Continuing medical educationTuberculosis in the age of biologic therapy
Section snippets
Mycobacterium tuberculosis: Microbiology
M tuberculosis is a non-motile, non–spore-forming, obligate aerobe responsible for causing the chronic infection known as TB. It has no known animal reservoirs and a slow replication time of approximately 12 hours, as compared to 30 minutes for most other bacteria.4 Mycobacterium species, including M tuberculosis, are distinguished histologically by their “acid-fast” staining. The waxy mycobacterial cell wall resists the destaining of carbofuschin by acid alcohol, and thus retains a red color
United States
The United States experienced a steady decline in the incidence of TB, from a peak of 84,304 cases in 1953 to 22,201 cases in 1985.5 In 1986, a 2.6% increase in cases heralded an era of TB resurgence, with a 16.4% net increase in cases over the subsequent years.6 The Centers for Disease Control and Prevention (CDC) attributes this resurgence to several factors, including HIV infection, TB among foreign-born immigrants, the rise of drug-resistant TB, the decline of TB control programs, and
Transmission
Transmission of TB is almost exclusively via the airborne route. The transmission cycle begins with the production of infectious particles by any activity involving forced expiration, including coughing, sneezing, singing, or breathing. This generates 1 to 5 μm droplets of respiratory secretions, each of which may contain one to three viable bacteria.15 These “droplet nuclei” can remain suspended in the air for hours.15 The likelihood of TB transmission depends on the concentration of organisms
Nonspecific immune response
Nonspecific immune responses begin when pulmonary dendritic cells and macrophages engulf tuberculous organisms in the alveolar spaces.20 The establishment of infection depends on the virulence of the infecting organism and the microbicidal activity of the ingesting macrophage. M tuberculosis has evolved specific mechanisms to avert destruction within the phagosomes of alveolar macrophages. Phagosome maturation is an orderly process involving acidification and subsequent fusion with lysosomes.
Clinical presentation and evaluation of suspected tuberculosis
A careful TB history should include the following: potential exposures, travel to countries where TB is endemic, previous purified protein derivative (PPD) testing, bacille Calmette-Guérin (BCG) vaccination, a previous history of active TB, and type and duration of any anti-TB therapy.30 Comorbidities that increase the risk of TB, such as HIV infection or organ transplantation, should also be elucidated. Homeless persons, intravenous drug users, prisoners, and immigrants may be at greater risk
Biologic treatment and tuberculosis
Biologic therapies represent a class of protein products engineered using recombinant DNA technology. These agents interact with distinct signaling pathways in the immune system to target the immunologic dysfunction underlying several cutaneous and systemic inflammatory conditions. Several biologic drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe chronic plaque psoriasis, including etanercept, infliximab, alefacept, efalizumab, and
Mycobacterium other than tuberculosis and anti-TNF therapy
Cases of nontuberculous mycobacterial infection have been reported in the setting of anti-TNF therapy. A review of the FDA AERS between January 1998 and September 2002 identified 22 cases of nontuberculous mycobacterial infection (species not specified) in association with infliximab use, and seven with etanercept use.48 Subsequent case reports include pulmonary M szulgai infection in a patient initially receiving etanercept for RA, whose clinical course later deteriorated while on adalimumab
Screening for latent tuberculosis infection
Worldwide clinical trial and postmarketing surveillance data reviewed in this paper demonstrate an increased incidence of TB associated with TNF-α blockade. The majority of these cases are presumed to result from reactivation of latent disease, while the rate of new infection is unknown. Both infliximab and adalimumab have black box warnings on their package inserts addressing the risk of TB and the need for screening before initiating therapy. While etanercept initially contained a bold
Diagnosis of active tuberculosis
The diagnosis of active TB differs from LTBI, and requires actual isolation and identification of M tuberculosis. Confirmation of infection may employ positive acid-fast smears, mycobacterial culture, or nucleic acid amplification tests. Both the TST and IGRA are not suitable tests for active disease because of issues of cross-reactivity, an inability to distinguish latent versus active disease, and variable test sensitivity (65-94%).100 As a rule, if clinical suspicion for TB is high, a single
Latent tuberculosis infection
Individuals with either a positive TST or high probability of cutaneous anergy, and who are unable to receive an alternate test for TB (eg, QTF-G assay) should be treated for LTBI through referral to a specialist. Active disease must first be ruled out by history, physical examination, chest radiography, and, when indicated, bacteriologic studies (ie, when there is high clinical suspicion based on these factors). Nine months of daily isoniazid (INH) has been the mainstay of therapy in the
Conclusion
Excitement over the new world of biologic therapies must be tempered by an awareness of the risks that accompany these new medications. It is important that dermatologists who prescribe biologics are also expert in the scope of their risks and the methods to ensure patient safety. Just as technological advances have provided new options for the diagnosis of TB, emerging patterns of mycobacterial resistance have renewed concerns over TB as a major health threat. Only by routine screening for
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Funding sources: None.
Reprints not available from the authors.
Conflicts of interest: Dr Hernandez has served as a consultant for Abbott, Genetech, and Amgen. Drs Cetner, Jordan, Puangsuvan, and Robinson have no conflicts of interest to disclose.