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1.  Manifestations of tuberculosis in HIV/AIDS patients and its relationship with CD4 count 
Background:
HIV/AIDS pandemic is responsible for the resurgence of TB worldwide, resulting in increased morbidity and mortality. HIV and Mycobacterium tuberculosis have a synergistic interaction; each propagates progression of the other. Coinfection with HIV infection leads to difficulties in both the diagnosis and treatment of tuberculosis, increase risk of death, treatment failure and relapse.
Objective:
The aim of the present study is to study the clinical, radiological profile of pulmonary and extrapulmonary tuberculosis (EPTB) in HIV-seropositive patients and their relationship to CD4 counts.
Materials and Methods:
It was a prospective study conducted over a period of 1 year in the department of medicine, Indira Gandhi Medical College, Shimla. We examined 87 HIV-infected patients with associated tuberculosis recruited from the department of medicine and antiretroviral center and were subjected to thorough clinical examination, X-ray chest, tuberculin testing and sputum examination for AFB and necessary relevant investigations for EPTB.
Results:
Most common affected age group was 31-40 years. EPTB is the commonest form of TB in our study detected in 65 patients. Commonest EPTB was CNS tuberculosis. Disseminated tuberculosis was only found in patient with CD4 count less than 200/cmm. Majority of lymph node TB was diagnosed by fine needle aspiration cytology (FNAC) examination. All patients with AFB-positive lymph node had CD4 count below 200/cum.
Conclusions:
The results of this study provide information regarding the various forms of TB and their presentation in HIV-infected persons. Early diagnosis of tuberculosis and prompt institution of antitubercular treatment (ATT) reduces mortality and morbidity significantly. In resource-poor areas, the diagnosis can be established with cytological/biochemical analysis of fluid, histopathological examination and ZN staining of tissue coupled with radiological features and response to ATT. Therefore, adequate knowledge of the manifestations of tuberculosis in HIV-infected patients is absolutely necessary for optimal management and to reduce mortality and morbidity.
doi:10.4103/0970-2113.85687
PMCID: PMC3213712  PMID: 22084539
AFB smear; CD4 count; extrapulmonary; HIV; pulmonary; tuberculosis
2.  National Profile and Treatment Outcomes of Patients with Extrapulmonary Tuberculosis in Bénin 
PLoS ONE  2014;9(4):e95603.
Background
In sub-Saharan Africa, there is a dearth of published literature on extrapulmonary tuberculosis (EPTB).
Objective
To describe demographic, diagnostic and HIV-status characteristics of patients with EPTB in Bénin, their treatment outcomes, and among those who completed their treatment in the Centre National Hospitalier de Pneumo-Phtisiologie (CNHP-P), the proportion whose bodyweight increased during treatment.
Material and Findings
This was a retrospective cohort study with comparisons made between EPTB and new smear-positive pulmonary tuberculosis (NPTB) patients diagnosed in the country from January to December 2011. There were 383 EPTB patients (9% of all TB cases) with a mean age of 35 years, male/female ratio of 1.3 and important regional variation. There were significantly more females (p = 0.001), children <15years (p<0.001) and HIV-positive patients (p = 0.005) with EPTB compared with NPTB. Pleural effusion, spinal and lymph node tuberculosis accounted for 66% of all EPTB. Children <15 years represented 16% of cases, with lymph node disease being most common among them (p<0.001). Of 130 EPTB patients registered in CNHP-P, 7% had a confirmed bacteriological/histological diagnosis. There were 331 (86%) patients who successfully completed treatment. More patients with EPTB were lost-to-follow-up compared with NPTB (p<0.001) with all these patients from one region. The best treatment completion rates were in children <15 years (OR:3.5, 95%CI:1.0–14.8) while patients with pleural effusion and ascites had the worst outcomes. Of 72 HIV-coinfected patients, 88% were on antiretroviral therapy (ART). HIV-positive status was associated with poor outcomes while those on ART fared better. In the CNHP-P, more than 80% who completed their treatment showed an increase in bodyweight and this was more evident in HIV-positive compared with HIV-negative patients (p = 0.03).
Conclusion
Patients with EPTB generally do well in Bénin, although the TB Programme would benefit through more attention to accurate diagnosis and earlier start of ART in HIV-infected patients.
doi:10.1371/journal.pone.0095603
PMCID: PMC3995824  PMID: 24755603
3.  Site of Extrapulmonary Tuberculosis is Associated with HIV Infection 
The site of extrapulmonary tuberculosis infection has a known effect on mortality. Authors use a large clinical case series to identify previously unconfirmed risk factors that are associated with site of extrapulmonary tuberculosis infection.
Background. In the United States, the proportion of patients with extrapulmonary tuberculosis (EPTB) has increased relative to cases of pulmonary tuberculosis. Patients with central nervous system (CNS)/meningeal and disseminated EPTB and those with human immunodeficiency virus (HIV)/AIDS have increased mortality. The purpose of our study was to determine risk factors associated with particular types of EPTB.
Methods. We retrospectively reviewed 320 cases of EPTB from 1995–2007 at a single urban US public hospital. Medical records were reviewed to determine site of EPTB and patient demographic and clinical characteristics. Multivariable logistic regression analyses were performed to determine independent associations between patient characteristics and site of disease.
Results. Patients were predominantly male (67%), African American (82%), and US-born (76%). Mean age was 40 years (range 18–89). The most common sites of EPTB were lymphatic (28%), disseminated (23%), and CNS/meningeal (22%) disease. One hundred fifty-four (48.1%) were HIV-infected, 40% had concomitant pulmonary tuberculosis, and 14.7% died within 12 months of EPTB diagnosis. Multivariable analysis demonstrated that HIV-infected patients were less likely to have pleural (adjusted odds ratio [AOR] 0.3; 95% confidence interval [CI] .2, .6) as site of EPTB disease than HIV-uninfected patients. Among patients with EPTB and HIV-infection, patients with CD4 lymphocyte cell count <100 were more likely to have severe forms of EPTB (CNS/meningeal and/or disseminated) (AOR 1.6; 95% CI, 1.0, 2.4).
Conclusions. Among patients hospitalized with EPTB, patients coinfected with HIV and low CD4 counts were more likely to have CNS/meningeal and disseminated disease. Care for similar patients should include consideration of these forms of EPTB since they carry a high risk of death.
doi:10.1093/cid/cis303
PMCID: PMC3493181  PMID: 22423123
4.  Determination of Sites Involved, HIV Co–Infection & Utility of Diagnostic Modalities in EPTB 
Background: Tuberculosis remains a major global public health problem and an on-going epidemic. Though the chief objectives of the Revised National Tuberculosis Control Programme (RNTCP) in detecting and curing the infectious pulmonary cases is well taken, there has been a steady rise in the number of Extra Pulmonary Tuberculosis (EPTB) cases as documented in several studies. EPTB which usually constitutes around 15%-20% of the total TB cases is now being increasingly reported due to a combination of better diagnostic facilities, and the HIV pandemic. Though several studies have shown increasing prevalence of EPTB, only few studies are available, especially in the Indian scenario, that study the pattern and risk factors. Hence, this retrospective observational study was undertaken to determine the sites of the involvement, HIV co-infection and usefulness of various diagnostic modalities in EPTB affecting patients attending a medical college DOTS clinic.
