Cara D. Varley

Mycobacterial diseases and antitumour necrosis factor therapy in USA

Objective In North America, tuberculosis and nontuberculous mycobacterial (NTM) disease rates associated with antitumour necrosis factor α (anti-TNFα) therapy are unknown. Methods At Kaiser Permanente Northern California, the authors searched automated pharmacy records to identify inflammatory disease patients who received anti-TNF therapy during 2000–2008 and used validated electronic search algorithms to identify NTM and tuberculosis cases occurring during anti-TNF drug exposure. Results Of 8418 anti-TNF users identified, 60% had rheumatoid arthritis (RA). Among anti-TNF users, 18 developed NTM and 16 tuberculosis after drug start. Anti-TNF associated rates of NTM and tuberculosis were 74 (95% CI: 37 to 111) and 49 (95% CI: 18 to 79) per 100 000 person-years, respectively. Rates (per 100, 000 person-years) for NTM and tuberculosis respectively for etanercept were 35 (95% CI: 1 to 69) and 17 (95% CI: 0 to 41); infliximab, 116 (95% CI: 30 to 203) and 83 (95% CI: 10 to 156); and adalimumab, 122 (95% CI: 3 to 241) and 91 (95% CI: 19 to 267). Background rates for NTM and tuberculosis in unexposed RA-patients were 19.2 (14.2 to 25.0) and 8.7 (5.3 to 13.2), and in the general population were 4.1 (95% CI 3.9 to 4.4) and 2.8 (95% CI 2.6 to 3.0) per 100, 000 person-years. Among anti-TNF users, compared with uninfected individuals, NTM case-patients were older (median age 68 vs 50 years, p<0.01) and more likely to have RA (100% vs 60%, p<0.01); whereas, tuberculosis case-patients were more likely to have diabetes (37% vs 16%, p=0.02) or chronic renal disease (25% vs 6%, p=0.02). Conclusions Among anti-TNF users in USA, mycobacterial disease rates are elevated, and NTM is associated with RA.

The reliability of diagnostic coding and laboratory data to identify tuberculosis and nontuberculous mycobacterial disease among rheumatoid arthritis patients using anti-tumor necrosis factor therapy.

Anti‐tumor necrosis factor‐alpha (anti‐TNF) therapies are associated with severe mycobacterial infections in rheumatoid arthritis patients. We developed and validated electronic record search algorithms for these serious infections.

Initiation of Anti-TNF Therapy and the Risk of Optic Neuritis: From the Safety Assessment of Biologic ThERapy (SABER) Study

PURPOSE To evaluate the incidence of optic neuritis (ON) in patients using anti-tumor necrosis factor (TNF) alpha therapy. DESIGN Retrospective, population-based cohort study. METHODS We identified new users of anti-TNF therapy (etanercept, infliximab, or adalimumab) or nonbiologic disease-modifying antirheumatic drugs (DMARDs) during 2000-2007 from the following data sources: Kaiser Permanente Northern California, Pharmaceutical Assistance Contract for the Elderly, Tennessee Medicaid, and National Medicaid/Medicare. Within this cohort, we used validated algorithms to identify ON cases occurring after onset of new drug exposure. We then calculated and compared ON incidence rates between exposure groups. RESULTS We identified 61 227 eligible inflammatory disease patients with either new anti-TNF or new nonbiologic DMARD use. Among this cohort, we found 3 ON cases among anti-TNF new users, occurring a median of 123 days (range, 37-221 days) after anti-TNF start. The crude incidence rate of ON across all disease indications among anti-TNF new users was 10.4 (95% CI 3.3-32.2) cases per 100 000 person-years. In a sensitivity analysis considering current or past anti-TNF or DMARD use, we identified a total of 6 ON cases: 3 among anti-TNF users and 3 among DMARD users. Crude ON rates were similar among anti-TNF and DMARD groups: 4.5 (95% CI 1.4-13.8) and 5.4 (95% CI 1.7-16.6) per 100 000 person-years, respectively. CONCLUSION Optic neuritis is rare among those who initiate anti-TNF therapy and occurs with similar frequency among those with nonbiologic DMARD exposure.

Distinguishing Tuberculosis from Nontuberculous Mycobacteria Lung Disease, Oregon, USA

To determine whether tuberculosis (TB) and nontuberculous mycobacteria (NTM) infection patients could be distinguished from one another with limited information, we compared pulmonary TB and NTM patients during 2005–2006. Our finding that age, birthplace, and presence of chronic obstructive pulmonary disease could differentiate TB and NTM disease could assist tuberculosis control efforts.

The tolerability of linezolid in the treatment of nontuberculous mycobacterial disease

Nontuberculous mycobacteria (NTM) disease is increasingly common and more prevalent than tuberculosis (TB) in many areas of the world [1, 2]. Treatment is challenging due to the multidrug-resistant nature of these organisms, and the need for prolonged multidrug therapy [2–4]. Linezolid can be tolerated long-term in the treatment of nontuberculous mycobacterial disease http://ow.ly/FilUm

Pulmonary disease associated with nontuberculous mycobacteria, Oregon, USA.

