Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

The intrinsic transmission dynamics of tuberculosis epidemics.

In developed countries the major tuberculosis epidemics declined long before the disease became curable in the 1940s. We present a theoretical framework for assessing the intrinsic transmission dynamics of tuberculosis. We demonstrate that it takes one to several hundred years for a tuberculosis epidemic to rise, fall and reach a stable endemic level. Our results suggest that some of the decline of tuberculosis is simply due to the natural behaviour of an epidemic. Although other factors must also have contributed to the decline, these causal factors were constrained to operate within the slow response time dictated by the intrinsic dynamics.

Does bleach processing increase the accuracy of sputum smear microscopy for diagnosing pulmonary tuberculosis?

Bleach digestion of sputum prior to smear preparation has been reported to increase the yield of microscopy for diagnosing pulmonary tuberculosis, even in high-HIV-prevalence settings. To determine the diagnostic accuracy of bleach microscopy, we updated a systematic review published in 2006 and applied the Grading of Recommendations Assessment, Development, and Evaluation framework to rate the overall quality of the evidence. We searched multiple databases (as of January 2009) for primary studies in all languages comparing bleach and direct microscopy. We assessed study quality using a validated tool and heterogeneity by standard methods. We used hierarchical summary receiver operating characteristic (HSROC) analysis to calculate summary estimates of diagnostic accuracy and random-effects meta-analysis to pool sensitivity and specificity differences. Of 14 studies (11 papers) included, 9 evaluated bleach centrifugation and 5 evaluated bleach sedimentation. Overall, examination of bleach-processed versus direct smears led to small increases in sensitivity (for bleach centrifugation, 6% [95% confidence interval [CI] = 3 to 10%, P = 0.001]; for bleach sedimentation, 9% [95% CI = 4 to 14%, P = 0.001]) and small decreases in specificity (for bleach centrifugation, -3% [95% CI = -4% to -1%, P = 0.004]; for bleach sedimentation, -2% [95% CI = -5% to 0%, P = 0.05]). Similarly, analysis of HSROC curves suggested little or no improvement in diagnostic accuracy. The quality of evidence was rated very low for both bleach centrifugation and bleach sedimentation. This updated systematic review suggests that the benefits of bleach processing are less than those described previously. Further research should focus on alternative approaches to optimizing smear microscopy, such as light-emitting diode fluorescence microscopy and same-day sputum collection strategies.

Control strategies for tuberculosis epidemics: new models for old problems.

Tuberculosis, although preventable and curable, causes more adult deaths than any other infectious disease. A theoretical framework for designing effective control strategies is developed and used to determine treatment levels for eradication, to assess the effects of noneradicating control, and to examine the global goals of the World Health Organization. The theory is extended to assess how suboptimal control programs contribute to the evolution of drug resistance. A new evaluation criterion is defined and used to suggest how control strategies can be improved. In order to control tuberculosis, treatment failure rates must be lower in developing countries than in developed countries.

T-cell assay conversions and reversions among household contacts of tuberculosis patients in rural India.

BACKGROUND: Interferon-gamma assays (IGRAs) are alternatives to the tuberculin skin test (TST), but IGRA conversions and reversions are not well understood. In a pilot study, we determined conversions and reversions using QuantiFERON-TB Gold In-Tube((R)) (QFT) among household contacts of TB cases, and evaluated the effect of using various definitions and criteria for conversions. DESIGN: In a cohort of 250 contacts in India, 46% were TST-positive at baseline and 54% were QFT-positive. We re-tested this cohort after 12 months. Conversion rates were estimated using several definitions. RESULTS: Of the 250 contacts, 205 (82%) underwent repeat testing. Among 85 contacts with baseline TST-negative/QFT-negative results, TST conversion rates ranged between 7.5% and 13.8%, and QFT conversion rates ranged between 11.8% and 21.2%, depending on the definitions used. Among 109 contacts who were QFT-positive at baseline, seven (6.4%) had QFT reversions. QFT reversions were most likely when the baseline TST was negative and QFT results were just above the diagnostic cut-off. CONCLUSIONS: QFT conversions and reversions occurred among contacts of TB cases. Conversion rates seemed to vary, depending on the test and definitions used for conversions. These findings need to be verified in larger studies in various settings.

Magnitude of Mycobacterium tuberculosis transmission among household and non-household contacts of TB patients.