Material and Methods: One hundred ten EPTB patients referred to the DOTS clinics of the TB & Chest department from the period Dec 2010– Mar 2012 were included in the study. The diagnosis of EPTB was established by combined clinical, microbiological, histopathological &/or imaging modalities. Their medical records were assessed to determine the age distribution, gender and anatomical sites of involvement. The presence of co-morbid conditions like smoking history, alcoholism, diabetic and HIV status were noted. BCG status and Mantoux test readings were recorded. The different diagnostic tests used in confirming EPTB at different sites were recorded. Chest x-ray was analysed for all patients to assess coexisting pulmonary involvement. All patients were followed to assess the outcome of treatment.
Results: The mean age of patients was 34.4. The male to female ratio was 58:52 showing a slight male predominance. The most common site of involvement was lymph node followed by pleural effusion and abdominal TB. The prevalence of lymph node TB was noted to be higher in female patients as compared to other sites of EPTB. Mantoux test was positive in 57 (51.8%) patients. HIV co-infection was noted in only 3 (2.7%) patients. Concomitant pulmonary involvement was seen in 19 (17.3%) patients.
Conclusions: Lymph node was the most common site involvement showing a significant female preponderance followed by pleural effusion and abdominal TB. The rates of HIV co-infection and diabetes mellitus were 2.7% and 20% respectively. The most useful diagnostic modality was tissue sampling followed by imaging. Mantoux test is not unequivocal for the diagnosis of EPTB.
doi:10.7860/JCDR/2013/6363.3301
PMCID: PMC3782920  PMID: 24086863
Extra–Pulmonary Tuberculosis; DOTS clinic; TB Lymphadenopathy; HIV co-infection; Mantoux test
5.  Predictors of pulmonary involvement in patients with extra-pulmonary tuberculosis 
Objectives:
The aim of this study is to assess the value of chest radiographs (CXRs) and sputum examinations in detecting pulmonary involvement of tuberculosis (TB) in patients with extra-pulmonary tuberculosis (EPTB).
Materials and Methods:
A retrospective analysis was performed among 248 EPTB patients with culture-proven diagnosis of tuberculosis seen between January 2001 and December 2007 at a tertiary teaching hospital, Riyadh, Saudi Arabia. Demographics, clinical, laboratory and radiological findings were reviewed and assessed. This study was approved by the hospital ethics and research committee.
Results:
One hundred twenty five of 233 EPTB patients (53.6%) had abnormal CXR findings. There was a significant difference in the occurrence of positive sputum culture results between patients with abnormal CXR findings (30/57) and those with normal CXR findings (4/17) (P = 0.04). Of 17 HIV-negative/unknown HIV-status EPTB patients with normal CXR results, 4 patients (23.5%) had positive sputum culture results. Intrathoracic lymphadenopathy (P < 0.001), pleural TB (P < 0. 001) and disseminated TB (P = 0.004) were associated with an increased risk of abnormal CXR findings. Patients with cough (52.9%), weight loss (41.2%) and night sweats (26.5%) are more likely to have positive sputum culture results.
Conclusion:
CXR findings are predictive of positive sputum culture results. However, the rate of normal CXR among EPTB patients with positive sputum culture results was relatively high. Therefore, respiratory specimen cultures should be obtained in TB suspects with a normal CXR to identify potentially infectious cases of TB.
doi:10.4103/2230-8229.98287
PMCID: PMC3410185  PMID: 22870411
Predictors; pulmonary; extra-pulmonary tuberculosis; radiology
6.  Characteristics of adults and children diagnosed with tuberculosis in Lilongwe, Malawi: findings from an integrated HIV/TB clinic 
Objectives
To describe initial registration characteristics of adult and pediatric TB patients at a large, public, integrated TB and HIV clinic in Lilongwe, Malawi, between January 2008 – December 2010.
Methods
Routine data on TB patient category and TB type, stratified by HIV and ART status, were used to explore differences in proportions among TB-only, TB/HIV co-infected patients not on ART, and TB/HIV co-infected patients on ART using Chi-square tests.. Trends over time illustrate strengths and weaknesses of integrated service provision.
Results
Among 10,143 adults, HIV ascertainment and ART uptake were high and increased over time. The proportion of relapse was highest among those on ART (5%). The proportion of smear-positive pulmonary TB (PTB) was highest among HIV-negative TB patients (34.9%); extra-pulmonary TB (EPTB) was lowest among TB-only (16.2%). Among 338 children <15 years, EPTB and smear-positive PTB were more common among TB-only patients. Time trends showed significant increases in the proportion of adults with smear-positive PTB and the proportion of adults already on ART before starting TB treatment. However, some co-infected patients still delay ART initiation.
Conclusions
HIV ascertainment and ART uptake among co-infected patients is successful and improving over time. However, delays in ART initiation indicate some weakness linking TB/HIV patients into ART during TB follow-up care. Improved TB diagnostics and screening efforts, especially for pediatric patients, may help improve quality care for co-infected patients. These results may aid efforts to prioritize TB and HIV prevention, education, and treatment campaigns for specific populations.
doi:10.1111/j.1365-3156.2012.03041.x
PMCID: PMC3767918  PMID: 22808948
TB/ART service integration; Malawi; TB; ART; HIV; smear-positive PTB
7.  Demographic and microbial characteristics of extrapulmonary tuberculosis cases diagnosed in Malatya, Turkey, 2001-2007 
BMC Public Health  2011;11:154.
Background
Extrapulmonary tuberculosis (EPTB) has an increasing rate in Turkey. The reason remains largely unknown. A better understanding of the demographic and microbial characteristics of EPTB in the Turkish population would extend the knowledgebase of EPTB and allow us to develop better strategies to control tuberculosis (TB).
Methods
We retrospectively evaluated clinical and laboratory data of 397 bacteriologically-confirmed TB cases diagnosed during an eight year-period using by chi-square analysis and multivariate logistic regression model.
Results
Of the 397 study patients, 103 (25.9%) had EPTB and 294 (74.1%) had pulmonary tuberculosis (PTB). The most commonly seen two types of EPTB were genitourinary TB (27.2%) and meningeal TB (19.4%). TB in bone/joints, pleural cavity, lymph nodes, skin, and peritoneal cavity occurred at a frequency ranging from 9.7% to 10.7%. The age distribution was significantly different (P < 0.01) between PTB and EPTB, with patients older than 45 years tending to have an increased risk of EPTB. Furthermore, the distribution of different types of EPTB differed significantly among age groups (P = 0.03). Meningeal and bone and/or joint TB were more commonly observed among the male patients, while lymphatic, genitourinary, and peritoneal TB cases were more frequently seen among females. Unique strain infection was statistically significantly associated with EPTB (OR: 2.82, 95% CI [1.59, 5.00])
Conclusions
EPTB accounted for a significant proportion of TB cases in Malatya, Turkey between 2001 and 2007. The current study has provided an insight into the dynamics of EPTB in Malatya, Turkey. However, the risk factors for having EPTB in Malatya, Turkey remain to be assessed in future studies using population-based or randomly selected sample.
doi:10.1186/1471-2458-11-154
PMCID: PMC3060117  PMID: 21385458
8.  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.
doi:10.1155/2012/360852
PMCID: PMC3512270  PMID: 23227329
9.  Therapy duration and long-term outcomes in extra-pulmonary tuberculosis 
BMC Infectious Diseases  2014;14:115.
