Management of Health Care Workers after Inadvertent Exposure to Tuberculosis: A Guide for the Use of Preventive Therapy

In a recent paper in Annals [1], Sepkowitz reviewed the changing attitudes during the last 70 years concerning the tuberculosis risk to hospital workers. These attitudes vary widely, from a firm conviction that workers are at no increased risk to the more realistic view that the risk is considerable. Israel and colleagues [2] reported that in the 1930s, 48% of student nurses at the Philadelphia General Hospital became infected within the first year of working at the hospital, 86% within 2 years, and 100% within 3 years. Tuberculosis developed in 62 of these nurses (9.7%) [2]. Because of the growing frequency of exposure to patients with active tuberculosis in hospitals, the Centers for Disease Control and Prevention now requires, among other measures, that hospitals become serious about periodic tuberculin testing of employees [3]. Most new tuberculous infections of health care workers should be detected by skin test conversion in the required annual retesting of nonreactors. In otherwise healthy persons, the infection can then be cured with 93% to 98% certainty by administration of isoniazid for 6 to 12 months before tuberculosis has developed [4-6]. After a period during which the importance of annual screening of hospital employees was debated [7, 8], the concern over occupational exposure of health care workers is now intensifying as the incidence of tuberculosis increases [9-13]. This is occurring at a time when, because of good public health work in recent decades, the prevalence of tuberculin reactivity, and thus some acquired immunity from an earlier infection, is at its lowest point ever in the United States. Inevitably, physicians will be called on more frequently to advise individuals and infection control nurses on the indications for preventive therapy after occupational exposure to tuberculosis. It has been well shown that the greater the exposure, the greater the chance for developing clinical tuberculosis [14, 15]. Persons at risk for developing tuberculosis should be given appropriate preventive therapy [5], but those at little risk should not be subjected to the potential of drug toxicity. The problem is deciding who among the exposed persons is at significant risk and who is not. Because isoniazid is not completely without risk, it should be given only if the risk for tuberculosis warrants it. Therefore, the first decision to make is whether the exposure is significant. My objective is to review data from six intense exposures of hospital personnel and to provide a guide for the most effective use of isoniazid to prevent tuberculosis in such situations. Background It is widely accepted that a healthy person with a positive tuberculin skin test result is at reduced risk for reinfection from subsequent exposure [16]. However, no recent studies support this premise, and there are several reports of well-documented reinfection [17-19]. The growing incidence of drug-resistant tuberculosis in urban hospitals raises this previously academic question to one of practical importance. Animal studies have consistently shown that an inactive primary tuberculous infection affords great immunity against developing tuberculosis from reinfection [20, 21], and epidemiologic studies suggest a similar protection in humans [22, 23]. However, several prominent European epidemiologists contend that exogenous reinfection is the principal cause of adult tuberculosis in developing countries where reexposure is extremely common [24, 25]. A controlled trial to determine the protection against reinfection from a healed tuberculous infection is precluded on ethical grounds. Thus, I have approached the question by studying experiments of nature, that is, inadvertent heavy tuberculosis exposures of health care workers for whom accurate records of skin test results before and after exposure are available. Efforts at a meta-analysis to supplement our experience were frustrated by wide variations in conditions, criteria for conversion of the tuberculin skin test result, and a paucity of information on the tuberculin skin test result status of all exposed persons before exposure. Such information is essential to differentiate tuberculin skin test reactors of long standing from skin test conversions related to the exposure. Data Sources and Definitions For this paper I draw on 5 outbreaks that ran their course before the chemotherapy era, 6 from the recent literature, and 22 among nursing home residents (Table 1). The recent outbreaks were all aborted by prompt preventive therapy, thus preventing many cases that otherwise would have developed. Table 1. Tuberculin Skin Test Status and Development of Tuberculosis after Exposure* It is important to define terms as used in this paper. The definition of a positive intradermal tuberculin skin test result has changed over time from an induration 5 mm from 1 unit of purified protein derivative 50 years ago to 10 mm from 5 