 patients had positive cultures. Symptom screening missed 54% (12/22) of smear-negative pulmonary TB (PTB) cases. Multivariate analysis found CD4+ cell level and CXR were significant PTB predictors. An algorithm combining four TB symptoms and TST presented a high sensitivity (100%), but poorly specific (24%) diagnostic performance for smear-negative PTB. Conclusion. Up to 54% of PTB cases in the HIV-infected population may be missed in the routine screening and diagnostic procedures used in Vietnam. Symptom screening was a poor overall diagnostic measure in detecting smear-negative TB in HIV patients. Our study results suggest that routine sputum cultures should be implemented to achieve a more accurate diagnosis of TB in HIV patients.
PMCID: PMC3512270  PMID: 23227329
22.  Pulmonary imaging of pandemic influenza H1N1 infection: relationship between clinical presentation and disease burden on chest radiography and CT 
The British Journal of Radiology  2010;83(992):645-651.
The potential for pulmonary involvement among patients presenting with novel swine-origin influenza A (H1N1) is high. To investigate the utility of chest imaging in this setting, we correlated clinical presentation with chest radiographic and CT findings in patients with proven H1N1 cases. Subjects included all patients presenting with laboratory-confirmed H1N1 between 1 May and 10 September 2009 to one of three urban hospitals. Clinical information was gathered retrospectively, including symptoms, possible risk factors, treatment and hospital survival. Imaging studies were re-read for study purposes, and CXR findings compared with CT scans when available. During the study period, 157 patients presented with subsequently proven H1N1 infection. Hospital admission was necessary for 94 (60%) patients, 16 (10%) were admitted to intensive care and 6 (4%) died. An initial CXR, carried out for 123 (78%) patients, was abnormal in only 40 (33%) cases. Factors associated with increased likelihood for radiographic lung abnormalities were dyspnoea (p<0.001), hypoxaemia (p<0.001) and diabetes mellitus (p = 0.023). Chest CT was performed in 21 patients, and 19 (90%) showed consolidation, ground-glass opacity, nodules or a combination of these findings. 4 of 21 patients had negative CXR and positive CT. Compared with CT, plain CXR was less sensitive in detecting H1N1 pulmonary disease among immunocompromised hosts than in other patients (p = 0.0072). A normal CXR is common among patients presenting to the hospital for H1N1-related symptoms without evidence of respiratory difficulties. The CXR may significantly underestimate lung involvement in the setting of immunosuppression.
PMCID: PMC3473510  PMID: 20551254
23.  Modeling the impact of novel diagnostic tests on pediatric and extrapulmonary tuberculosis 
BMC Infectious Diseases  2014;14:477.
Extrapulmonary tuberculosis (EPTB) and most pediatric TB cannot be diagnosed using sputum-based assays. The epidemiological impact of different strategies to diagnose EPTB and pediatric TB is unclear.
We developed a dynamic epidemic model of TB in a hypothetical population with epidemiological characteristics similar to India. We evaluated the impact of four alternative diagnostic test platforms on adult EPTB and pediatric TB mortality over 10 years: (1) Nucleic acid amplification test optimized for diagnosis of EPTB (“NAAT-EPTB”); (2) NAAT optimized for pediatric TB (“NAAT-Peds”); (3) more deployable NAAT for sputum-based diagnosis of adult pulmonary TB (“point-of-care (POC) sputum NAAT”); and (4) more deployable NAAT capable of diagnosing all forms of TB using non-invasive, non-sputum specimens (“POC non-sputum NAAT”).
NAAT-EPTB lowered adult EPTB mortality by a projected 7.6% (95% uncertainty range [UR]: 6.5-8.8%). NAAT-Peds lowered pediatric TB mortality by 6.8% (UR: 4.9-8.4%). POC sputum NAAT, though only able to diagnose pulmonary TB, reduced projected pediatric TB deaths by 13.3% (UR: 4.6-15.7%) and adult EPTB deaths by 8.4% (UR 2.0-9.3%) simply by averting transmission of disease. POC non-sputum NAAT had the greatest effect, lowering pediatric TB mortality by 34.7% (UR: 26.8-38.7), and adult EPTB mortality by 38.5% (UR: 30.7-41.2). The relative impact of a POC sputum NAAT (i.e., enhanced deployability) versus NAAT-EPTB (i.e., enhanced ability to specifically diagnose TB-NSP) on adult EPTB mortality depends most strongly on factors that influence transmission, with settings of higher transmission (e.g., higher per-person transmission rate, lower diagnostic rate) favoring POC sputum NAAT.