Background
Tuberculosis is classified as either pulmonary or extra-pulmonary (EPTB). While much focus has been paid to pulmonary tuberculosis, EPTB has received scant attention. Moreover, EPTB is viewed as one wastebasket diagnosis, as “the other” which is not pulmonary.
Methods
This is a retrospective cohort study of all patients treated for EPTB in the state of Texas between January 2000 and December 2005, who had no pulmonary disease. Clinical and epidemiological factors were abstracted from electronic records of the Report of Verified Case of Tuberculosis. The long-term outcome, which is death by December 2011, was established using the Social Security Administration Death Master File database. Survival in EPTB patients was compared to those with latent tuberculosis, as well as between different types of EPTB, using Cox proportional hazard models. A hybrid of the machine learning method of classification and regression tree analyses and standard regression models was used to identify high-order interactions and clinical factors predictive of long-term all-cause mortality.
Results
Four hundred and thirty eight patients met study criteria; the median study follow-up period for the cohort was 7.8 (inter-quartile range 6.0-10.1) years. The overall all-cause mortality rate was 0.025 (95% confidence interval [CI]: 0.021-0.030) per 100 person-year of follow-up. The significant predictors of poor long-term outcome were age (hazard ratio [HR] for each year of age-at-diagnosis was 1.05 [CI: 1.04-1.06], treatment duration, type of EPTB and HIV-infection (HR = 2.16; CI: 1.22, 3.83). Mortality in genitourinary tuberculosis was no different from latent tuberculosis, while meningitis had the poorest long-term outcome of 46.2%. Compared to meningitis the HR for death was 0.50 (CI: 0.27-0.91) for lymphatic disease, 0.42 (CI: 0.21-0.81) for bone/joint disease, and 0.59 (CI: 0.27-1.31) for peritonitis. The relationship between mortality and therapy duration for each type of EPTB was a unique “V” shaped curve, with the lowest mortality observed at different therapy durations for each, beyond which mortality increased.
Conclusions
EPTB is comprised of several different diseases with different outcomes and durations of therapy. The “V” shaped relationship between therapy duration and outcome leads to the hypothesis that longer duration of therapy may lead to higher patient mortality.
doi:10.1186/1471-2334-14-115
PMCID: PMC3943436  PMID: 24580808
Extra-pulmonary tuberculosis; Therapy duration; Survival; Peritoneal; Meningitis
10.  Exploring the Sociodemographic and Clinical Features of Extrapulmonary Tuberculosis in Saudi Arabia 
PLoS ONE  2015;10(2):e0101667.
Background
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.
Methodology
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.
Conclusions
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.
doi:10.1371/journal.pone.0101667
PMCID: PMC4315397  PMID: 25647300
11.  Insight to the Epidemiology and Risk Factors of Extrapulmonary Tuberculosis in Tianjin, China during 2006-2011 
PLoS ONE  2014;9(12):e112213.
Background
The proportion of extrapulmonary tuberculosis (EPTB) among all the reported tuberculosis (TB) cases has increased in different populations. Despite the large burden of TB in China, the epidemiology of EPTB in China remains largely understudied and the risk factors for having EPTB diagnosis in China have not been identified.
Methods
To gain insight to EPTB epidemiology in China, we analyzed TB surveillance data collected in Tianjin, China, during 2006 to 2011. The frequency of EPTB among all TB cases and within different socio-demographic groups of the study patients aged 15 years and older was determined for EPTB in general and by specific types. The distribution of socio-demographic characteristics was compared between pulmonary TB (PTB) group and EPTB group by chi-square test. Crude and multiple logistic regression-derived adjusted odds ratios (aOR) and 95% confidence intervals (CI) were determined to assess the associations between having EPTB diagnosis and each individual explanatory variable in question.
Results
About one-tenth (1,512/14,561) of the patients investigated in this study had EPTB. Of these 1,512 EPTB cases, about two thirds were pleural TB. Significant difference in age, occupation, and urbanity of residence were found between PTB and EPTB groups (p<0.05). Patients with EPTB diagnosis were more likely to be 65 years or older (aOR = 1.22, 95% CI: 1.02, 1.46), to be retired (aOR = 1.37, 95% CI: 1.08, 1.75), and to live in urban areas (aOR = 1 38, 95% CI: 1.22, 1.55).
Conclusions
The findings of this study extends the knowledgebase of EPTB epidemiology in developing countries and highlight the need for improved EPTB detection in China, especially in subpopulations with high risk for EPTB or having limited access to medical facilities with adequate capacity for EPTB diagnosis.
doi:10.1371/journal.pone.0112213
PMCID: PMC4262301  PMID: 25494360
12.  Comparison of Xpert MTB/RIF with Other Nucleic Acid Technologies for Diagnosing Pulmonary Tuberculosis in a High HIV Prevalence Setting: A Prospective Study 
PLoS Medicine  2011;8(7):e1001061.
In this prospective, real-world cohort study nested within a national screening program for tuberculosis, Lesley Scott and colleagues compare the performance of Xpert MTB/RIF on a single sputum sample with different TB sputum detection technologies.
Background
The Xpert MTB/RIF (Cepheid) non-laboratory-based molecular assay has potential to improve the diagnosis of tuberculosis (TB), especially in HIV-infected populations, through increased sensitivity, reduced turnaround time (2 h), and immediate identification of rifampicin (RIF) resistance. In a prospective clinical validation study we compared the performance of Xpert MTB/RIF, MTBDRplus (Hain Lifescience), LightCycler Mycobacterium Detection (LCTB) (Roche), with acid fast bacilli (AFB) smear microscopy and liquid culture on a single sputum specimen.
