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1.  Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients 
Ahuja, Shama D. | Ashkin, David | Avendano, Monika | Banerjee, Rita | Bauer, Melissa | Bayona, Jamie N. | Becerra, Mercedes C. | Benedetti, Andrea | Burgos, Marcos | Centis, Rosella | Chan, Eward D. | Chiang, Chen-Yuan | Cox, Helen | D'Ambrosio, Lia | DeRiemer, Kathy | Dung, Nguyen Huy | Enarson, Donald | Falzon, Dennis | Flanagan, Katherine | Flood, Jennifer | Garcia-Garcia, Maria L. | Gandhi, Neel | Granich, Reuben M. | Hollm-Delgado, Maria G. | Holtz, Timothy H. | Iseman, Michael D. | Jarlsberg, Leah G. | Keshavjee, Salmaan | Kim, Hye-Ryoun | Koh, Won-Jung | Lancaster, Joey | Lange, Christophe | de Lange, Wiel C. M. | Leimane, Vaira | Leung, Chi Chiu | Li, Jiehui | Menzies, Dick | Migliori, Giovanni B. | Mishustin, Sergey P. | Mitnick, Carole D. | Narita, Masa | O'Riordan, Philly | Pai, Madhukar | Palmero, Domingo | Park, Seung-kyu | Pasvol, Geoffrey | Peña, Jose | Pérez-Guzmán, Carlos | Quelapio, Maria I. D. | Ponce-de-Leon, Alfredo | Riekstina, Vija | Robert, Jerome | Royce, Sarah | Schaaf, H. Simon | Seung, Kwonjune J. | Shah, Lena | Shim, Tae Sun | Shin, Sonya S. | Shiraishi, Yuji | Sifuentes-Osornio, José | Sotgiu, Giovanni | Strand, Matthew J. | Tabarsi, Payam | Tupasi, Thelma E. | van Altena, Robert | Van der Walt, Martie | Van der Werf, Tjip S. | Vargas, Mario H. | Viiklepp, Pirett | Westenhouse, Janice | Yew, Wing Wai | Yim, Jae-Joon
PLoS Medicine  2012;9(8):e1001300.
Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.
Background
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Methods and Findings
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1–6.0]), ofloxacin (aOR: 2.5 [1.6–3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3–2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7–4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7–4.3]), ofloxacin (aOR: 2.3 [1.3–3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4–2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9–3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4–6.0]).
Conclusions
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2010, 8.8 million people developed tuberculosis—a contagious bacterial infection—and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs.
Why Was This Study Done?
Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called “individual patient data meta-analysis.” In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB.
What Did the Researchers Do and Find?
The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1–8.5 months and with the total duration of treatment up to 18.6–21.5 months.
What Do These Findings Mean?
These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300.
The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available
The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB
The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour
MedlinePlus has links to further information about tuberculosis (in English and Spanish)
TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB
The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis
doi:10.1371/journal.pmed.1001300
PMCID: PMC3429397  PMID: 22952439
2.  Association between Diabetes Mellitus and Tuberculosis in United States-Born and Foreign-Born Populations in San Francisco 
PLoS ONE  2014;9(12):e114442.
Setting
The impact of diabetes on tuberculosis in United States and foreign-born populations in San Francisco has not been studied.
Objective
To determine the characteristics, prevalence and temporal trends of diabetes in US and foreign-born persons attending the San Francisco Tuberculosis Clinic.
Design
We analyzed data from individuals seeking medical attention at the San Francisco Tuberculosis Clinic. We included patients with diagnosis of tuberculosis, latent infection, or not infected with Mycobacterium tuberculosis. We assessed the temporal trend and the characteristics of individuals with and without diabetes.
Result
Between 2005 and 2012, there were 4371 (19.0%) individuals without evidence of tuberculosis infection, 17,856 (77.6%) with latent tuberculosis, and 791 (3.4%) with tuberculosis. 66% were born in the United States, China, Mexico, and the Philippines. The prevalence of diabetes was the highest among individuals with tuberculosis and increased during the study period. Patients with tuberculosis and diabetes were more likely to be male, older than 45 years and born in the Philippines. There was a disproportionate association of TB and DM relative to LTBI and DM among Filipinos in individuals older than 45 years old.
