Sarah K. Brode

Increased risk of mycobacterial infections associated with anti-rheumatic medications

Rationale Anti-tumour necrosis factor (TNF) agents and other anti-rheumatic medications increase the risk of TB in rheumatoid arthritis (RA). Whether they increase the risk of infections with nontuberculous mycobacteria (NTM) is uncertain. Objectives To determine the effect of anti-TNF therapy and other anti-rheumatic drugs on the risk of NTM disease and TB in older patients with RA. Methods Population-based nested case–control study among Ontario seniors aged ≥67 years with RA who were prescribed at least one anti-rheumatic medication between 2001 and 2011. We identified cases of TB and NTM disease microbiologically and identified drug exposures using linked prescription drug claims. We estimated ORs using conditional logistic regression, controlling for several potential confounders. Measurements and main results Among 56 269 older adults with RA, we identified 37 cases of TB and 211 cases of NTM disease; each case was matched to up to 10 controls. Individuals with TB or NTM disease were both more likely to be using anti-TNF therapy (compared with non-use); adjusted ORs (95% CIs) were 5.04 (1.27 to 20.0) and 2.19 (1.10 to 4.37), respectively. Exposure to leflunomide and other anti-rheumatic drugs with high immunosuppressing potential also were associated with both TB and NTM disease, while oral corticosteroids and hydroxychloroquine were associated with NTM disease. Conclusions Anti-TNF use is associated with increased risk of both TB and NTM disease, but appears to be a relatively greater risk for TB. Several other anti-rheumatic drugs were also associated with mycobacterial infections.

Risk of Mycobacterial Infections Associated With Rheumatoid Arthritis in Ontario, Canada

OBJECTIVE Patients with rheumatoid arthritis (RA) are at increased risk of TB. Little is known about the risk of nontuberculous mycobacteria (NTM) disease in these patients. We sought to ascertain the rate of NTM infection and TB in all residents of Ontario, Canada, with and without RA. METHODS In a cohort study, all Ontarians aged ≥ 15 years in January 2001 were followed until December 2010. Individuals with RA were identified using a validated algorithm to search hospitalization and physician billing claims. We linked Public Health Ontario Laboratory data to identify all cases of laboratory-confirmed TB and NTM disease. Analysis was performed using Cox proportional hazards regression. RESULTS We identified 113,558 Ontarians with RA and 9,760,075 Ontarians without RA. Relative to the non-RA group, adjusted hazard ratios (HRs) and 95% CIs for TB (1.92, [1.50-2.47]) and NTM disease (2.07, [1.84-2.32]) demonstrated increased risks in the RA group. Among those with RA, per 100,000 person-years, NTM disease (HR, 41.6; 95% CI, 37.1-46.5) was more common than TB (HR, 8.5; 95% CI, 6.5-10.8). After full adjustment, people with RA who developed NTM disease were 1.81 times as likely to die than uninfected people with RA. CONCLUSIONS Mycobacterial infections are more common in Ontarians with RA, with NTM disease more likely than TB. NTM disease is associated with an increased risk of death in patients with RA. Given the rising rates of NTM disease worldwide, determining whether this risk is due to the use of immunosuppressive medications vs RA itself is an important objective for future research.

Dual therapy in IPAH and SSc-PAH. A qualitative systematic review.

