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Pyrazinamide Resistance, Mycobacterium tuberculosis Lineage and Treatment Outcomes in San Francisco, California
Jonathan M. Budzik, Leah G. Jarlsberg, Julie Higashi, Jennifer Grinsdale, Phil C. Hopewell, Midori Kato-Maeda, Payam Nahid
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095645
Abstract: 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.
Serum Antibody Levels to the Pneumocystis jirovecii Major Surface Glycoprotein in the Diagnosis of P. jirovecii Pneumonia in HIV+ Patients
Kpandja Djawe,Laurence Huang,Kieran R. Daly,Linda Levin,Judy Koch,Alexandra Schwartzman,Serena Fong,Brenna Roth,Anuradha Subramanian,Katherine Grieco,Leah Jarlsberg,Peter D. Walzer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0014259
Abstract: Pneumocystis jirovecii remains an important cause of fatal pneumonia (Pneumocystis pneumonia or PcP) in HIV+ patients and other immunocompromised hosts. Despite many previous attempts, a clinically useful serologic test for P. jirovecii infection has never been developed.
Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis
Payam Nahid, Leah G Jarlsberg, Irina Rudoy, Bouke C de Jong, Alon Unger, L Masae Kawamura, Dennis H Osmond, Philip C Hopewell, Charles L Daley
BMC Infectious Diseases , 2011, DOI: 10.1186/1471-2334-11-1
Abstract: Retrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.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.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.Tuberculosis is a leading cause of death worldwide. According to the World Health Organization (WHO) over 1.7 million people with tuberculosis died in 2008 [1]. Advanced age, male gender, delays in diagnosis and treatment, drug resistance, and co-morbid conditions including HIV co-infection, diabetes, renal disease and COPD, have been associated with increased risk of death in patients with active tuberculosis [2-8]. A substantial proportion of deaths occur during tuberculosis treatment despite patient
Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment
Mary A. De Groote, Payam Nahid, Leah Jarlsberg, John L. Johnson, Marc Weiner, Grace Muzanyi, Nebojsa Janjic, David G. Sterling, Urs A. Ochsner
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061002
Abstract: In an unbiased approach to biomarker discovery, we applied a highly multiplexed proteomic technology (SOMAscan, SomaLogic, Inc, Boulder, CO) to understand changes in proteins from paired serum samples at enrollment and after 8 weeks of TB treatment from 39 patients with pulmonary TB from Kampala, Uganda enrolled in the Center for Disease Control and Prevention’s Tuberculosis Trials Consortium (TBTC) Study 29. This work represents the first large-scale proteomic analysis employing modified DNA aptamers in a study of active tuberculosis (TB). We identified multiple proteins that exhibit significant expression differences during the intensive phase of TB therapy. There was enrichment for proteins in conserved networks of biological processes and function including antimicrobial defense, tissue healing and remodeling, acute phase response, pattern recognition, protease/anti-proteases, complement and coagulation cascade, apoptosis, immunity and inflammation pathways. Members of cytokine pathways such as interferon-gamma, while present, were not as highly represented as might have been predicted. The top proteins that changed between baseline and 8 weeks of therapy were TSP4, TIMP-2, SEPR, MRC-2, Antithrombin III, SAA, CRP, NPS-PLA2, LEAP-1, and LBP. The novel proteins elucidated in this work may provide new insights for understanding TB disease, its treatment and subsequent healing processes that occur in response to effective therapy.
Childhood Tuberculosis in Northern Viet Nam: A Review of 103 Cases
Robert J. Blount, Bao Tran, Leah G. Jarlsberg, Ha Phan, Van Thanh Hoang, Nhung Viet Nguyen, Deborah A. Lewinsohn, Payam Nahid
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0097267
Abstract: 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.
The Lung Microbiome of Ugandan HIV-Infected Pneumonia Patients Is Compositionally and Functionally Distinct from That of San Franciscan Patients
Shoko Iwai, Delphine Huang, Serena Fong, Leah G. Jarlsberg, William Worodria, Samuel Yoo, Adithya Cattamanchi, J. Lucian Davis, Sylvia Kaswabuli, Mark Segal, Laurence Huang, Susan V. Lynch
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095726
Abstract: 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.
Serologic Responses to Recombinant Pneumocystis jirovecii Major Surface Glycoprotein among Ugandan Patients with Respiratory Symptoms
Robert J. Blount, Leah G. Jarlsberg, Kieran R. Daly, William Worodria, J. Lucian Davis, Adithya Cattamanchi, Kpandja Djawe, Alfred Andama, Judith Koch, Peter D. Walzer, Laurence Huang, International HIV-Associated Opportunistic Pneumonias (IHOP) Study
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051545
Abstract: 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.
Ambient Air Pollution Associated with Suppressed Serologic Responses to Pneumocystis jirovecii in a Prospective Cohort of HIV-Infected Patients with Pneumocystis Pneumonia
Robert J. Blount, Kpandja Djawe, Kieran R. Daly, Leah G. Jarlsberg, Serena Fong, John Balmes, Robert F. Miller, Peter D. Walzer, Laurence Huang, on behalf of the International HIV-associated Opportunistic Pneumonias (IHOP) Study.
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0080795
Abstract: 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.
Rights with Capabilities: Towards a Social Justice Framework for Migrant Activism
Leah Briones
Studies in Social Justice , 2011,
Abstract: The paradigm of rights, established throughout the academic, policy and migrant activism arenas, governs the protection of vulnerable migrant workers against abuse. To what extent this approach has achieved social justice for the migrant worker in the current global political economy climate is, however, uncertain. In analyzing the use of rights in migrant activism in Hong Kong, this paper shows the limitation of rights in the migrant experience at the same time as it shows how a new paradigm based on the Capablities Approach could provide a more appropriate framework from which to achieve social justice for the migrant worker.
Une parole libératrice: le discours féminin de l’endurance dans Un alligator nommé Rosa de Marie-Célie Agnant et Syngué Sabour: pierre de patience d’Atiq Rahimi
Leah Roth
Voix Plurielles , 2012,
Abstract: Cet article examine le discours féminin de l’endurance dans deux romans de l’extrême contemporain, Un alligator nommé Rosa (2007) de Marie-Célie Agnant et Syngué Sabour : pierre de patience (2008) d’Atiq Rahimi. S’appuyant sur les écrits de Dominique Maingueneau sur le discours littéraire, cette étude analyse d’abord la manière dont l’endurance de la femme est racontée dans la littérature de l’extrême contemporain. Elle examine ensuite la visée éthique, telle que proposée par Paul Ric ur, qui se manifeste à travers ce discours de l’endurance dans les textes et qui s’avère si importante pour le monde d’aujourd’hui.
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