To the Editor: Nontuberculous mycobacteria (NTM) are environmental organisms ubiquitous in soil and water, including municipal water supplies. When inhaled, these organisms cause chronic, severe lung disease in susceptible persons (1). Recent epidemiologic studies suggest NTM pulmonary disease is increasingly prevalent in North America, with annual incidence rates of 13 cases per 100,000 population in persons >50 years of age and 2–4-fold higher in older age groups (2–4). The current distribution of pulmonary NTM disease has been poorly characterized with regard to environment, climate, and other factors. We recently performed a statewide NTM surveillance project in Oregon, United States, where we documented higher pulmonary disease rates within the moister, temperate western regions of the state. Oregon is bisected north-south by mountains into 2 distinct climate zones. Western Oregon, where 87% of the state’s population lives, is temperate and wet; eastern Oregon is primarily rural, with an arid, high desert climate. Our goal was to evaluate whether disease clustering within the state could be explained by population density. For all Oregon residents who had newly diagnosed and existing pulmonary NTM disease during 2005 and 2006, we used case-patient home ZIP code and county of residence to construct statewide disease maps (4). We obtained state ZIP code and county-level census data for 2005 and 2006 from the Portland State University Population Research Center and used Oregon Office of Rural Health criteria to designate ZIP codes as urban or rural and counties as rural (nonmetropolitan), micropolitan, or metropolitan (5,6). Unlike ZIP code data, which lacked age information, county census data were age stratified and consisted of population numbers aggregated in 5-year age groups (e.g., 0–4 years, 5–9 years). Because nearly all pulmonary NTM disease occurred in persons >50 years of age, we calculated age-adjusted disease prevalence rates (by using 95% Poisson exact confidence intervals) for patients >50 years of age in the county census data. We used the Cochran-Armitage test for trend to evaluate differences in rates by rural, micropolitan, and metropolitan county designations. Statewide, 385 (94%) of 411 NTM cases occurred among residents of western Oregon, and the crude rate of annual disease prevalence was significantly higher in western than in eastern Oregon (6.0 vs. 2.7/100,000; p 50 years of age were similar (7.6 cases/100,000 population) to those in rural counties within western Oregon (6.5/100,000). Table Prevalence of pulmonary nontuberculous mycobacterial disease, by geographic region and population density, Oregon, USA, 2005 and 2006* In Oregon, where most pulmonary NTM disease is caused by Mycobacterium avium complex (MAC), our findings suggest that the higher rates of disease in the wet western portion of the state are best explained by differences in population density (4). Disease rates there were highly correlated with increasing population density, and in rural areas of western Oregon, disease rates were similar to those in the arid, primarily rural eastern portion of the state. Humans presumably are exposed to NTM daily through showering, bathing, and other activities where water or soil is aerosolized (7). Previous environmental studies suggest that persons living in urban areas could potentially have greater NTM exposure during these activities because NTM is more prevalent in piped networks of municipal water systems than in well-water systems primarily used in rural regions (8). A study in Japan in the 1980s found a similar association of pulmonary NTM disease (primarily MAC) with urban and wet environments compared with arid and rural regions in our study but unlike our study was not able to evaluate differences in disease rates between urban and rural areas independent of climate differences (9). A 1979 Texas study found an association of pulmonary NTM with rural living, although this result was driven by M. kansasii disease, and rates of MAC were actually higher in rural areas (10). These and other similar studies were conducted decades ago when the epidemiology of NTM was substantially different (i.e., predominantly a disease of male patients) and before the formulation of the 2007 American Thoracic Society/Infectious Diseases Society of America pulmonary NTM disease criteria (1). We were limited in drawing firm conclusions about why pulmonary NTM is more common in urban areas because we were not able to evaluate patients or regional water systems within our study. Persons living rurally might be less likely to seek medical care and thus have NTM diagnosed, which would account for the differences in our study. However, given the reasonably close proximity of western Oregon’s rural regions to major medical centers, we believe this scenario is unlikely. Our findings suggest that pulmonary NTM disease is closely associated with urban living. We suspect the difference in disease rates between urban and rural areas might reflect differences in host exposure to these pathogens. Further studies should be undertaken to elucidate the environmental exposures associated with pulmonary NTM.