Conclusions
Our data suggest that Filipinos older than 45 years old are more likely to have tuberculosis probably due to a higher prevalence of diabetes. In San Francisco, tuberculosis-screening programs in individuals with diabetes and latent tuberculosis may be beneficial in patients older than 45 years old especially from the Philippines.
doi:10.1371/journal.pone.0114442
PMCID: PMC4257695  PMID: 25478954
3.  Childhood Tuberculosis in Northern Viet Nam: A Review of 103 Cases 
PLoS ONE  2014;9(5):e97267.
Background
Childhood tuberculosis causes significant morbidity and mortality in Southeast Asia, yet little is known about the epidemiology and clinical characteristics of this disease in Viet Nam.
Objectives
To determine the demographics, clinical presentations, radiographic and microbiologic findings, treatment regimens, and outcomes of children admitted with tuberculosis (TB) to a national referral hospital in Viet Nam.
Methods
We conducted a retrospective case series study of children ≤ 15 years old with bacteriologically confirmed or clinically diagnosed TB admitted to a national referral hospital in Ha Noi, Viet Nam from January through December 2007.
Results
One hundred three children were identified: median age 5 years (IQR 2-10), 44% female, 99% Kinh ethnicity, 27% residing in Ha Noi, 88% with BCG vaccination, 27% with known TB contact, and 38% malnourished. Intrathoracic TB was present in 62%, extrathoracic in 52%, both intra and extrathoracic in 19%, and undetermined site in 5%. The most common extrathoracic manifestation was peripheral lymphadenitis, and children under 5 were more likely to have miliary TB or both intra and extrathoracic TB. Fever and failure to thrive were common presenting symptoms among all participants (65% and 56%, respectively), 66% of those with intrathoracic TB presented with cough, and 92% of those with TB meningitis presented with severe neurologic impairment. Acid-fast bacilli smears and mycobacterial cultures were positive in 18% and 21% of children tested, and histopathology was positive in 88% of those biopsied. There were no adverse drug reactions necessitating change in therapy, and no inpatient mortality.
Conclusions
Extrathoracic TB was common, treatment well tolerated and clinical outcomes excellent. Culture confirmation rates were low and emphasize the need for improved diagnostics.
doi:10.1371/journal.pone.0097267
PMCID: PMC4018290  PMID: 24818967
4.  Dihydropteroate Synthase Mutations in Pneumocystis Pneumonia: Impact of Applying Different Definitions of Prophylaxis, Mortality Endpoints and Mutant in a Single Cohort 
Medical mycology  2013;51(6):568-575.
Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations are well-reported. Although sulfa prophylaxis generally is associated with DHPS mutant infection, whether mutant infection is associated with poorer clinical outcomes is less clear. The differing definitions of sulfa prophylaxis and the different mortality endpoints used in these studies may be one explanation for the conflicting study results. Applying different definitions of prophylaxis, mortality endpoints and DHPS mutant to 301 HIV-infected patients with Pneumocystis pneumonia, we demonstrate that prophylaxis, irrespective of definition, increased the risk of infection with pure mutant (any prophylaxis: AOR 4.00, 95% CI: 1.83–8.76, p<0.001) but not mixed genotypes (any prophylaxis: AOR 0.78, 95% CI: 0.26–2.36, p=0.65). However, infection with mutant DHPS, irrespective of definition, was not associated with increased mortality (all-cause or PCP death) at the three time-intervals examined (all p>0.05). Future studies should standardize key variables associated with DHPS mutant infection as well as examine DHPS mutant subtypes (pure mutant vs. mixed infections) – perhaps even individual DHPS mutant genotypes – so that data can be pooled to better address this issue.
doi:10.3109/13693786.2013.770604
PMCID: PMC4008324  PMID: 23470037
Pneumocystis jirovecii; PCP; dihydropteroate synthase; DHPS; DHPS mutant
5.  Molecular Epidemiology of Tuberculosis in Foreign-Born Persons Living in San Francisco 
Rationale: In San Francisco, 70% of the tuberculosis cases occur among foreign-born persons, mainly from China, the Philippines, and Mexico. We postulate that there are differences in the characteristics and risk factors for tuberculosis among these populations.