The household and non-household contacts of patients with tuberculosis (TB) face varying degrees of risk of infection by Mycobacterium tuberculosis. To quantify new infection and to determine the risk factors associated with new infection among named contacts in San Francisco, CA, USA. We performed a cohort study in patients with culture-positive pulmonary TB. We analyzed patient, contact, environmental and bacterial characteristics. Of the 2422 contacts named by 256 patients, 149 (6.2%) had new infection due to recent transmission from 79 (30.9%) patients. Of the 149 new infections, 87 (58.4%) occurred among household contacts and 62 (41.6%) among non-household contacts. Numerous acid-fast bacilli in sputum (odds ratio [OR] 2.64, 95%CI 1.32-5.25) and contacts being named by more than one patient (OR 2.90, 95%CI 1.23-6.85) were associated with new infection among household contacts. Being older than 50 years (OR 1.93, 95%CI 1.09-3.41) and an Asian/Pacific Islander (OR 3.09, 95%CI 1.50-6.37) were associated with new infection among non-household contacts. Fewer than one third of patients caused new infection to his/her contacts. A substantial proportion of transmission resulting in new infection occurred outside of the household. The risk factors for infection among household and non-household contacts are different and should be considered when prioritizing control interventions. .

Interplay of strain and race/ethnicity in the innate immune response to M. tuberculosis.

BACKGROUND: The roles of host and pathogen factors in determining innate immune responses to M. tuberculosis are not fully understood. In this study, we examined host macrophage immune responses of 3 race/ethnic groups to 3 genetically and geographically diverse M. tuberculosis lineages. METHODS: Monocyte-derived macrophages from healthy Filipinos, Chinese and non-Hispanic White study participants (approximately 45 individuals/group) were challenged with M. tuberculosis whole cell lysates of clinical strains Beijing HN878 (lineage 2), Manila T31 (lineage 1), CDC1551 (lineage 4), the reference strain H37Rv (lineage 4), as well as with Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA) and TLR4 agonist lipopolysaccharide (TLR4/LPS). Following overnight incubation, multiplex assays for nine cytokines: IL-1ß, IL-2, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα, and GM-CSF, were batch applied to supernatants. RESULTS: Filipino macrophages produced less IL-1, IL-6, and more IL-8, compared to macrophages from Chinese and Whites. Race/ethnicity had only subtle effects or no impact on the levels of IL-10, IL-12p70, TNFα and GM-CSF. In response to the Toll-like receptor 2 agonist lipoteichoic acid (TLR2/LTA), Filipino macrophages again had lower IL-1 and IL-6 responses and a higher IL-8 response, compared to Chinese and Whites. The TLR2/LTA-stimulated Filipino macrophages also produced lower amounts of IL-10, TNFα and GM-CSF. Race/ethnicity had no impact on IL-12p70 levels released in response to TLR2/LTA. The responses to TLR4 agonist lipopolysaccharide (TLR4/LPS) were similar to the TLR2/LTA responses, for IL-1, IL-6, IL-8, and IL-10. However, TLR4/LPS triggered the release of less IL-12p70 from Filipino macrophages, and less TNFα from White macrophages. CONCLUSIONS: Both host race/ethnicity and pathogen strain influence the innate immune response. Such variation may have implications for the development of new tools across TB therapeutics, immunodiagnostics and vaccines.

Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review.

Current international tuberculosis (TB) guidelines recommend the microscopic examination of three sputum specimens for acid-fast bacilli in the evaluation of persons suspected of having pulmonary TB. We conducted a systematic review of studies that quantified the diagnostic yield of each of three sputum specimens. By searching multiple databases and sources, we identified a total of 37 eligible studies. The incremental yield in smear-positive results (in studies using all smear-positive cases as the denominator) and the increase in sensitivity (in studies that used all culture-positive cases as the denominator) of the third specimen were the main outcomes of interest. Although heterogeneity in study methods and results presented challenges for data synthesis, subgroup analyses suggest that the average incremental yield and/or the increase in sensitivity of examining a third specimen ranged between 2% and 5%. Reducing the recommended number of specimens examined from three to two (particularly to two specimens collected on the same day) could benefit TB control programs, and potentially increase case detection for several reasons. A number of operational research issues need to be addressed. Studies examining the most effective and efficient means to utilize current technologies for microscopic examination of sputum would be most useful if they followed an internationally coordinated and standardized approach, both to strengthen the country-specific evidence base and to permit comparison among studies.

'It makes the patient's spirit weaker': tuberculosis stigma and gender interaction in Dar es Salaam, Tanzania.