units for the past 30 years. Now, an induration 5 mm is considered a positive result when human immunodeficiency virus (HIV) infection is suspected. Nonreactor and tuberculin skin test-negative indicate a reaction smaller than a given author's cut-point (Table 2). Reactor and skin test-positive signify a documented positive reaction as defined by the author before the exposure. Converter and conversion mean an increase of specified amount (shown for the six recent studies in Table 2) in the size of the skin test result after exposure from a reaction of less than 5 mm before exposure. In the studies in which I was involved, we used an increase 15 mm as recommended for elderly persons in nursing homes [26] because it more reliably distinguishes conversions from simple boosted or recalled reactions. Nonconverter signifies persons who remain skin test negative at least 8 weeks after exposure and may be considered uninfected [27]. Preventive chemotherapy or chemoprophylaxis means a course of isoniazid 300 mg daily for 6 to 12 months. Tuberculosis case refers to someone with clinical tuberculosis or isolation of Mycobacterium tuberculosis from sputum at least 8 weeks after exposure. Table 2. Criteria for Positive Skin Test Result and for Conversion* Reinfection tuberculosis refers to disease that develops as a result of reexposure to tuberculosis of a known reactor. The terms normal and healthy simply mean not infected by HIV or otherwise seriously immunocompromised, regardless of tuberculin status. In analyses of results of exposure of nursing home residents in Arkansas, the term no exposure is used to designate nursing homes in which no infectious case (sputum smear-positive) and no tuberculin conversions had been found in 7 years. Heavy exposure designates nursing homes in which an infectious case (sputum smear- and culture-positive) was found in association with skin test conversion in 25% of nonreactors. The strength of the data reviewed here lies in the availability of reliable skin test results before exposure, which permits accurate classification of each person by skin test result status. The weakness lies in the paucity of data on the outcome of exposed tuberculin reactors in older reports and in the fact that the full impact of the exposure of nonreactors is obscured by prompt treatment with isoniazid in most converters. Outbreaks in the Era before Chemotherapy In her review of 109 epidemics of tuberculosis, Lincoln [28] emphasizes that for a tuberculosis outbreak to occur, a large proportion of the individuals exposed must be tuberculin negative. This state is usually associated with a lack of acquired immunity seen in. geographic areas where the rate of tuberculosis is very low [28]. Few physicians have experienced the devastation once seen after a heavy exposure to tuberculosis because outbreaks today are generally aborted by preventive therapy with isoniazid. Two classic papers remind us of the havoc such outbreaks can wreak when they run their natural course (Table 1). Heimbeck [29] reported that 210 (95%) of 220 tuberculin skin test-negative nursing students converted to positive during 3 years of training and that 48 (22%) of these developed tuberculosis. This is strikingly different from 3 of 200 initially skin test-positive students (1.5%) who developed tuberculosis, possibly as reactivation of their earlier infection. Hyge [30] reported that 70 (67%) of 105 skin test-negative students converted to positive after exposure to an infectious teacher and that 41 (59%) of these developed tuberculosis. Of 130 skin test-positive classmates, only 2 (1.5%) developed tuberculosis, again possibly from reactivation of an earlier infection. No nonconverter developed the disease. Finally, among the 109 outbreaks summarized by Lincoln [28], 3 involved adults and provided the information necessary for epidemiologic analysis (Table 1). Among these, 176 (30%) of 591 who were skin test negative before exposure converted to positive; 78 (44%) of these developed tuberculosis. Although the author did not explicitly state that no tuberculosis developed among the 134 persons who had positive skin test results before exposure, the point of the article is that few, if any, did. Experience in More Recent Outbreaks Catanzaro [31] reported on 51 health care workers who had been exposed to tuberculosis during bronchoscopy of a patient with pulmonary tuberculosis. Tuberculin skin test conversion occurred in 14 (31%) of the 45 who were skin test negative, 2 (14%) of whom developed tuberculosis before chemotherapy could be started. The 12 treated converters, 31 nonconverters, and 6 known reactors, none of whom was treated, remained well. (The number of reactors exposed and follow-up of all persons were obtained by personal communication with Dr. A. Catanzaro). Kantor and colleagues [32] reported that 9 (16%) of 56 tuberculin skin test-negative health care workers showed skin test conversion after exposure to a patient with tuberculosis. Three (33%) had developed tuberculosis before the