Objectives: To determine the clinical, epidemiological and microbiological characteristics of tuberculosis caused by recent infection and rapid evolution in the major groups of foreign-born and the U.S.-born populations.
Methods: We analyzed data from a 20-year prospective community-based study of the molecular epidemiology of tuberculosis in San Francisco. We included all culture-positive tuberculosis cases in the City during the study period.
Measurements and Main Results: We calculated and compared incidence rates, clinical and microbiological characteristics, and risk factors for being a secondary case between the various foreign-born and U.S.-born tuberculosis populations. Between 1991 and 2010, there were 4,058 new cases of tuberculosis, of which 1,226 (30%) were U.S.-born and 2,832 (70%) were foreign-born. A total of 3,278 (81%) were culture positive, of which 2,419 (74%) had complete data for analysis. The incidence rate, including the incidence rate of tuberculosis due to recent infection and rapid evolution, decreased significantly in the U.S.-born and the major foreign-born populations. The clinical and microbiological characteristics and the risk factors for tuberculosis due to recent infection differed among the groups.
Conclusions: There are differences in the characteristics and the risk factors for tuberculosis due to recent transmission among the major foreign-born and U.S.-born populations in San Francisco. These differences should be considered for the design of targeted tuberculosis control interventions.
doi:10.1164/rccm.201212-2239OC
PMCID: PMC3707362  PMID: 23471470
tuberculosis; foreign-born populations; epidemiology; Mycobacterium tuberculosis
6.  Pyrazinamide Resistance, Mycobacterium tuberculosis Lineage and Treatment Outcomes in San Francisco, California 
PLoS ONE  2014;9(4):e95645.
Background
Pyrazinamide (PZA) is a first line agent for the treatment of active tuberculosis. PZA is also considered a potent companion drug for newer regimens under development. There are limited data on the demographic, clinical, and pathogen characteristics of PZA resistant tuberculosis.
Methods
Using a retrospective cohort study design, we evaluated all PZA resistant M. tuberculosis (M.tb) and M. bovis cases reported in San Francisco from 1991 to 2011. Demographic, clinical, and molecular data were analyzed. M.tb lineage was determined for all PZA resistant strains and compared to PZA susceptible strains.
Results
PZA resistance was identified in 1.8% (50 of 2,842) of mycobacterial isolates tested, corresponding to a case rate of 0.3 per 100,000 in the population. Monoresistant PZA infection was associated with the Hispanic population ([OR], 6.3; 95% [CI], 1.97–20.16) and 48% of cases were due to M. bovis. Infection with monoresistant PZA was also associated with extrapulmonary disease ([OR], 6.0; 95% [CI], 2.70–13.26). There was no statistically significant difference between treatment failure and mortality rates in patients infected with PZA monoresistance compared to pansusceptible controls (4% vs. 8%, p = 0.51), or those with PZA and MDR resistance (PZA-MDR) compared to MDR controls (18% vs. 29%, p = 0.40). PZA resistance was not associated with M.tb lineage.
Conclusions
Across two decades of comprehensive epidemiologic data on tuberculosis in San Francisco County, PZA resistance was uncommon. PZA resistance caused predominantly extrapulmonary disease and was more common in Hispanics compared to other ethnicities, with nearly half the cases attributed to M. bovis. No association was found between PZA monoresistance and M.tb lineage. Treatment outcomes were not adversely influenced by the presence of PZA resistance.
doi:10.1371/journal.pone.0095645
PMCID: PMC3997554  PMID: 24759760
7.  The Lung Microbiome of Ugandan HIV-Infected Pneumonia Patients Is Compositionally and Functionally Distinct from That of San Franciscan Patients 
PLoS ONE  2014;9(4):e95726.