SETTING: Dar es Salaam, Tanzania. OBJECTIVES: To describe tuberculosis (TB) related stigma and to understand how it interacts with gender to affect access to care. DESIGN: Eight focus group discussions were held among 48 TB patients and their household members, and a thematic content analysis was carried out. RESULTS: The main components of stigma were fear, self-isolation, ostracization, loss of status in the community, and discrimination by providers. Participants described the cultural context in which stigma operated as characterized by a general lack of health knowledge, cultural beliefs about TB, and engendered beliefs about disease in general. Both genders described some similar effects of stigma, including relationship difficulties and specifically challenges forming new relationships, but many effects of stigma were distinct by gender: women described challenges including assumptions about promiscuity and infidelity, as well as rejection by partners, while men described survival challenges. Stigma acted as a barrier to care through a cyclical pattern of stigma and fear, leading to health-seeking delays, with resulting continued transmission and poor health outcomes that further reinforced stigma. CONCLUSION: TB-related stigma is prevalent in this setting and operates differently for men and women. Interventions designed to increase case detection must address stigma and its interaction with gender.

Impact of Euro-American sublineages of Mycobacterium tuberculosis on new infections among named contacts.

BACKGROUND: The impact of demographic, clinical, and bacterial factors on new infection by Euro-American lineage Mycobacterium tuberculosis among contacts of patients with tuberculosis (TB) has not been evaluated. OBJECTIVE: To describe the risk factors for new infection by Euro-American M. tuberculosis sublineages in San Francisco, California. DESIGN: We included contacts of patients with TB due to Euro-American M. tuberculosis. Sublineages were determined by large-sequence polymorphisms. We used tuberculin skin testing or QuantiFERON®-TB Gold In-Tube to identify contacts with new infection. Regression models with generalized estimating equations were used to determine the risk factors for new infection. RESULTS: We included 1488 contacts from 134 patients with TB. There were 79 (5.3%) contacts with new infection. In adjusted analyses, contacts of patients with TB due to region of difference 219 M. tuberculosis sublineage were less likely to have new infection (OR 0.23, 95%CI 0.06-0.84) than those with other sublineages. Other risk factors for new infection were contacts exposed to more than one patient with TB, contacts exposed for 30 days, or contacts with a history of smoking or excessive alcohol consumption. CONCLUSIONS: In addition to well-known exposure and clinical characteristics, bacterial characteristics independently contribute to the transmissibility of TB in San Francisco.

Clinical and bacteriological characteristics associated with clustering of multidrug-resistant tuberculosis.

SETTING: The impact of the genetic characteristics of Mycobacterium tuberculosis on the clustering of multidrug-resistant tuberculosis (MDR-TB) has not been analyzed together with clinical and demographic characteristics. OBJECTIVE: To determine factors associated with genotypic clustering of MDR-TB in a community-based study. DESIGN: We measured the proportion of clustered cases among MDR-TB patients and determined the impact of clinical and demographic characteristics and that of three M. tuberculosis genetic characteristics: lineage, drug resistance-associated mutations, and rpoA and rpoC compensatory mutations. RESULTS: Of 174 patients from California and Texas included in the study, the number infected by East-Asian, Euro-American, Indo-Oceanic and East-African-Indian M. tuberculosis lineages were respectively 70 (40.2%), 69 (39.7%), 33 (19.0%) and 2 (1.1%). The most common mutations associated with isoniazid and rifampin resistance were respectively katG S315T and rpoB S531L. Potential compensatory mutations in rpoA and rpoC were found in 35 isolates (20.1%). Hispanic ethnicity (OR 26.50, 95%CI 3.73-386.80), infection with an East-Asian M. tuberculosis lineage (OR 30.00, 95%CI 4.20-462.40) and rpoB mutation S531L (OR 4.03, 95%CI 1.05-23.10) were independent factors associated with genotypic clustering. CONCLUSION: Among the bacterial factors studied, East-Asian lineage and rpoB S531L mutation were independently associated with genotypic clustering, suggesting that bacterial factors have an impact on the ability of M. tuberculosis to cause secondary cases.

A 13-year molecular epidemiological analysis of tuberculosis in San Francisco.