Methods and Findings
Consecutive adults with suspected TB attending a primary health care clinic in Johannesburg, South Africa, were prospectively enrolled and evaluated for TB according to the guidelines of the National TB Control Programme, including assessment for smear-negative TB by chest X-ray, clinical evaluation, and HIV testing. A single sputum sample underwent routine decontamination, AFB smear microscopy, liquid culture, and phenotypic drug susceptibility testing. Residual sample was batched for molecular testing. For the 311 participants, the HIV prevalence was 70% (n = 215), with 120 (38.5%) culture-positive TB cases. Compared to liquid culture, the sensitivities of all the test methodologies, determined with a limited and potentially underpowered sample size (n = 177), were 59% (47%–71%) for smear microscopy, 76% (64%–85%) for MTBDRplus, 76% (64%–85%) for LCTB, and 86% (76%–93%) for Xpert MTB/RIF, with specificities all >97%. Among HIV+ individuals, the sensitivity of the Xpert MTB/RIF test was 84% (69%–93%), while the other molecular tests had sensitivities reduced by 6%. TB detection among smear-negative, culture-positive samples was 28% (5/18) for MTBDRplus, 22% (4/18) for LCTB, and 61% (11/18) for Xpert MTB/RIF. A few (n = 5) RIF-resistant cases were detected using the phenotypic drug susceptibility testing methodology. Xpert MTB/RIF detected four of these five cases (fifth case not tested) and two additional phenotypically sensitive cases.
Conclusions
The Xpert MTB/RIF test has superior performance for rapid diagnosis of Mycobacterium tuberculosis over existing AFB smear microscopy and other molecular methodologies in an HIV- and TB-endemic region. Its place in the clinical diagnostic algorithm in national health programs needs exploration.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Tuberculosis (TB)—a contagious bacterial infection that mainly affects the lungs—is a global public health problem. In 2009, 9.4 million people developed TB, and 1.7 million people died from the disease; a quarter of these deaths were in HIV-positive individuals. People who are infected with HIV, the virus that causes AIDS, are particularly susceptible to TB because of their weakened immune system. Consequently, TB is a leading cause of illness and death among people living with HIV. TB is caused by Mycobacterium tuberculosis, which is spread in airborne droplets when people with the disease cough or sneeze. Its characteristic symptoms are a persistent cough, night sweats, and weight loss. Diagnostic tests for TB include sputum smear analysis (the microscopic examination of mucus brought up from the lungs by coughing for the presence of M. tuberculosis) and mycobacterial liquid culture (in which bacteriologists try to grow M. tuberculosis from sputum samples and test its drug sensitivity). TB can usually be cured by taking several powerful drugs daily for at least six months.
Why Was This Study Done?
Mycobacterial culture is a sensitive but slow way to diagnose TB. To halt the disease's spread, it is essential that TB—particularly TB that is resistant to several treatment drugs (multidrug-resistant, or MDR, TB)—is diagnosed quickly. Recently, several nucleic acid amplification technology (NAAT) tests have been developed that rapidly detect M. tuberculosis DNA in patient samples and look for DNA changes that make M. tuberculosis drug-resistant. In December 2010, the World Health Organization (WHO) endorsed Xpert MTB/RIF—an automated DNA test that detects M. tuberculosis and rifampicin resistance (an indicator of MDR TB) within two hours—for the investigation of patients who might have TB, especially in regions where MDR TB and HIV infection are common. TB diagnosis in HIV-positive people can be difficult because they are more likely to have smear-negative TB than HIV-negative individuals. In this prospective study, the researchers compare the performance of Xpert MTB/RIF on a single sputum sample with that of smear microscopy, liquid culture, and two other NAAT tests (MTBDRplus and LightCycler Mycobacterium Detection) in adults who might have TB in Johannesburg (South Africa), a region where many adults are HIV-positive.
What Did the Researchers Do and Find?
The researchers evaluated adults with potential TB attending a primary health care clinic for TB according to national guidelines and determined their HIV status. A sputum sample from 311 participants underwent smear microscopy, liquid culture, and drug susceptibility testing; 177 samples were also tested for TB using NAAT tests. They found that 70% of the participants were HIV-positive and 38.5% had culture-positive TB. Compared to liquid culture, smear microscopy, MTBDRplus, LightCycler Mycobacterium Detection, and Xpert MTB/RIF had sensitivities of 59%, 76%, 76%, and 86%, respectively. That is, assuming that liquid culture detected everyone with TB, Xpert MTB/RIF detected 86% of the cases. The specificity of all the tests compared to liquid culture was greater than 97%. That is, they all had a low false-positive rate. Among people who were HIV-positive, the sensitivity of Xpert MTB/RIF was 84%; the sensitivities of the other NAAT tests were 70%. Moreover, Xpert MTB/RIF detected TB in 61% of smear-negative, culture-positive samples, whereas the other NAATs detected TB in only about a quarter of these samples. Finally, although some TB cases were identified as drug-resistant by one test but drug-sensitive by another, the small number of drug-resistant cases means no firm conclusions can be made about the accuracy of drug resistance determination by the various tests.
What Do These Findings Mean?
Although these findings are likely to be affected by the study's small size, they suggest that Xpert MTB/RIF may provide a more accurate rapid diagnosis of TB than smear microscopy and other currently available NAAT tests in regions where HIV and TB are endemic (i.e., always present). Indeed, the reported accuracy of Xpert MTB/RIF for TB diagnosis—85% sensitivity and 97% specificity—has the potential to save more than 400,000 lives per year. Taken together with the results of other recent studies (including an accompanying article by Lawn et al. that investigates the use of Xpert MTB/RIF for screening for HIV-associated TB and rifampicin resistance), these findings support the WHO recommendation that Xpert MTB/RIF, rather than smear microscopy, should be the initial test in HIV-infected individuals who might have TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001061.
This study is further discussed in a PLoS Medicine Perspective by Carlton Evans; a related PLoS Medicine Research Article by Lawn et al. is also available
WHO provides information (in several languages) on all aspects of tuberculosis, including general information on tuberculosis diagnostics and specific information on the Xpert MTB/RIF test; further information about WHO's endorsement of Xpert MTB/RIF is included in a recent Strategic and Technical Advisory Group for Tuberculosis report
WHO also provides information about tuberculosis and HIV
The US National Institute of Allergy and Infectious Diseases has detailed information on tuberculosis and HIV/AIDS
The US Centers for Disease Control and Prevention also has information about tuberculosis, including information on the diagnosis of and on tuberculosis and HIV co-infection
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including information on HIV-related tuberculosis (in English and Spanish)
doi:10.1371/journal.pmed.1001061
PMCID: PMC3144192  PMID: 21814495
13.  Extrapulmonary Tuberculosis: Mycobacterium tuberculosis Strains and Host Risk Factors in a Large Urban Setting in Brazil 
PLoS ONE  2013;8(10):e74517.
Background
Factors related to the development of extrapulmonary forms of tuberculosis (EPTB) are still poorly understood, particularly in high-endemic countries like Brazil. The objective of the paper is to determine host and Mycobacterium tuberculosis (MTB) strain-related factors associated with the development of EPTB in Espírito Santo state, Brazil.