Sub-Saharan Africa represents 69% of the total number of individuals living with HIV infection worldwide and 72% of AIDS deaths globally. Pulmonary infection is a common and frequently fatal complication, though little is known regarding the lower airway microbiome composition of this population. Our objectives were to characterize the lower airway microbiome of Ugandan HIV-infected patients with pneumonia, to determine relationships with demographic, clinical, immunological, and microbiological variables and to compare the composition and predicted metagenome of these communities to a comparable cohort of patients in the US (San Francisco). Bronchoalveolar lavage samples from a cohort of 60 Ugandan HIV-infected patients with acute pneumonia were collected. Amplified 16S ribosomal RNA was profiled and aforementioned relationships examined. Ugandan airway microbiome composition and predicted metagenomic function were compared to US HIV-infected pneumonia patients. Among the most common bacterial pulmonary pathogens, Pseudomonas aeruginosa was most prevalent in the Ugandan cohort. Patients with a richer and more diverse airway microbiome exhibited lower bacterial burden, enrichment of members of the Lachnospiraceae and sulfur-reducing bacteria and reduced expression of TNF-alpha and matrix metalloproteinase-9. Compared to San Franciscan patients, Ugandan airway microbiome was significantly richer, and compositionally distinct with predicted metagenomes that encoded a multitude of distinct pathogenic pathways e.g secretion systems. Ugandan pneumonia-associated airway microbiome is compositionally and functionally distinct from those detected in comparable patients in developed countries, a feature which may contribute to adverse outcomes in this population.
doi:10.1371/journal.pone.0095726
PMCID: PMC3994144  PMID: 24752365
8.  Ambient Air Pollution Associated with Suppressed Serologic Responses to Pneumocystis jirovecii in a Prospective Cohort of HIV-Infected Patients with Pneumocystis Pneumonia 
PLoS ONE  2013;8(11):e80795.
Background
Ambient air pollution (AAP) may be associated with increased risk for Pneumocystis pneumonia (PCP). The mechanisms underlying this association remain uncertain.
Objectives
To determine if real-life exposures to AAP are associated with suppressed IgM antibody responses to P. jirovecii in HIV-infected (HIV+) patients with active PCP, and to determine if AAP, mediated by suppressed serologic responses to Pneumocystis, is associated with adverse clinical outcomes.
Methods
We conducted a prospective cohort study in HIV+ patients residing in San Francisco and admitted to San Francisco General Hospital with microscopically confirmed PCP. Our AAP predictors were ambient air concentrations of particulate matter of < 10 µm in diameter (PM10) and < 2.5 µm in diameter (PM2.5), nitrogen dioxide (NO2), ozone (O3), and sulfur dioxide (SO2) measured immediately prior to hospital admission and 2 weeks prior to admission. Our primary outcomes were the IgM serologic responses to four recombinant P. jirovecii major surface glycoprotein (Msg) constructs: MsgC1, MsgC3, MsgC8, and MsgC9.
Results
Elevated PM10 and NO2 exposures immediately prior to and two weeks prior to hospital admission were associated with decreased IgM antibody responses to P. jirovecii Msg. For exposures immediately prior to admission, every 10 µg/m3 increase in PM10 was associated with a 25 to 35% decrease in IgM responses to Msg (statistically significant for all the Msg constructs), and every 10 ppb increase in NO2 was associated with a 19-45% decrease in IgM responses to Msg (statistically significant for MsgC8 and MsgC9). Similar findings were seen with exposures two weeks prior to admission, but for fewer of the Msg constructs.
Conclusions
Real life exposures to PM10 and NO2 were associated with suppressed IgM responses to P. jirovecii Msg in HIV+ patients admitted with PCP, suggesting a mechanism of immunotoxicity by which AAP increases host susceptibility to pulmonary infection.
doi:10.1371/journal.pone.0080795
PMCID: PMC3827464  PMID: 24236202
9.  Antibody Responses against Pneumocystis jirovecii in Health Care Workers Over Time 
Emerging Infectious Diseases  2013;19(10):1613-1620.