BACKGROUND: We examined the molecular epidemiology of tuberculosis (TB) in San Francisco during a 13-year period encompassing the peak of TB resurgence and subsequent decline to historic low levels. OBJECTIVE: To compare rates of TB caused either by rapid progression of recent Mycobacterium tuberculosis infection or by reactivation of latent infection. METHODS: All TB cases reported from 1991 to 2003 were included. Genotyping was performed to identify clustered cases. RESULTS: The annual TB case rate decreased significantly from 50.8 to 28.8 cases/100000 persons from 1992 to 1999 (P < 0.0001). After 1999, no significant decrease was observed for the population as a whole or in any subgroup examined. Similarly, the rate of clustered cases decreased significantly from 1992 to 1999 (11.4 to 3.1 cases/100000, P < 0.0001). Although the rate of non-clustered cases also declined significantly (25.6 to 17.6 cases/100,000, P < 0.0001), there was a disproportionate reduction in clustered cases (94.7% vs. 50.8%, P < 0.0001). Neither clustered nor non-clustered cases decreased significantly after 1999. CONCLUSIONS: TB case rates reached a plateau despite ongoing application of control measures implemented in 1993. These data suggest that intensification of measures designed to identify and treat persons with latent TB infection will be necessary to further reduce TB incidence.

Xpert(®) MTB/RIF detection of rifampin resistance and time to treatment initiation in Harare, Zimbabwe.

BACKGROUND: Patients at elevated risk of drug-resistant tuberculosis (TB) are prioritized for Xpert(®) MTB/RIF testing; however, the clinical usefulness of the test in this population is understudied. DESIGN: From November 2011 to June 2014, consecutive out-patients with a history of previous TB in high-density suburbs of Harare, Zimbabwe, were tested using Xpert, solid and liquid culture, and the microscopic observation drug susceptibility assay. Diagnostic accuracy for rifampin (RMP) resistance and time to initiation of second-line regimens were ascertained. The rpoB gene was sequenced in cases with culture-confirmed RMP resistance and genotypic susceptibility. RESULTS: Among 352 retreatment patients, 71 (20%) were RMP-resistant, 98 (28%) RMP-susceptible, 64 (18%) culture-negative/Xpert-positive, and 119 (34%) culture-negative/Xpert-negative. Xpert had a sensitivity of 86% (95%CI 75-93) and a specificity of 98% (95%CI 92-100) for RMP-resistant TB. The positive predictive value of Xpert-determined RMP resistance for multidrug-resistant TB (MDR-TB) was 82% (95%CI 70-91). Of 71 (83%) participants, 59 initiated treatment with second-line drugs, with a median time to treatment initiation of 18 days (IQR 10-44). CONCLUSION: The diagnostic accuracy of Xpert for RMP resistance is high, although the predictive value for MDR-TB was lower than anticipated. Xpert allows for faster initiation of second-line treatment than culture-based drug susceptibility testing under programmatic conditions.

Treatment of non-cavitary pulmonary tuberculosis with shortened fluoroquinolone-based regimens: a meta-analysis.

SETTING: Several recent trials evaluating 4-month fluoroquinolone (FQ) containing regimens found that none of the experimental regimens were non-inferior to standard 6-month therapy in treating patients with drug-susceptible pulmonary tuberculosis (PTB). OBJECTIVE: To answer whether FQ-containing duration-shortened regimens are non-inferior to standard therapy in the treatment of patients with non-cavitary PTB. DESIGN: Systematic review of all randomized and quasi-randomized trials that substituted an FQ into standard therapy for less than 6 months' duration to treat drug-susceptible, non-cavitary PTB. Non-inferiority was based on a 6% margin of difference. RESULTS: Of 4594 total participants in the three trials that met the inclusion criteria, 1066 patients had non-cavitary disease. The pooled difference in unfavorable outcomes was 5% (95%CI -3 to 13) in patients with non-cavitary disease treated with FQ-containing regimens vs. standard therapy. In subgroup analyses, the pooled difference in unfavorable outcomes was 1% (95%CI -3 to 5) when comparing the daily form of intervention regimen with standard therapy, and -1% (95%CI -5 to 4) between regimens replacing ethambutol (EMB) with an FQ and standard therapy. No difference in risk of adverse events was noted. CONCLUSION: Daily administered 4-month regimens with substitution of EMB by an FQ may be non-inferior to standard therapy in patients with culture-confirmed, non-cavitary, drug-susceptible PTB.

Factors Associated with Prevalent Tuberculosis Among Patients Receiving Highly Active Antiretroviral Therapy in a Nigerian Tertiary Hospital.