Persistence of Staphylococcus aureus colonization among individuals with immune-mediated inflammatory diseases treated with TNF-α inhibitor therapy

OBJECTIVE We investigated the relationship between Staphylococcus aureus colonization and the use of immunosuppressive therapies in patients with immune-mediated inflammatory diseases (IMIDs). METHODS We prospectively enrolled IMID patients from the rheumatology and dermatology departments of Oregon Health & Science University. At enrolment, we surveyed patients for S. aureus infection risk factors and those using immune-modulating therapies, and evaluated their colonization status with bilateral nares and inguinal fold cultures. Patients were asked to follow up 6-12 months later for reassessment of colonization status by repeat culture. S. aureus isolates were tested for the presence of methicillin resistance by PCR. RESULTS We enrolled a total of 548 IMID patients. At enrolment, 219 (40.0%) patients were colonized with S. aureus, of which 27 (12.3%) were methicillin-resistant S. aureus (MRSA). Baseline colonization rates were similar between TNF-α inhibitor users and non-users (40.5% and 39.4%, P = 0.79), but were significantly higher for psoriasis patients compared with those with RA (43.5% and 31.8%, P = 0.02). A total of 384 patients were available for follow-up. Patients who were colonized at enrolment were more likely to be colonized at follow-up if they were treated with TNF-α inhibitors during the study as compared to patients without TNF-α inhibitor exposure [odds ratio (OR) = 2.2 (95% CI 1.1, 4.2), P = 0.02]. CONCLUSION Patients with psoriasis are more likely to be colonized with S. aureus than patients with RA. Patients who are colonized with S. aureus are more likely to remain colonized if exposed to TNF-α inhibitors.

Disseminated Nontuberculous Mycobacteria in HIV-Infected Patients, Oregon, USA, 2007–2012

We determined disseminated nontuberculous mycobacteria incidence in the HIV-infected population of Oregon, USA, during 2007–2012 by using statewide laboratory surveillance. We identified 37 disseminated nontuberculous mycobacteria cases among 7,349 patients with median annual incidence of 110/100,000 HIV person-years and the highest incidence in those with CD4 counts <50 cells/mm3 (5,300/100,000 person-years).

Tuberculosis of the nasolacrimal duct.

Nasolacrimal tuberculosis is rare. The authors present a young Peruvian-born female with subacute onset of right eye epiphora, isolated right inferior turbinate enlargement, and ipsilateral cervical lymphadenopathy. Turbinate and neck mass incisional biopsies demonstrated histopathological findings consistent with tuberculosis. QuantiFERON-TB Gold-In-Tube testing was positive. Complete resolution of symptoms occurred after dacryocystorhinostomy and 9 months of standard 4-drug antituberculosis therapy. Tuberculosis of the nasolacrimal duct is highly unusual but should be considered in patients with tuberculosis risk factors who present with nasolacrimal obstruction from an inferior turbinate mass.

Long-term outcomes in a population-based cohort with respiratory nontuberculous mycobacteria isolation

Rationale: The natural history of nontuberculous mycobacteria (NTM) respiratory infection in the general population is poorly understood. Objectives: To describe the long‐term clinical, microbiologic, and radiographic outcomes of patients with respiratory NTM isolates. Methods: We previously identified a population‐based cohort of patients with respiratory NTM isolation during 2005‐2006 and categorized patients as cases or noncases using the American Thoracic Society/Infectious Diseases Society of America pulmonary NTM disease criteria at that time. During 2014‐2015, we reviewed medical charts of patients alive on January 1, 2007. Outcomes of interest were the proportion of baseline noncases who later met case criteria and the proportions of patients with culture conversion or findings consistent with persistent disease at least 2‐5 years and at least 5 years after first isolation. We defined disease persistence radiographically as infiltrate, nodules, or cavities and microbiologically as a positive respiratory mycobacterial culture. We used logistic regression to evaluate factors associated with evidence of persistence. Results: The study included 172 patients (62% of 278 eligible); those not included either refused consent (n = 47) or were not located (n = 56). One hundred two (59%) included patients met case criteria at baseline. Mycobacterium avium complex was commonly isolated among baseline cases (n = 91 [89%]) and noncases (n = 52 [74%]). Overall, 57 (55%) baseline cases had died, as compared with 43 (61%) noncases (P = 0.47). Among baseline noncases, only four (5.7%) later met case criteria. Overall, 55 (54%) baseline cases and 6 (9%) noncases initiated NTM treatment. Among cases, cultures were converted in 25 (64.1%) treated versus 4 (40%) untreated patients (P = 0.04). Of 89 cases alive 2 years after isolation, 61 (69%) had additional radiography, and 35 (39%) had respiratory cultures. Of these individuals, 54 (89%) had radiographic evidence and 17 (49%) had microbiologic evidence of disease persistence at 5 years after first isolation. These figures were 36 (82%) and 13 (54%), respectively. Women were more likely to have persistent radiographic findings and microbiologic persistence, and patients with chronic obstructive pulmonary disease were less likely to have microbiologic persistence. Conclusions: In the general population, follow‐up beyond 2 years of patients with respiratory NTM isolation is limited. Among those with additional evaluations, at least half of individuals have persistent positive cultures or radiographic findings consistent with NTM at least 2 years after isolation.