In a previous cross-sectional study, we showed that clinical staff working in a hospital had significantly higher antibody levels than nonclinical staff to Pneumocystis jirovecii. We conducted a longitudinal study, described here, to determine whether occupation and self-reported exposure to a patient with P. jirovecii pneumonia were associated with antibody levels to P. jirovecii over time. Baseline and quarterly serum specimens were collected and analyzed by using an ELISA that targeted different variants of the Pneumocystis major surface glycoprotein (MsgA, MsgB, MsgC1, MsgC3, MsgC8, and MsgC9). Clinical staff had significantly higher estimated geometric mean antibody levels against MsgC1 and MsgC8 than did nonclinical staff over time. Significant differences were observed when we compared the change in antibody levels to the different MsgC variants for staff who were and were not exposed to P. jirovecii pneumonia–infected patients. MsgC variants may serve as indicators of exposure to P. jirovecii in immunocompetent persons.
doi:10.3201/eid1910.121836
PMCID: PMC3810734  PMID: 24048016
Pneumocystis jirovecii; transmission; health care worker–patient; human immunodeficiency virus; HIV; major surface glycoprotein; pneumonia; respiratory diseases; fungi; HIV/AIDS and other retroviruses
10.  Beijing Sublineages of Mycobacterium tuberculosis Differ in Pathogenicity in the Guinea Pig 
The Beijing family of Mycobacterium tuberculosis strains is part of lineage 2 (also known as the East Asian lineage). In clinical studies, we have observed that isolates from the sublineage RD207 of lineage 2 were more readily transmitted among humans. To investigate the basis for this difference, we tested representative strains with the characteristic Beijing spoligotype from four of the five sublineages of lineage 2 in the guinea pig model and subjected these strains to comparative whole-genome sequencing. The results of these studies showed that all of the clinical strains were capable of growing and causing lung pathology in guinea pigs after low-dose aerosol exposure. Differences between the abilities of the four sublineages to grow in the lungs of these animals were not overt, but members of RD207 were significantly more pathogenic, resulting in severe lung damage. The RD207 strains also induced much higher levels of markers associated with regulatory T cells and showed a significant loss of activated T cells in the lungs over the course of the infections. Whole-genome sequencing of the strains revealed mutations specific for RD207 which may explain this difference. Based on these data, we hypothesize that the sublineages of M. tuberculosis are associated with distinct pathological and clinical phenotypes and that these differences influence the transmissibility of particular M. tuberculosis strains in human populations.
doi:10.1128/CVI.00250-12
PMCID: PMC3416080  PMID: 22718126
11.  Serologic Responses to Recombinant Pneumocystis jirovecii Major Surface Glycoprotein among Ugandan Patients with Respiratory Symptoms 
PLoS ONE  2012;7(12):e51545.
Background
Little is known about the serologic responses to Pneumocystis jirovecii major surface glycoprotein (Msg) antigen in African cohorts, or the IgM responses to Msg in HIV-positive and HIV-negative persons with respiratory symptoms.
Methods
We conducted a prospective study of 550 patients, both HIV-positive (n = 467) and HIV-negative (n = 83), hospitalized with cough ≥2 weeks in Kampala, Uganda, to evaluate the association between HIV status, CD4 cell count, and other clinical predictors and antibody responses to P. jirovecii. We utilized ELISA to measure the IgM and IgG serologic responses to three overlapping recombinant fragments that span the P. jirovecii major surface glycoprotein: MsgA (amino terminus), MsgB (middle portion) and MsgC1 (carboxyl terminus), and to three variations of MsgC1 (MsgC3, MsgC8 and MsgC9).
Results
HIV-positive patients demonstrated significantly lower IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 compared to HIV-negative patients. We found the same pattern of low IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 among HIV-positive patients with a CD4 cell count <200 cells/µl compared to those with a CD4 cell count ≥200 cells/µl. HIV-positive patients on PCP prophylaxis had significantly lower IgM responses to MsgC3 and MsgC9, and lower IgG responses to MsgA, MsgC1, MsgC3, and MsgC8. In contrast, cigarette smoking was associated with increased IgM antibody responses to MsgC1 and MsgC3 but was not associated with IgG responses. We evaluated IgM and IgG as predictors of mortality. Lower IgM responses to MsgC3 and MsgC8 were both associated with increased in-hospital mortality.