Methods and Findings
We conducted a retrospective laboratory-based surveillance study of new tuberculosis (TB) cases diagnosed in Espírito Santo state, Brazil between 1998 and 2007. We genotyped 612 isolates of MTB from 606 TB patients using spoligotyping and IS6110-restriction fragment length polymorphism (RFLP) typing and compared sociodemographic and clinical characteristics of patients with pulmonary TB (PTB) and EPTB. Among 606 patients, 464 (77%) had PTB, 79 (13%) had EPTB, 51 (8%) had both, and 12 (2%) had miliary TB. The IS6110 RFLP analysis demonstrated that 250 (41%) isolates belonged to clustered RFLP patterns, 27 (11%) of which were from EPTB. We identified 73 clusters including 35 (48%) composed of 2 isolates each. By spoligotyping, 506 (83%) MTB isolates fell into known patterns and 106 (17%) fell into patterns with no family assignment; 297 (48%) isolates belonged to the Latin-American Mediterranean family. Higher school level (4-7 years OR: 0.16 95% CI 0.34-0.73 and > 8 years of education, OR 0.06 95% CI 0.009-0.50) white ethnicity (OR: 2.54 95% CI 1.03-6.25) and HIV infection (OR: 16.83 95% CI 5.23-54.18) were associated with EPTB. No specific strain lineage or percentage of clustering was associated with EPTB.
Conclusions
These results demonstrate that risk factors for EPTB are related more to host than to MTB strain lineage characteristics.
doi:10.1371/journal.pone.0074517
PMCID: PMC3788772  PMID: 24098337
14.  Comparison of pulmonary and extrapulmonary tuberculosis in Nepal- a hospital-based retrospective study 
Background
Studies from developed countries have reported on host-related risk factors for extra-pulmonary tuberculosis (EPTB). However, similar studies from high-burden countries like Nepal are lacking. Therefore, we carried out this study to compare demographic, life-style and clinical characteristics between EPTB and PTB patients.
Methods
A retrospective analysis was carried out on 474 Tuberculosis (TB) patients diagnosed in a tertiary care hospital in western Nepal. Characteristics of demography, life-style and clinical features were obtained from medical case records. Risk factors for being an EPTB patient relative to a PTB patient were identified using logistic regression analysis.
Results
The age distribution of the TB patients had a bimodal distribution. The male to female ratio for PTB was 2.29. EPTB was more common at younger ages (< 25 years) and in females. Common sites for EPTB were lymph nodes (42.6%) and peritoneum and/or intestines (14.8%). By logistic regression analysis, age less than 25 years (OR 2.11 95% CI 1.12–3.68) and female gender (OR 1.69, 95% CI 1.12–2.56) were associated with EPTB. Smoking, use of immunosuppressive drugs/steroids, diabetes and past history of TB were more likely to be associated with PTB.
Conclusion
Results suggest that younger age and female gender may be independent risk factors for EPTB in a high-burden country like Nepal. TB control programmes may target young and female populations for EPTB case-finding. Further studies are necessary in other high-burden countries to confirm our findings.
doi:10.1186/1471-2334-8-8
PMCID: PMC2245948  PMID: 18218115
15.  Clinico-epidemiological profile and diagnostic procedures of pediatric tuberculosis in a tertiary care hospital of western Nepal-a case-series analysis 
BMC Pediatrics  2010;10:57.
Background
Changing epidemiology and diagnostic difficulties of paediatric tuberculosis (TB) are being increasingly reported. Our aim was to describe clinico-epidemiological profile and diagnostic procedures used for paediatric TB.
Methods
A retrospective case-series analysis was carried out in a tertiary care teaching hospital of western Nepal. All pediatric TB (age 0-14 years) patients registered in DOTS clinic during the time period from March, 2003 to July, 2008 were included. Medical case files were reviewed for information on demography, clinical findings, investigations and final diagnosis. Analysis was done on SPSS package. Results were expressed as rates and proportions. Chi square test was used to test for statistical significance.
Results
About 17.2% (162/941) of TB patients were children. Common symptoms were cough, fever and lymph node swelling. The types of TB were pulmonary TB (46.3%, 75/162), followed by extra-pulmonary TB (41.4%, 67/162). Twelve patients (7.4%) had disseminated TB. Distribution of types of TB according to gender was similar. PTB was common in younger age than EPTB which was statistically significant. EPTB was mainly localized to lymph node (38, 50.7%), and abdomen (9, 12%). Five main investigations namely Mantoux test, BCG test, chest radiograph, erythrocyte sedimentation rate (ESR) and fine needle aspiration cytology (FNAC) or biopsy were carried out to diagnose TB.
Conclusions
Paediatric TB in both pulmonary and extrapulmonary forms is a common occurrence in our setting. Age incidence according to type of TB was significant. Diagnosis was based on a combination of epidemiological and clinical suspicion supported by results of various investigations.
doi:10.1186/1471-2431-10-57
PMCID: PMC2923129  PMID: 20696041
16.  Evaluation of the 2007 WHO Guideline to Improve the Diagnosis of Tuberculosis in Ambulatory HIV-Positive Adults 
PLoS ONE  2011;6(4):e18502.
Background
In 2007 WHO issued a guideline to improve the diagnosis of smear-negative and extrapulmonary tuberculosis (EPTB) in HIV-positive patients. This guideline relies heavily on the acceptance of HIV-testing and availability of chest X-rays.
Methods and Findings
Cohort study of TB suspects in four tuberculosis (TB) clinics in Phnom Penh, Cambodia. We assessed the operational performance of the guideline, the incremental yield of investigations, and the diagnostic accuracy for smear-negative tuberculosis in HIV-positive patients using culture positivity as reference standard. 1,147 (68.9%) of 1,665 TB suspects presented with unknown HIV status, 1,124 (98.0%) agreed to be tested, 79 (7.0%) were HIV-positive. Compliance with the guideline for chest X-rays and sputum culture requests was 97.1% and 98.3% respectively. Only 35 of 79 HIV-positive patients (44.3%) with a chest X-ray suggestive of TB started TB treatment within 10 days. 105 of 442 HIV-positive TB suspects started TB treatment (56.2% smear-negative pulmonary TB (PTB), 28.6% smear-positive PTB, 15.2% EPTB). The median time to TB treatment initiation was 5 days (IQR: 2–13 days), ranging from 2 days (IQR: 1–11.5 days) for EPTB, over 2.5 days (IQR: 1–4 days) for smear-positive PTB to 9 days (IQR: 3–17 days) for smear-negative PTB. Among the 34 smear-negative TB patients with a confirmed diagnosis, the incremental yield of chest X-ray, clinical suspicion or abdominal ultrasound, and culture was 41.2%, 17.6% and 41.2% respectively. The sensitivity and specificity of the algorithm to diagnose smear-negative TB in HIV-positive TB suspects was 58.8% (95%CI: 42.2%–73.6%) and 79.4% (95%CI: 74.8%–82.4%) respectively.
Conclusions
Pending point-of-care rapid diagnostic tests for TB disease, diagnostic algorithms are needed. The diagnostic accuracy of the 2007 WHO guideline to diagnose smear-negative TB is acceptable. There is, however, reluctance to comply with the guideline in terms of immediate treatment initiation.
doi:10.1371/journal.pone.0018502
PMCID: PMC3071837  PMID: 21494694
17.  Prevalence and Predictors of Tuberculosis Coinfection among HIV-Seropositive Patients Attending the Aminu Kano Teaching Hospital, Northern Nigeria 
Journal of Epidemiology  2009;19(2):81-87.