BACKGROUND Use of endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and prostaglandin analogues has resulted in improved outcomes in idiopathic pulmonary arterial hypertension (IPAH) and systemic sclerosis-associated PAH (SSc-PAH) patients. However, patients often deteriorate on monotherapy. The objective of this study is to evaluate the effect of dual therapy on outcomes in IPAH and SSc-PAH. METHODS A systematic review of MEDLINE (1950-2011), EMBASE (1980-2011) and CINAHL (inception-2011) was conducted to identify studies that evaluated the effect of any dual combination of ERA, PDE-5 inhibitors or prostaglandin analogues on 6-min walk distance (6MWD), functional class (FC), haemodynamics, quality-of-life (QoL) or time-to-clinical-worsening in IPAH or SSc-PAH. A standardized form was used to abstract design, sample size, aetiology, outcome and treatment effect. RESULTS Twenty-six observational studies and 6 randomized trials were identified. Using combination PDE-5 inhibitor and prostaglandin analogues, 6/7 studies reported improvement in 6MWD, 6/8 studies reported improvement in FC, 6/6 studies reported improvement in haemodynamics and 1 trial demonstrated improvement in QoL and time-to-clinical-worsening. Using combination ERA and prostaglandin analogues, 4/6 studies and 1 trial reported improvement in 6MWD, 3/3 studies and 1 trial reported improvement in FC, 4/5 studies and 1 trial reported improvement in PAP. Using combination ERA and PDE-5 inhibitor, 4/7 studies reported an improvement in 6MWD, and 2/6 report improvement in FC. CONCLUSION The evidence suggests a beneficial effect of dual therapy in IPAH and SSc-PAH, particularly those who are deteriorating on monotherapy. Research should focus on subsets of patients to identify the optimal timing and combination of dual therapy.

The risk of mycobacterial infections associated with inhaled corticosteroid use

Inhaled corticosteroid (ICS) use is associated with an increased risk of pneumonia. This study was performed to determine if ICS use is associated with an increased risk of nontuberculous mycobacterial pulmonary disease (NTM-PD) or tuberculosis (TB). We conducted a population-based nested case–control study using linked laboratory and health administrative databases in Ontario, Canada, including adults aged ≥66 years with treated obstructive lung disease (i.e. asthma, chronic obstructive pulmonary disease (COPD) or asthma–COPD overlap syndrome) between 2001 and 2013. We estimated odds ratios comparing ICS use with nonuse among NTM-PD and TB cases and controls using conditional logistic regression. Among 417 494 older adults with treated obstructive lung disease, we identified 2966 cases of NTM-PD and 327 cases of TB. Current ICS use was associated with NTM-PD compared with nonuse (adjusted OR (aOR) 1.86, 95% CI 1.60–2.15) and was statistically significant for fluticasone (aOR 2.09, 95% CI 1.80–2.43), but not for budesonide (aOR 1.19, 95% CI 0.97–1.45). There was a strong dose–response relationship between incident NTM-PD and cumulative ICS dose over 1 year. There was no significant association between current ICS use and TB (aOR 1.43, 95% CI 0.95–2.16). This study suggests that ICS use is associated with an increased risk of NTM-PD, but not TB. Inhaled corticosteroid use in older adults with obstructive lung disease increases with risk of NTM lung infection http://ow.ly/k2mL30cDO1b

Risk of nontuberculous mycobacterial pulmonary disease with obstructive lung disease

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasingly prevalent [1] and especially common in the elderly [2]. It is usually chronic, requiring complex therapy with suboptimal outcomes [3]. Risk factors for NTM-PD may be covert, presumably disordered mucociliary defences, or overt structural lung abnormalities. In one study, 56% of NTM-PD patients had unexplained nontuberculous mycobacteria (NTM) and among the rest with structural lung disease, chronic obstructive pulmonary disease (COPD) was the most common predisposing condition [4]. High incidence of NTM pulmonary disease in people with COPD and asthma (142 and 53 per 100 000 person-years) http://ow.ly/2laN300kLOV

Pulmonary Nontuberculous Mycobacteria–Associated Deaths, Ontario, Canada, 2001–2013

Survival implications of nontuberculous mycobacterial pulmonary disease (NTM-PD) and NTM pulmonary isolation without disease (NTM-PI) are unclear. To study deaths associated with NTM-PD and NTM-PI and differences in survival between them, we conducted a population-based cohort study of persons with microbiologically defined NTM-PD or NTM-PI diagnosed during 2001–2013 in Ontario, Canada. We used propensity score matching and Cox proportional hazards models to compare survival. Among 9,681 NTM-PD patients and 10,936 NTM-PI patients, 87% and 91%, respectively, were successfully matched with unexposed controls. Both NTM-PD and NTM-PI were associated with higher rates of death for all species combined and for most individual species. Compared with NTM-PI, NTM-PD was associated with higher death rates for all species combined, Mycobacterium avium complex, and M. xenopi. NTM-PD and NTM-PI were significantly associated with death, NTM-PD more so than NTM-PI.