Conclusions
HIV infection and degree of immunosuppression are associated with reduced IgM responses to Msg. In addition, low IgM responses to MsgC3 and MsgC8 are associated with increased mortality.
doi:10.1371/journal.pone.0051545
PMCID: PMC3528778  PMID: 23284710
12.  Correction: Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients 
Ahuja, Shama D. | Ashkin, David | Avendano, Monika | Banerjee, Rita | Bauer, Melissa | Bayona, Jamie N. | Becerra, Mercedes C. | Benedetti, Andrea | Burgos, Marcos | Centis, Rosella | Chan, Eward D. | Chiang, Chen-Yuan | Cox, Helen | D'Ambrosio, Lia | DeRiemer, Kathy | Dung, Nguyen Huy | Enarson, Donald | Falzon, Dennis | Flanagan, Katherine | Flood, Jennifer | Garcia-Garcia, Maria L. | Gandhi, Neel | Granich, Reuben M. | Hollm-Delgado, Maria G. | Holtz, Timothy H. | Iseman, Michael D. | Jarlsberg, Leah G. | Keshavjee, Salmaan | Kim, Hye-Ryoun | Koh, Won-Jung | Lancaster, Joey | Lange, Christophe | de Lange, Wiel C. M. | Leimane, Vaira | Leung, Chi Chiu | Li, Jiehui | Menzies, Dick | Migliori, Giovanni B. | Mishustin, Sergey P. | Mitnick, Carole D. | Narita, Masa | O'Riordan, Philly | Pai, Madhukar | Palmero, Domingo | Park, Seung-kyu | Pasvol, Geoffrey | Peña, Jose | Pérez-Guzmán, Carlos | Quelapio, Maria I. D. | Ponce-de-Leon, Alfredo | Riekstina, Vija | Robert, Jerome | Royce, Sarah | Schaaf, H. Simon | Seung, Kwonjune J. | Shah, Lena | Shim, Tae Sun | Shin, Sonya S. | Shiraishi, Yuji | Sifuentes-Osornio, José | Sotgiu, Giovanni | Strand, Matthew J. | Tabarsi, Payam | Tupasi, Thelma E. | van Altena, Robert | Van der Walt, Martie | Van der Werf, Tjip S. | Vargas, Mario H. | Viiklepp, Pirett | Westenhouse, Janice | Yew, Wing Wai | Yim, Jae-Joon
PLoS Medicine  2012;9(9):10.1371/annotation/230240bc-bcf3-46b2-9b21-2e6e584f7333.
doi:10.1371/annotation/230240bc-bcf3-46b2-9b21-2e6e584f7333
PMCID: PMC4188481
13.  Racial Differences in Tuberculosis Infection in United States Communities: The Coronary Artery Risk Development in Young Adults Study 
Previously reported associations between race/ethnicity and tuberculosis infection have lacked sufficient adjustment for socioeconomic factors. We analyzed race/ethnicity and self-reported tuberculosis infection data from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a well-characterized cohort of 5115 black and white participants, and found that after adjusting for sociodemographic and clinical factors, black participants were more likely to report tuberculosis infection and/or disease (odds ratio, 2.0; 95% confidence interval, 1.5–2.9).
doi:10.1093/cid/cir378
PMCID: PMC3137794  PMID: 21765079
14.  Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis 
Background
Tuberculosis is a leading cause of death worldwide, yet the determinants of death are not well understood. We sought to determine risk factors for mortality during treatment of drug-susceptible pulmonary tuberculosis under program settings.
Methods
Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.
Results
Of 565 patients meeting eligibility criteria, 37 (6.6%) died during the study period. Of 37 deaths, 12 (32.4%) had tuberculosis listed as a contributing factor. In multivariate analysis controlling for follow-up time, four characteristics were independently associated with mortality: HIV co-infection (HR = 2.57, p = 0.02), older age at tuberculosis diagnosis (HR = 1.52 per 10 years, p = 0.001); initial sputum smear positive for acid fast bacilli (HR = 3.07, p = 0.004); and experiencing an interruption in tuberculosis therapy (HR = 3.15, p = 0.002). The association between treatment interruption and risk of death was due to non-adherence during the intensive phase of treatment (HR = 3.20, p = 0.001). The median duration of treatment interruption did not differ significantly in either intensive or continuation phases between those who died and survived (23 versus 18 days, and 37 versus 29 days, respectively). No deaths were directly attributed to adverse drug reactions.