BACKGROUND: Tuberculosis (TB) causes significant morbidity/mortality among human immunodeficiency virus-infected individuals in Africa. Reducing TB burden in the era of highly active antiretroviral therapy (HAART) is a public health priority. AIM: We determined the factors associated with prevalent TB among patients receiving HAART. SUBJECTS AND METHODS: We conducted a cross-sectional study of adult patients who had received HAART for ≥12 weeks in a Nigerian tertiary hospital. Patients whose TB diagnosis predated HAART were excluded from the study. Pre-HAART data were collected from the clinic records, whereas post-HAART data were obtained through medical history, physical examination, and laboratory investigations. Standard TB screening/diagnostic algorithms as applicable in Nigeria were used. Logistic regression analysis was used to determine factors independently associated with prevalent TB. RESULTS: about 65.8% (222/339) were women. The mean age was 41.1 (10.0) years and 23.6% (73/339) had past history of TB. The prevalence of active TB was 7.7% (26/339). Among these patients, 42.3% (11/26) had pulmonary TB, 34.6% (9/26) had disseminated TB, whereas 23.1% (6/26) had only extra-pulmonary disease. Only 45% (9/20) of patients with pulmonary involvement had positive sputum smear. Factors independently associated with prevalent TB were lower social class (adjusted odds ratio [aOR]: 31.7; 95% confidence interval [CI]: 1.1-1417.3), HAART non-adherence (aOR125.5; 95% CI: 9.6-1636.3), baseline CD4 <200cells/µl (aOR31.0; 95%CI: 1.6-590.6), previous TB (aOR13.8; 95% CI: 2.0-94.1), and current hemoglobin <10 g/dl (aOR10.3; 95% CI: 1.1-99.2). CONCLUSION: Factors associated with prevalent TB were a lower social class, HAART non-adherence, severe immunosuppression before HAART initiation, previous TB, and anemia post-HAART. TB case finding should be intensified in these high-risk groups.

Attitudes of medical residents regarding intensive care for patients with the acquired immunodeficiency syndrome.

We recently surveyed the medical house staff at the University of California, San Francisco, and found that residents had a good understanding of the poor prognosis of patients with the acquired immunodeficiency syndrome (AIDS) and Pneumocystis carinii pneumonia who require intensive care for respiratory failure, and tended to favor early discussions with patients regarding resuscitation and intensive care. We used the same questionnaire to survey the house staffs of four other programs varying in geography and exposure to patients with AIDS. We found a striking correlation between the number of patients with AIDS cared for by the residents, the assessment of the prognosis of patients with AIDS with P carinii pneumonia, and house-staff attitudes toward discussions about resuscitation and intensive care. The results of this study suggest that the intensity of exposure to patients with AIDS determines the assessment of prognosis, and that one or both of these factors strongly influences attitudes toward intensive care. Regardless of these attitudes, early discussion of resuscitation and intensive care between physicians and patients with AIDS and P carinii pneumonia seems warranted.

Coexistent lymphoid interstitial pneumonia, pernicious anemia, and agammaglobulinemia.

Immunologic factors have been incriminated in the pathogenesis of lymphoid interstitial pneumonia. The discovery of a patient with coexistent lymphoid interestitial pneumonia, pernicious anemia, and common variable hypogammaglobulinemia focused attention on the possible autoimmune nature of this pulmonary disease. Extensive immunologic studies demonstrated a noticeably impaired bonemarrow-dependent (B cell) system and intact thymus-dependent (T cell) system. No evidence of humoral or cellular hypersensitivity to homologous lung determinants was found.

Toxoplasma gondii pneumonitis in patients infected with the human immunodeficiency virus.

Pulmonary toxoplasmosis is a rarely recognized opportunistic infection in immunocompromised patients. A few case reports have described pulmonary toxoplasmosis in human immunodeficiency virus-infected patients in association with Toxoplasma gondii central nervous system disease. We encountered six cases of pulmonary toxoplasmosis in human immunodeficiency virus-infected patients who presented with a protracted febrile illness, respiratory symptoms, and an abnormal chest roentgenogram in the absence of neurologic findings. No clinical or roentgenographic features distinguished T gondii pneumonitis from more common opportunistic pulmonary infections. As the acquired immunodeficiency syndrome epidemic progresses, the presenting illnesses have evolved. Toxoplasma gondii must be considered a potential cause of pulmonary disease during the evaluation of human immunodeficiency virus-infected patients with respiratory symptoms.