Nontuberculous Mycobacteria and Anti–TNF-α | CDC EID

EID Journal Home > Volume 15, Number 10–October 2009
Volume 15, Number 10–October 2009
Research
Nontuberculous Mycobacteria Infections and Anti–Tumor Necrosis Factor-α Therapy
Kevin L. Winthrop, Eric Chang, Shellie Yamashita, Michael F. Iademarco, and Philip A. LoBue
Author affiliations: Oregon Health and Sciences University, Portland, Oregon, USA (K.L. Winthrop, E. Chang, S. Yamashita); US Public Health Service, Washington, DC, USA (M.F. Iademarco); and Centers for Disease Control and Prevention, Atlanta, Georgia, USA (P.A. LoBue)

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Abstract
Patients receiving anti–tumor necrosis factor-α (anti–TNF-α) therapy are at increased risk for tuberculosis and other granulomatous diseases, but little is known about illness caused by nontuberculous mycobacteria (NTM) in this setting. We reviewed the US Food and Drug Administration MedWatch database for reports of NTM disease in patients receiving anti–TNF-α therapy. Of 239 reports collected, 105 (44%) met NTM disease criteria. Median age was 62 years; the majority of patients (66, 65%) were female, and most (73, 70%) had rheumatoid arthritis. NTM infections were associated with infliximab (n = 73), etanercept (n = 25), and adalimumab (n = 7); most patients were taking prednisone (n = 68, 65%) or methotrexate (n = 58, 55%) concurrently. Mycobacteria avium (n = 52, 50%) was most commonly implicated, and 9 patients (9%) had died at the time their infections were reported. A high rate of extrapulmonary manifestations (n = 46, 44%) was also reported.

Nontuberculous mycobacteria (NTM) are a large, diverse group of environmental organisms ubiquitous in water and soil (1). They cause a variety of diseases in humans, notably severe, protracted lung disease in patients with underlying lung disorders. Conditions such as bronchiectasis, emphysema, previous tuberculosis (TB) or other lung infections, cystic fibrosis, rheumatoid arthritis, and other chronic diseases with pulmonary manifestations can predispose a person to NTM pulmonary disease (2). In addition to lung infections, NTM cause skin and soft tissue infections, lymphadenitis (predominantly in young children), and disseminated disease in HIV-infected patients or others with severely compromised immune systems. The immunologic mechanism and related dysfunction that predispose persons to NTM disease are largely unknown, although defects in interleukin-12 or interferon-γ production are known to increase the risk for disseminated NTM disease in humans (3).

Although the epidemiology of NTM disease is not well described, the belief that these infections are increasing in prevalence, particularly among women, is widespread (2). Assessment of the epidemiology of these infections may be increasingly useful because newer forms of biologic, immunosuppressive therapies have become widely used for treating patients with rheumatoid arthritis, Crohn disease, and other autoimmune inflammatory conditions. Many of these conditions are associated with lung manifestations known to be associated with NTM pulmonary infections (2).

To date, TB and NTM infections and concurrent biologic therapies that inhibit tumor necrosis factor-α (TNF-α) have been reported. These therapies include infliximab (Remicade; Centocor, Malvern, PA, USA), etanercept (Enbrel; Immunex, Seattle, WA, USA), and adalimumab (Humira; Abbott Biotechnology, Abbott Park, IL, USA), which have been approved in the United States and elsewhere to treat patients with rheumatoid arthritis and selected other autoimmune inflammatory diseases (4). Because TNF-α is integral to granuloma generation and maintenance (5,6), patients using these agents are at increased risk for granulomatous infections, including activation of latent TB infection (7,8).

The US Food and Drug Administration (FDA) postmarketing surveillance system (MedWatch) (www.fda.gov/medwatch) collects voluntary reports of adverse drug events from physicians. The most recent review of this system in 2004 for reports of granulomatous infections that occurred during TNF-α blockade found that mycobacteria disease was more common than other granulomatous diseases; TB was reported 5–10× more frequently than NTM, dimorphic fungi, and other intracellular infections in this setting (7). (Although this program does not specifically target participation outside the United States, it also includes nondomestic case reports.) Subsequently, much attention has been focused on prevention of TB in patients who are using anti–TNF-α agents. To date, little is known regarding the types and relative frequencies of NTM infections that occur in such patients.

We recently conducted a survey among infectious disease physicians within the Emerging Infections Network of the Infectious Diseases Society of America (IDSA). This survey suggested that cases of NTM disease associated with anti–TNF-α therapy occur twice as frequently as cases of TB associated with anti–TNF-α therapy in the United States (9). NTM infections are likely underreported to the FDA, relative to TB, for a variety of reasons (10). NTM disease is generally insidious, sometimes difficult to diagnose, and is not reportable to health authorities. Accordingly, we reviewed the MedWatch database for NTM reports through January 1, 2007, to evaluate whether these case reports met clinical case criteria, to describe their clinical spectrum and outcome, and to evaluate the relative reporting frequency of cases among the different anti–TNF-α agents now in widespread use.

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