Conclusions
In addition to advanced age, HIV and characteristics of advanced tuberculosis, experiencing an interruption in anti-tuberculosis therapy, primarily due to non-adherence, was also independently associated with increased risk of death. Improving adherence early during treatment for tuberculosis may both improve tuberculosis outcomes as well as decrease mortality.
doi:10.1186/1471-2334-11-1
PMCID: PMC3022714  PMID: 21199579
15.  Comparison of Restriction Fragment Length Polymorphism with the Polymorphic Guanine-Cytosine-Rich Sequence and Spoligotyping for Differentiation of Mycobacterium tuberculosis Isolates with Five or Fewer Copies of IS6110▿  
Journal of Clinical Microbiology  2009;48(2):575-578.
The use of IS6110 as a marker for molecular epidemiological studies is limited when a Mycobacterium tuberculosis isolate has five or fewer copies of IS6110. Restriction fragment length polymorphism analysis with a highly polymorphic GC-rich repetitive sequence located in the plasmid pTBN12 (PGRS RFLP) and spoligotyping (based on the polymorphism of the DR region) are two frequently used secondary typing methods. The aim of this study was to compare the performance of these two methods in a population-based study in San Francisco. We included all patients with culture-positive tuberculosis from 1999 to 2007 with IS6110 RFLP results presenting five or fewer bands. PGRS RFLP and spoligotyping were performed using standardized methods. We determined the concordance between the two methods regarding cluster status and the risk factors for an isolate to be in a cluster with each of the methods. Our data indicate that both methods had similar discriminatory power and that the risk factors associated with clustering by either method were the same. Although the cluster/unique status was concordant in 84% of the isolates, patients were clustered differently depending on the method. Therefore, the methods are not interchangeable, and the same method should be used for longitudinal studies.
doi:10.1128/JCM.01604-09
PMCID: PMC2815604  PMID: 20032250
16.  Severity and outcomes of Pneumocystis pneumonia in patients newly diagnosed with HIV infection: an observational cohort study 
It is unclear whether patients who are unaware of their HIV infection have different severity or outcomes of Pneumocystis pneumonia (PCP) compared to patients who have been previously diagnosed with HIV. In this retrospective observational cohort study of consecutive HIV-infected patients with microscopically diagnosed PCP at San Francisco General Hospital between 1997 and 2006, 121 of 522 patients (23%) were unaware of their HIV infection prior to their diagnosis of PCP. The proportion of patients with concurrently diagnosed HIV and PCP each year remained unchanged during the study period. Patients with newly diagnosed HIV had a significantly higher alveolar-arterial oxygen gradient at presentation (median 51 versus 45 mm Hg, p=0.03), but there were no differences in mortality, frequency of mechanical ventilation, or admission to intensive care compared to patients with previously diagnosed HIV infection. In multivariate analysis, patients who reported a sexual risk factor for HIV infection were more likely to be newly diagnosed with HIV than patients who reported injection drug use as their only HIV risk factor (odds ratio = 3.14, 95% confidence interval 1.59–6.18, p = 0.001). This study demonstrates a continued need for HIV education and earlier HIV testing, particularly in patients with high-risk sexual behavior.
doi:10.1080/00365540903051633
PMCID: PMC2806953  PMID: 19521925
17.  Clinical Characteristics and Treatment Outcomes of Isoniazid Mono-Resistant Tuberculosis 
Background
Risk factors and treatment outcomes under program conditions for isoniazid (INH) mono-resistant tuberculosis have not been well described.
Methods
Medical charts were retrospectively reviewed for all culture-confirmed, INH mono-resistant tuberculosis cases (N=137) reported to the San Francisco Tuberculosis Control Section between 1993 and 2005 and compared to a time-matched sample of drug susceptible cases (N=274).
Results
In multivariate analysis, only history of treatment for latent (OR 3.1, 95% CI 1.5–6.4, p=0.003) and active (OR 2.7, 95% CI 1.4–5, p=0.002) tuberculosis were significantly associated with INH mono-resistant tuberculosis. Of the 119 patients who completed treatment, 49 (41%) completed a 6-month treatment regimen. Treatment was extended to between 7 and 12 months in 53 (45%) patients and to greater than 12 months in 17 (14%) patients. Treatment was most commonly extended when pyrazinamide was not given for the recommended 6-month duration (N=35, 29%). Despite variation in treatment regimens, the combined endpoint of treatment failure or relapse was uncommon in INH mono-resistant cases and not significantly different than for drug susceptible cases (1.7% vs. 2.2%, p=0.73).