Background
The HIV/AIDS epidemic has been accompanied by a severe epidemic of tuberculosis (TB), although the prevalence of coinfection is largely unknown, especially in developing countries, including Nigeria. The aim of this study was to determine the prevalence and predictors of TB coinfection among HIV-seropositive Nigerians.
Methods
The case files of HIV/AIDS patients attending Aminu Kano Teaching Hospital, Nigeria from January to December 2006 were reviewed.
Results
A total of 1320 HIV/AIDS patients had complete records and were reviewed, among which 138 (10.5%) were coinfected with TB (95% CI, 8.9% to 12.2%). Pulmonary TB was diagnosed in 103 (74.6%) patients, among whom only 18 (17.5%) were sputum-positive. Fifty (36.2%) coinfected patients had some type of extrapulmonary TB (EPTB); 15 had both pulmonary TB and EPTB. Among the 35 patients with EPTB only, 20 (57.1%) had abdominal TB, 5 (14.3%) had TB adenitis, 5 (14.3%) had spinal TB, 3 (8.6%) were being monitored for tuberculous meningitis, and 1 (2.9%) each had renal TB and tuberculous adrenalitis. The highest prevalence of TB, 13.7% (n = 28), was seen among patients aged 41–50 years. TB coinfection was significantly associated with marital status, WHO clinical stage, and CD4 count. Marital status (OR, 2.1; 95% CI, 1.28–3.59; P = 0.04), WHO clinical stage at presentation (4.81; 1.42–8.34; P = 0.001), and baseline CD4 count (2.71; 1.51–6.21; P = 0.02) remained significant predictors after adjustment for confounding.
Conclusions
The moderately high prevalence of TB among HIV-seropositive patients underscores the urgent need for strategies that lead to rapid identification and treatment of coinfection with active or latent TB.
doi:10.2188/jea.JE20080026
PMCID: PMC3924118  PMID: 19265273
tuberculosis; HIV; coinfection; prevalence; Kano; Nigeria
18.  Cost-effectiveness analysis of PCR for the rapid diagnosis of pulmonary tuberculosis 
Background
Tuberculosis is one of the most prominent health problems in the world, causing 1.75 million deaths each year. Rapid clinical diagnosis is important in patients who have co-morbidities such as Human Immunodeficiency Virus (HIV) infection. Direct microscopy has low sensitivity and culture takes 3 to 6 weeks [1-3]. Therefore, new tools for TB diagnosis are necessary, especially in health settings with a high prevalence of HIV/TB co-infection.
Methods
In a public reference TB/HIV hospital in Brazil, we compared the cost-effectiveness of diagnostic strategies for diagnosis of pulmonary TB: Acid fast bacilli smear microscopy by Ziehl-Neelsen staining (AFB smear) plus culture and AFB smear plus colorimetric test (PCR dot-blot).
From May 2003 to May 2004, sputum was collected consecutively from PTB suspects attending the Parthenon Reference Hospital. Sputum samples were examined by AFB smear, culture, and PCR dot-blot. The gold standard was a positive culture combined with the definition of clinical PTB. Cost analysis included health services and patient costs.
Results
The AFB smear plus PCR dot-blot require the lowest laboratory investment for equipment (US$ 20,000). The total screening costs are 3.8 times for AFB smear plus culture versus for AFB smear plus PCR dot blot costs (US$ 5,635,760 versus US$ 1,498, 660). Costs per correctly diagnosed case were US$ 50,773 and US$ 13,749 for AFB smear plus culture and AFB smear plus PCR dot-blot, respectively. AFB smear plus PCR dot-blot was more cost-effective than AFB smear plus culture, when the cost of treating all correctly diagnosed cases was considered. The cost of returning patients, which are not treated due to a negative result, to the health service, was higher in AFB smear plus culture than for AFB smear plus PCR dot-blot, US$ 374,778,045 and US$ 110,849,055, respectively.
Conclusion
AFB smear associated with PCR dot-blot associated has the potential to be a cost-effective tool in the fight against PTB for patients attended in the TB/HIV reference hospital.
doi:10.1186/1471-2334-9-216
PMCID: PMC2811112  PMID: 20043842
19.  Ultrasound findings in cases of extrapulmonary TB in patients with HIV infection in Jeddah, Saudi Arabia 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/S2222-1808(14)60306-6
PMCID: PMC4027353
HIV; Extra-pulmonary tuberculosis; Ultrasound; Diagnosis
20.  Extrapulmonary and Pulmonary Tuberculosis in Antananarivo (Madagascar): High Clustering Rate in Female Patients 
Journal of Clinical Microbiology  2002;40(11):3964-3969.
Antananarivo, the capital city of Madagascar, has an endemic focus of tuberculosis (TB). We specifically studied patients with extrapulmonary TB (EPTB) and grouped patients according to infected body site. The strains were characterized by IS6110 fingerprinting and compared with those isolated from patients with pulmonary TB (PTB) during the same period in order to determine the possible association between the genotype and the clinical expression of TB. A total of 316 TB patients were included in this study: 151 individuals with EPTB, 10 with both PTB and EPTB, and 155 with PTB alone. Pleural TB was the major EPTB localization (77%) and was found more often in older patients, while PTB or EPTB in which the localization was other than pleural (other EPTB) was found in younger patients. The male-to-female ratio was slightly higher in pleural TB patients (3.06:1) than in patients with other EPTB (1.35:1). There was no significant difference in the BCG status among patients with PTB, pleural TB, and other EPTB. Analysis of IS6110 patterns showed that 167 patients (52.8%) were assigned to 37 clusters of 2 to 34 patients. Analysis of the IS6110 clusters and the IS6110 families did not show any association with a particular clinical expression of the disease. Patients with PTB or other EPTB were more likely to have strains with one IS6110 copy than patients with pleural TB. The clustering rate was found to be significantly higher in female patients (62%) than in male patients (48%) (P = 0.029), suggesting that Malagasy women were more likely to progress to disease after infection than men.
doi:10.1128/JCM.40.11.3964-3969.2002
PMCID: PMC139634  PMID: 12409359
21.  Effectiveness of the Standard WHO Recommended Retreatment Regimen (Category II) for Tuberculosis in Kampala, Uganda: A Prospective Cohort Study 
PLoS Medicine  2011;8(3):e1000427.
Prospective evaluation of the effectiveness of the WHO-recommended standardized retreatment regimen for tuberculosis by Edward Jones-López and colleagues reveals an unacceptable proportion of unsuccessful outcomes.
Background
Each year, 10%–20% of patients with tuberculosis (TB) in low- and middle-income countries present with previously treated TB and are empirically started on a World Health Organization (WHO)-recommended standardized retreatment regimen. The effectiveness of this retreatment regimen has not been systematically evaluated.