Health‐related quality of life, comorbidities and mortality in pulmonary nontuberculous mycobacterial infections: A systematic review

Nontuberculous mycobacterial (NTM) infections are increasing in disease frequency worldwide. This systematic review examines health‐related quality of life (HRQOL), comorbidities and mortality associated with pulmonary NTM disease. We searched MEDLINE, EMBASE, CINAHL, Scopus Life Sciences, conference proceedings and Google (earliest date available to February 2015) for primary studies. Eligible studies compared populations with and without pulmonary NTM disease in high‐income jurisdictions. We excluded studies on HIV/AIDS. All languages were accepted. Two reviewers followed MOOSE and PRISMA reporting guidelines and independently appraised quality using STROBE. All studies were summarized qualitatively regardless of quality. Of 3193 citations screened, we included 17 studies mostly from Taiwan (n = 5) and the USA (n = 4). Two studies assessed HRQOL; one assessed comorbidities, 11 assessed mortality, and three assessed multiple outcomes. Populations with pulmonary NTM reported significantly worse or similar HRQOL than the general population, depending on the instruments used. Some suggested greater prevalence of having bronchiectasis (n = 2) and greater risk of developing pulmonary tuberculosis (n = 1). Most (n = 7) suggested no difference in mortality, although only one was age‐matched and gender‐matched to the general population. Four suggested NTM populations had higher mortality—two of which compared with the general population and were deemed of high quality, while two compared with non‐NTM patients from hospital. High clinical heterogeneity in study design may explain discordant results. Bias assessments and controlling for confounding were carried out poorly. No consistent trends were observed although there is suggestion of an increased health burden from respiratory diseases and increased mortality associated with pulmonary NTM disease.

Multidrug-resistant tuberculosis: Treatment and outcomes of 93 patients

BACKGROUND Tuberculosis (TB) remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB) poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011. RESULTS Eighty-nine patients were foreign born. Fifty-six percent had a previous diagnosis of TB and most (70%) had only pulmonary involvement. Symptoms included productive cough, weight loss, fever and malaise. The average length of inpatient stay was 126 days. All patients had a peripherally inserted central catheter for the intensive treatment phase because medications were given intravenously. Treatment lasted for 24 months after bacteriologic conversion, and included a mean (± SD) of 5 ± 1 drugs. A successful outcome at the end of treatment was observed in 84% of patients. Bacteriological conversion was achieved in 98% of patients with initial positive sputum cultures; conversion occurred by four months in 91%. CONCLUSIONS MDR TB can be controlled with the available anti-TB drugs.

Multilocus Sequence Typing of Mycobacterium xenopi

ABSTRACT Mycobacterium xenopi is an opportunistic mycobacterial pathogen of increasing clinical importance. Surveillance of M. xenopi is hampered by the absence of tools for genotyping and molecular epidemiology. In this study, we describe the development and evaluation of an effective multilocus sequence typing strategy for M. xenopi.

NTM Disease Caused by M. kansasii, M. xenopi, M. malmoense, and Other Slowly Growing NTM

Slowly growing NTM are very commonly encountered species in the management of NTM pulmonary disease (NTM-PD) and non-pulmonary infections. With the exception of M. avium complex, this chapter discusses 14 of the more problematic species of this group, providing information to guide the clinician in assessing and managing these infections. The commonly encountered M. kansasii, M. xenopi, and M. malmoense are discussed in greatest detail. Discussions include environmental sources of the organism, common patient phenotypes, typical anatomic sites of infection (pulmonary, non-pulmonary, disseminated), epidemiology, clinical presentation, diagnosis, antimicrobial treatment, and monitoring. Highlighted are areas where there is useful information regarding the role of antimicrobial drug susceptibility testing. Although guideline criteria are considered as the starting point for making a diagnosis of NTM-PD, specifically discussed is the concept that species of varying pathogenicity ought to be assessed with commensurate levels of suspicion. To make appropriate diagnostic and treatment decisions, clinicians must carefully consider what is known about the pathogenicity of the species in addition to all available clinical information. Summary tables present information regarding frequency and anatomic site of disease and antimicrobial treatment recommendations reflecting current guidelines and recent literature.