Although novel tests for pediatric TB and EPTB are likely to reduce TB mortality, major reductions in pediatric and EPTB incidence and mortality also require better diagnostic tests for adult pulmonary TB that reach a larger population.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2334-14-477) contains supplementary material, which is available to authorized users.
PMCID: PMC4168123  PMID: 25186052
Tuberculosis; Diagnostics; Pediatrics; Extrapulmonary; Modeling
24.  The value of end-of-treatment chest radiograph in predicting pulmonary tuberculosis relapse 
Patients with cavitary pulmonary tuberculosis (TB) on baseline chest radiograph (CXR) who remain culture-positive after 8 weeks of treatment are at high risk of relapse. The role of end-of-treatment (EOT) CXR in predicting relapse is unclear.
To determine whether EOT CXR independently predicts TB relapse.
We conducted a secondary analysis of a randomized trial of intermittent treatment using rifapentine in the continuation phase of TB treatment among 1004 human immunodeficiency virus seronegative adults with culture-proven pulmonary TB.
Relapse occurred in 17.3% of subjects with persistent cavity on EOT CXR, in 7.6% of subjects with a cavity that resolved by EOT, and 2.5% (P = 0.002 for trend) of subjects who never had a cavity. In multivariable analysis, patients with persistent cavity on EOT CXR were significantly more likely to relapse than patients with no cavity on baseline or 2-month CXR (hazard ratio [HR] 4.22, 95%CI 2.00–8.91), and were more likely to relapse than subjects whose early cavity had resolved by EOT CXR (HR 1.92, 95%CI 1.09–3.39).
A persistent cavity after 6 months of TB treatment was independently associated with disease relapse after controlling for other variables. EOT CXR may help predict those likely to relapse.
PMCID: PMC3785322  PMID: 18713505
tuberculosis; relapse; chest radiograph
25.  The effect of a tuberculosis chest X-ray image reference set on non-expert reader performance 
European Radiology  2013;23(9):2459-2468.
In low-resource settings, limitations in diagnostic accuracy of chest X-rays (CXR) for pulmonary tuberculosis (PTB) relate partly to non-expert interpretation. We piloted a TB CXR Image Reference Set (TIRS) to improve non-expert performance in an operational setting in Malawi.
Nineteen doctors and clinical officers read 60 CXR of patients with suspected PTB, at baseline and using TIRS. Two officers also used the CXR Reading and Recording System (CRRS). Correct treatment decisions were assessed against a “gold standard” of mycobacterial culture and expert performance.
TIRS significantly increased overall non-expert sensitivity from 67.6 (SD 14.9) to 75.5 (SD 11.1, P = 0.013), approaching expert values of 84.2 (SD 5.2). Among doctors, correct decisions increased from 60.7 % (SD 7.9) to 67.1 % (SD 8.0, P = 0.054). Clinical officers increased in sensitivity from 68.0 % (SD 15) to 77.4 % (SD 10.7, P = 0.056), but decreased in specificity from 55.0 % (SD 23.9) to 40.8 % (SD 10.4, P = 0.049). Two officers made correct treatment decisions with TIRS in 62.7 %. CRRS training increased this to 67.8 %.
Use of a CXR image reference set increased correct decisions by doctors to treat PTB. This tool may provide a low-cost intervention improving non-expert performance, translating into improved clinical care. Further evaluation is warranted.
Key Points
• Tuberculosis treatment decisions are influenced by CXR findings, despite improved laboratory diagnostics.
• In low-resource settings, CXR interpretation is performed largely by non-experts.
• We piloted the effect of a simple reference training set of CXRs.
• Use of the reference set increased the number of correct treatment decisions. This effect was more marked for doctors than clinical officers.
• Further evaluation of this simple training tool is warranted.
Electronic supplementary material
The online version of this article (doi:10.1007/s00330-013-2840-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3738845  PMID: 23652843
Radiography; Tuberculosis; Malawi; Sensitivity and Specificity; Teaching

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