Methods and Findings
From July 2003 to January 2007, we enrolled smear-positive, pulmonary TB patients into a prospective cohort to study treatment outcomes and mortality during and after treatment with the standardized retreatment regimen. Median time of follow-up was 21 months (interquartile range 12–33 months). A total of 29/148 (20%) HIV-uninfected and 37/140 (26%) HIV-infected patients had an unsuccessful treatment outcome. In a multiple logistic regression analysis to adjust for confounding, factors associated with an unsuccessful treatment outcome were poor adherence (adjusted odds ratio [aOR] associated with missing half or more of scheduled doses 2.39; 95% confidence interval (CI) 1.10–5.22), HIV infection (2.16; 1.01–4.61), age (aOR for 10-year increase 1.59; 1.13–2.25), and duration of TB symptoms (aOR for 1-month increase 1.12; 1.04–1.20). All patients with multidrug-resistant TB had an unsuccessful treatment outcome. HIV-infected individuals were more likely to die than HIV-uninfected individuals (p<0.0001). Multidrug-resistant TB at enrolment was the only common risk factor for death during follow-up for both HIV-infected (adjusted hazard ratio [aHR] 17.9; 6.0–53.4) and HIV-uninfected (14.7; 4.1–52.2) individuals. Other risk factors for death during follow-up among HIV-infected patients were CD4<50 cells/ml and no antiretroviral treatment (aHR 7.4, compared to patients with CD4≥200; 3.0–18.8) and Karnofsky score <70 (2.1; 1.1–4.1); and among HIV-uninfected patients were poor adherence (missing half or more of doses) (3.5; 1.1–10.6) and duration of TB symptoms (aHR for a 1-month increase 1.9; 1.0–3.5).
Conclusions
The recommended regimen for retreatment TB in Uganda yields an unacceptable proportion of unsuccessful outcomes. There is a need to evaluate new treatment strategies in these patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
One-third of the world's population is currently infected with Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), and 5%–10% of HIV-uninfected individuals will go on to develop disease and become infectious. The risk of progression from infection to disease in HIV infected is much higher. If left untreated, each person with active TB may infect 10 to 15 people every year, reinforcing the public health priority of controlling TB through adequate treatment. Patients with a previous history of TB treatment are a major concern for TB programs throughout the world because these patients are at a much higher risk of harboring a form of TB that is resistant to the drugs most frequently used, resulting in poorer treatment outcomes and significantly complicating current management strategies. More then 1 million people in over 90 countries need to be “re-treated” after failing, interrupting, or relapsing from previous TB treatment.
Every year, 10%–20% of people with TB in low- and middle-income countries are started on a standardized five-drug retreatment regimen as recommended by the World Health Organization (WHO). Yet, unlike treatment regimens for newly diagnosed TB patients, the recommended retreatment regimen (also known as the category II regimen) has never been properly evaluated in randomized clinical trials or prospective cohort studies. Rather, this regimen was recommended by experts before the current situation of widespread drug-resistant TB and HIV infection.
Why Was This Study Done?
WHO surveillance data suggest that the retreatment regimen is successful in about 70% of patients, but retrospective studies that have evaluated the regimen's efficacy showed variable treatment responses with success rates ranging from 26% to 92%. However, these studies have generally only assessed outcomes at the completion of the retreatment regimen, and few have examined the risk of TB recurrence, especially in people who are also infected with HIV and so are more likely to experience TB recurrence—an issue of particular concern in sub-Saharan Africa. Therefore, in this study based in Kampala, Uganda, the researchers conducted a prospective cohort study to assess treatment and survival outcomes in patients previously treated for TB and to identify factors associated with poor outcomes. Given the overwhelming contribution of HIV infection to death, the researchers categorized their survival analysis by HIV status.
What Did the Researchers Do and Find?
The researchers recruited consecutive smear-positive TB patients who were admitted to Mulago Hospital, Kampala, Uganda, for the retreatment of TB with the standard retreatment regimen between July 2003 and January 2007. Eligible patients received daily directly observed therapy and after hospital discharge, were seen every month during their 8-month TB-retreatment course. Home health visitors assessed treatment adherence through treatment card review, monthly pill counts, and patient self-report. After the completion of the retreatment regimen, patients were evaluated for TB recurrence every 3 months for a median of 21 months. The researchers then used a statistical model to identify treatment outcomes and mortality HIV-uninfected and HIV-infected patients.
The researchers found that 29/148 (20%) of HIV-uninfected and 37/140 (26%) of HIV-infected patients had an unsuccessful treatment outcome. Factors associated with an unsuccessful treatment outcome were poor adherence, HIV infection, increasing age, and duration of TB symptoms. All patients with multidrug resistant TB, a form of TB that is resistant to the two most important drugs used to treat TB, had an unsuccessful treatment outcome. In addition, HIV-infected subjects were more likely to die than HIV-uninfected subjects (p<0.0001), and having multidrug resistant TB at enrollment was the only common risk factor for death during follow-up for both HIV-infected and HIV uninfected patients. Other risk factors for death among HIV-infected patients were CD4<50 cells/ml and no antiretroviral therapy treatment and among HIV-uninfected patients were poor adherence and duration of TB symptoms.
What Do These Findings Mean?
The researchers found that although 70%–80% of patients had a successful treatment outcome on completion of antituberculous therapy (a result that compares well with retrospective studies), the standard retreatment regimen had low treatment response rates and was associated with poor long-term outcomes in certain subgroups of patients, particularly those with multidrug resistant TB and HIV.
These findings indicate that the standard retreatment approach to TB as implemented in low- and middle-income settings is inadequate and stress the importance of a new, more effective, strategies. Improved access to rapid diagnostics for TB drug-resistance, second-line TB treatment, and antiretroviral therapy is urgently needed, along with a strong evidence base to guide clinicians and policy makers on how best to use these tools.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000427.
The World Health Organization has information on TB, TB retreatment, and multidrug-resistant TB
WHO also provides information on TB/HIV coinfection
The Stop TB Partnership provides information on the global plan to stop TB
doi:10.1371/journal.pmed.1000427
PMCID: PMC3058098  PMID: 21423586
22.  Childhood and adult tuberculosis in a rural hospital in Southeast Ethiopia: a ten-year retrospective study 
BMC Public Health  2010;10:215.
Background
Many DOTS experiences in developing countries have been reported. However, experience in a rural hospital and information on the differences between children and adults are limited. We described the epidemiology and treatment outcome of adult and childhood tuberculosis (TB) cases, and identified risk factors associated with defaulting and dying during TB treatment in a rural hospital over a 10-year period (1998 to 2007).
Methods
Retrospective data collection using TB registers and treatment cards in a rural private mission hospital. Information was collected on number of cases, type of TB and treatment outcomes using standardised definitions.