Conclusions
A history of latent or active tuberculosis treatment was associated with subsequent INH mono-resistance. Treatment outcomes for INH mono-resistant cases were excellent and no different than for drug susceptible cases. However, new short course regimens are needed since a low proportion of patients completed the 6-month ATS/CDC/IDSA-recommended treatment regimen, primarily due to pyrazinamide intolerance.
doi:10.1086/595689
PMCID: PMC2756509  PMID: 19086909
Epidemiology; Drug resistance; Tuberculosis; Treatment Outcomes
18.  Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study 
Thorax  2009;64(12):1070-1076.
Background
Although the use of antiretroviral therapy has led to dramatic declines in AIDS-associated mortality, Pneumocystis pneumonia (PCP) remains a leading cause of death in HIV-infected patients.
Objectives
To measure mortality, identify predictors of mortality at time of illness presentation, and derive a PCP mortality prediction rule that stratifies patients by risk for mortality.
Methods
Observational cohort study with case note review of all HIV-infected persons with a laboratory diagnosis of PCP at San Francisco General Hospital from 1997–2006.
Results
451 patients were diagnosed with PCP on 524 occasions. In-hospital mortality was 10.3%. Multivariate analysis identified five significant predictors of mortality: age (adjusted odds ratio [AOR] per 10-year increase, 1.69; 95% confidence interval [CI] 1.08–2.65; p=0.02); recent injection drug use (AOR 2.86; 95% CI 1.28–6.42; p=0.01); total bilirubin >0.6 mg/dL (AOR 2.59; 95% CI 1.19–5.62; p=0.02); serum albumin <3 g/dL (AOR 3.63; 95% CI 1.72–7.66; p=0.001); and alveolar-arterial oxygen gradient ≥50 mm Hg (AOR 3.02; 95% CI 1.41–6.47; p=0.004). Using these five predictors, we derived a six point PCP mortality prediction rule that stratifies patients according to increasing risk of mortality: score 0–1, 4%; score 2–3, 12%; score 4–5, 48%.
Conclusions
Our PCP mortality prediction rule stratifies patients by mortality risk at the time of illness presentation and should be validated as a clinical tool.
doi:10.1136/thx.2009.117846
PMCID: PMC2788120  PMID: 19825785
Pneumonia; Pneumocystis; HIV/AIDS; antiretroviral therapy; highly active
19.  Healthcare Worker Occupation and Immune Response to Pneumocystis jirovecii 
Emerging Infectious Diseases  2009;15(10):1590-1597.
Humans may be a reservoir for this pathogen and transmit it from person to person.
The reservoir and mode of transmission of Pneumocystis jirovecii remain uncertain. We conducted a cross-sectional study of 126 San Francisco General Hospital staff in clinical (n = 103) and nonclinical (n = 23) occupations to assess whether occupational exposure was associated with immune responses to P. jirovecii. We examined antibody levels by ELISA for 3 overlapping fragments that span the P. jirovecii major surface glycoprotein (Msg): MsgA, MsgB, and MsgC1. Clinical occupation participants had higher geometric mean antibody levels to MsgC1 than did nonclinical occupation participants (21.1 vs. 8.2, p = 0.004); clinical occupation was an independent predictor of higher MsgC1 antibody levels (parameter estimate = 0.89, 95% confidence interval 0.29–1.48, p = 0.003). In contrast, occupation was not significantly associated with antibody responses to either MsgA or MsgB. Healthcare workers may have occupational exposure to P. jirovecii. Humans may be a reservoir for P. jirovecii and may transmit it from person to person.
doi:10.3201/eid1510.090207
PMCID: PMC2866396  PMID: 19861050
Pneumocystis; health personnel; HIV/AIDS and other retroviruses; opportunistic infections; antibodies; fungal; fungi; serologic tests; research

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