Leah G. Jarlsberg

Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients

Dick Menzies and colleagues report findings from a collaborative, individual patient-level meta-analysis of treatment outcomes among patients with multidrug-resistant tuberculosis.

Factors associated with mortality in patients with drug-susceptible pulmonary tuberculosis

BackgroundTuberculosis 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.MethodsRetrospective chart review of patients with drug-susceptible tuberculosis reported to the San Francisco Tuberculosis Control Program from 1990-2001.ResultsOf 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.ConclusionsIn 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.

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis

The broadest pattern of tuberculosis drug resistance for which a consensus definition exists is extensively drug-resistant tuberculosis (XDR-TB). It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR-alone and three non-mutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) capreomycin and kanamycin/amikacin (XDR+2sli); XDR plus resistance to second-line injectables and to ≥1 Group 4 drug, i.e. : ethionamide/prothionamide, cycloserine/terizidone or PAS (XDR+sliG4); and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR-alone; 68 XDR+2sli; 48 XDR+sliG4; and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted Odds Ratio (aOR): 0.4; 95% Confidence Interval: 0.2–0.8) compared to XDR-alone, while odds of failure+death were higher in all XDR patients with additional resistance (aOR range: 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current DST methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2–0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6–2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB.

Elucidating Novel Serum Biomarkers Associated with Pulmonary Tuberculosis Treatment

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.

Clinical characteristics and treatment outcomes of patients with isoniazid-monoresistant tuberculosis.

BACKGROUND Risk factors and treatment outcomes under program conditions for isoniazid (INH)-monoresistant tuberculosis have not been well described. METHODS Medical charts were retrospectively reviewed for all cases of culture-confirmed, INH-monoresistant tuberculosis ( n = 137) reported to the San Francisco Department of Public Health Tuberculosis Control Section from October 1992 through October 2005, and those cases were compared with a time-matched sample of drug-susceptible tuberculosis cases (n = 274) RESULTS In multivariate analysis, only a history of treatment for latent tuberculosis (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.5-6.4; P = .003) or for active tuberculosis (OR, 2.7; 95% CI, 1.4-5.0; P = .002) were significantly associated with INH-monoresistant tuberculosis. Of the 119 patients who completed treatment, 49 (41%) completed a 6-month treatment regimen. Treatment was extended to 7-12 months for 53 (45%) of the patients and to >12 months for 17 (14%). Treatment was most commonly extended because pyrazinamide was not given for the recommended 6-month duration (35 patients [29%]). Despite variation in treatment regimens, the combined end point of treatment failure or relapse was uncommon among patients with INH-monoresistant tuberculosis and was not significantly different for patients with drug-susceptible tuberculosis (1.7% vs. 2.2%; P = .73). CONCLUSIONS A history of treatment for latent or active tuberculosis was associated with subsequent INH monoresistance. Treatment outcomes for patients with INH-monoresistant tuberculosis were excellent and were no different from those for patients with drug-susceptible tuberculosis. However, new, short-course regimens are needed because a small proportion of patients completed the 6-month treatment regimen recommended by the American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America, primarily because of pyrazinamide intolerance.

Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study

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: An 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 to 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% CI 1.08 to 2.65; p = 0.02); recent injection drug use (AOR 2.86; 95% CI 1.28 to 6.42; p = 0.01); total bilirubin >0.6 mg/dl (AOR 2.59; 95% CI 1.19 to 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 to 6.47; p = 0.004). Using these five predictors, a six-point PCP mortality prediction rule was derived that stratifies patients according to increasing risk of mortality: score 0–1, 4%; score 2–3, 12%; score 4–5, 48%. Conclusions: The PCP mortality prediction rule stratifies patients by mortality risk at the time of illness presentation and should be validated as a clinical tool.

Beijing sublineages of Mycobacterium tuberculosis differ in pathogenicity in the guinea pig.

ABSTRACT 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.

Selective provision of asthma self-management tools to families.

OBJECTIVE. Providing asthma education in a primary care setting can be challenging because of time and resource constraints. The purpose of this work was to determine factors associated with the provision of different asthma self-management tools. METHODS. We conducted a cross-sectional survey with 896 parents of children with asthma (age 2–12 years). We collected information regarding demographics and asthma care, including parent receipt of an asthma action plan, a symptom diary, and asthma information materials; whether an asthma management plan was sent to the childs school; and whether the physician reviewed written instructions on use of a metered-dose inhaler. We used multivariate logistic regression methods to determine factors associated with receipt of different asthma self-management tools controlling for demographic factors. RESULTS. For families where parents only completed high school, there was greater likelihood of receipt of an asthma action plan and physician review of written instructions about how to use an inhaler. For families with a household income less than twice the poverty line, there was greater likelihood of receipt of an asthma action plan, the physician sending a letter to the childs school regarding the childs asthma, and receipt of an asthma symptom diary. CONCLUSIONS. In our sample, primary care pediatricians do not routinely provide asthma education in accordance with National Heart, Lung, and Blood Institute asthma guidelines and “triage” which families receive additional asthma education. We believe that the use of targeted asthma education is a symptom of the limited time and competing demands during a typical visit. As a result, those involved in quality improvement need to help physicians become more efficient and effective at providing asthma education within such time constraints or develop alternative systems of providing asthma education.

The lung microbiome of Ugandan HIV-infected pneumonia patients is compositionally and functionally distinct from that of San Franciscan patients.

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.

Parents' Specific Concerns about Daily Asthma Medications for Children

Specific concerns from 706 parents regarding their childrens (M age = 8.0, SD = 3.9) use of daily asthma medications were systematically identified and organized. 270 (38.2%) of 706 parents expressed a total of 470 concerns (M = 1.74, SD = 0.93; Range 1–5), including concerns about side effects (48.9%; e.g., growth retardation); aspects of the regimen (29.3%; e.g., medication amount); and “steroid” use (10.4%). Independent predictors of parental concern included use of inhaled corticosteroids (OR = 1.60, 95% CI 1.07–2.40), nasal corticosteroids (OR = 1.70, 95% CI 1.21–2.38), and alternative therapies (OR = 1.84, 95% CI 1.32–2.56). Providers should be prepared to address a wide range of medication concerns, especially those related to side effects.