Results
2225 patients were registered, 46.3% of whom were children. A total of 646 patients had smear-positive pulmonary TB (PTB), [132 (20.4%) children]; 816 had smear-negative PTB [556 (68.2%) children], and 763 extra-PTB (EPTB) [341 (44.8%) children]. The percentage of treatment defaulters was higher in paediatric (13.9%) than in adult patients (9.3%) (p = 0.001). The default rate declined from 16.8% to 3.5%, and was independently positively associated with TB meningitis (AOR: 2.8; 95% CI: 1.2-6.6) and negatively associated with smear-positive PTB (AOR: 0.6; 95% CI: 0.4-0.8). The mortality rate was 5.3% and the greatest mortality was associated with adult TB (AOR: 1.7; 95% CI: 1.1-2.5), TB meningitis (AOR: 3.6; 95% CI:1.2-10.9), and HIV infection (AOR: 4.3; 95% CI: 1.9-9.4). Decreased mortality was associated with TB lymphadenitis (AOR: 0.24; 95% CI: 0.11-0.57).
Conclusion
(1) The registration of TB cases can be useful to understand the epidemiology of TB in local health facilities. (2) The defaulter and mortality rate of childhood TB is different to that of adult TB. (3) The rate of defaulting from treatment has declined over time.
doi:10.1186/1471-2458-10-215
PMCID: PMC2876992  PMID: 20423494
23.  Mapping the Pattern and Trends of Extrapulmonary Tuberculosis 
Background and Objectives:
There has been a rapid expansion of the directly observed treatment short-term (DOTS) under the revised national tuberculosis control program throughout India in the last decade. Few reports exist detailing individual DOTS centers’ experiences with regard to extrapulmonary tuberculosis (EPTB) in a medical college hospital setting.
Materials and Methods:
This is a retrospective, record-based study of patients with the diagnosis of EPTB, in all age groups. Data on all consecutive EPTB cases diagnosed at the K. S. Hegde Medical College and Hospital, Deralakatte, Mangalore from 1 January 2005 to 31 December 2011 at the DOTS centre attached to this hospital were collected, analyzed by Mantel-Haenszel Chi square for linear trend and described in proportion or percentages.
Results:
Among 1267 cases registered for treatment of all forms of tuberculosis, 528 (41.67%) had EPTB. Around half of the cases of EPTB (269, 51%) were among adult age groups and the majority of cases (342, 64.77%) received Category-I treatment. Pleural TB was the commonest type of EPTB (n = 148, 28.03%), followed by lymph node TB (n = 131, 24.81%). Involvement of lymph nodes was the commonest manifestation among the less than 14 years’ age group (27, 58.7%), while involvement of pleura was more common among > 65 years’ age group (23, 45.1%). The difference in the occurrence of EPTB by site between males and females is statistically significant with a P value of <0.005. There is a significant increase in the number of cases of tuberculosis affecting bones and joints, and other forms of tuberculosis over the years.
Conclusion:
The burden of EPTB is more among the productive age group. Increase in the trend of bone and joint tuberculosis, and other rare forms of EPTB is a point of concern highlighting the importance of strengthening the services towards this group.
doi:10.4103/0974-777X.112277
PMCID: PMC3703211  PMID: 23853432
Directly observed treatment short-course; Extrapulmonary tuberculosis; India; Revised national tuberculosis control program
24.  Epidemiology of extrapulmonary tuberculosis in Brazil: a hierarchical model 
Background
Although extrapulmonary tuberculosis (EPTB) is less frequent than Pulmonary Tuberculosis (PTB) and is a secondary target for national TB control programs, its significance has increased worldwide during the HIV epidemic. The objective of this study was to examine the epidemiology of EPTB in Brazil between 2007 and 2011.
Methods
Cross-sectional study involving all cases of TB reported to the Brazilian Notifiable Diseases Surveillance System (Sistema de Informações de Agravo de Notificação - SINAN) in Brazil between 2007 and 2011. Sociodemographic and clinical characteristics of patients with exclusively PTB and exclusively EPTB were compared. Following analysis with Pearson’s chi-square test, variables with p < 0.05 were included in a hierarchical regression model. Variables with p < 0.05 in the corresponding level were kept in the model.
Results
A total of 427,548 cases of TB were included. Of these, 356,342 cases (83.35%; 95% confidence interval (CI) 83.23% - 83.45%) were PTB, 57,217 (13.37%; 95% CI 13.28% - 13.48%) were EPTB, 13,989 (3.27%; 95% CI 3.21% - 3.32%) were concurrent pulmonary and extrapulmonary TB. Patients with EPTB were mainly white (16.7%), and most (29.1%) patients had five to eight years of education. Among comorbidities, HIV infection was prominent (OR 2.15; 95% CI 2.09 – 2.21), although the proportion of cases awaiting test results or untested was high (39%). Ethanol use (OR 0.45; 95% CI 0.43 – 0.46), diabetes mellitus (OR 0.54; 95% CI 0.51 – 0.57) and mental illness (OR 0.88; 95% CI 0.82 – 0.95) were associated with PTB.
Conclusions
Thirteen percent of patients diagnosed with TB in Brazil have only EPTB. More effective diagnostic strategies and control measures are needed to reduce the number of cases of extrapulmonary TB in Brazil.
doi:10.1186/1471-2334-14-9
PMCID: PMC3893400  PMID: 24400848
25.  Mycobacterial heparin-binding haemagglutinin adhesion-induced interferon & antibody for detection of tuberculosis 
Background & objectives:
Mycobacterial heparin-binding haemagglutinin adhesin (HBHA) plays an important role in humoral and cellular immune response and is a potential diagnostic tool for tuberculosis (TB) serodiagnosis. This study was carried out to assess the usefulness of HBHA in TB clinics for differential diagnosis of pulmonary and extra-pulmonary TB (PTB, EPTB).
Methods:
In this study, 165 outpatients and 133 healthy volunteers were included to investigate the role of HBHA in TB diagnosis including the serodiagnostic tests and the interferon-γ release assays (IGRAs). The healthy volunteers were all without BCG vaccination including 73 subjects with purified protein derivative (PPD) (-) and 60 ones with PPD (+) (that is P-B- and P+B-). Of all the 165 outpatients 77 were PTB and 88 were EPTB. HBHA protein was used for serodiagnostic tests and IGRAs in peripheral blood mononuclear cells.
Results:
HBHA-specific antibody levels in the serum of healthy subjects were significantly different from the patients with PTB or EPTB (P<0.05). HBHA specific antibody levels in PTB patients could differentiate from EPTB with limited sensitivity (77.08%; 95%CI, 62.69 to 87.97%) and specificity (87.50%; 95%CI, 74.75 to 95.27%). IFN-γ levels in the healthy (P+B- and P-B-) groups were significantly different (P<0.01) with a detection sensitivity of 84.8% (95%CI, 68.54 to 93.02%) and specificity of 80.7% (95%CI, 65.22 to 92.62%). The PTB and EPTB subjects showed no difference in IFN-γ production.
Interpretation & conclusions:
HBHA serodiagnostic test with IGRAs had the limited potential for use as auxiliary tools for the differential diagnosis of PTB and EPTB, since both methods showed low sensitivity and specificity.
PMCID: PMC3103176  PMID: 21537096
Binding haemagglutinin; differential diagnosis; heparin; interferon-γ level; serodiagnostic test; tuberculosis

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