Aspirin effects on lymphocyte cyclic AMP levels in normal human subjects.

In purified lymphocytes from the peripheral blood of healthy human subjects who had ingested therapeutic doses of aspirin, there was a significant decrease in resting cyclic AMP levels as well as a partial inhibition of the rise in cyclic AMP with isoproterenol or prostaglandin E1. These changes were seen as early as 30 min after aspirin ingestion and did not appear to result from aspirin effects on lymphocyte recovery, purity, viability, or relative number of thymus- or bone marrow-derived lymphocytes. In contrast, the direct addition of aspirin to suspensions of purified peripheral lymphocytes did not significantly alter their cyclic AMP levels. However, an effect of aspirin could be obtained in vitro if aspirin was added to unprocessed whole blood during the dextran sedimentation phase of the cell purification. Thus the effect of aspirin on lymphocyte cyclic AMP metabolism, may be indirect, through other cells present in the peripheral blood.

Efficacy of BCG vaccination in prevention of cancer: an update.

From 1949 to 1951, a controlled trial of BCG vaccinations was conducted in Puerto Rico. The 191,827 children, 1-18 years of age, initially enrolled in the study were skin-tested with tuberculin to determine their eligibility for vaccination. A total of 82,269 children were classified as reactors and not vaccinated. Of the 109, 558 nonreactors, 31,586 refused vaccination, 50,634 were vaccinated with BCG, and 27,338 were left unvaccinated as controls. We ascertained the incidence of cancer over an average follow-up period of 23.3 years in the latter two groups using the Puerto Rico Central Cancer Registry. By the end of December 1973, a total of 77 cancers had been diagnosed among the controls and 150 among the vaccinees. The overall incidence of cancer among the two groups was similar. Although a number of differences existed between the vaccinee group and the controls in regard to the incidence of cancer at various "sites", none of these differences was statistically significant. However, when cases of lymphosarcoma and Hodgkin's disease were combined for analysis, a statistically significant excess of cases occurred among the vaccinees. We concluded that BCG vaccination had no protective effect on the subsequent development of cancer in this population. The slight excess of cases of lymphosarcoma and Hodgkin's disease among the vaccinees raised the possibility that BCG may have had an adverse effect.

Tuberculosis control among homeless populations.

The prevalence of tuberculosis infection and disease among homeless persons is high. Several recent outbreaks have been reported in shelters for the homeless. To address this problem, the Centers for Disease Control, Atlanta, convened a group of consultants who made the following recommendations: (1) Tuberculosis should be suspected and sputum samples should be collected from any homeless individual with a productive cough. (2) Diagnosed or suspected tuberculosis in a homeless individual should be immediately reported to the health department. (3) Therapy should be fully supervised by a responsible person, and an intensive multidrug, six-month regimen should be utilized whenever possible. (4) A contact investigation should be conducted around each infectious case, and preventive therapy should be prescribed for high-risk infected individuals. (5) Shelter staff should receive a tuberculin skin test when they start work and every six to 12 months thereafter. (6) Skin test reactors should be considered for preventive therapy according to current guidelines. (7) Installation of ultraviolet lights to reduce transmission should be considered in some situations.

Should women taking antituberculosis drugs breast-feed?

Most of the commonly used antituberculosis drugs are excreted in the breast milk of nursing mothers. However, only a small fraction of the adult dose appears in breast milk, and we estimate that breast-fed infants would receive no more than 20% of the usual therapeutic dose for infants for any of these drugs. Based on these considerations, we believe the risk of toxic reactions to drugs in infants of nursing mothers receiving antituberculosis drugs is very low. Nevertheless, the decision to breast-feed while taking antituberculosis drugs must be an individual one that takes into account the known facts, professional opinion, and the patient's values and preferences.

Acquired immunodeficiency syndrome and extrapulmonary tuberculosis in the United States.

Of 48,712 acquired immunodeficiency syndrome (AIDS) cases reported to the Centers for Disease Control from October 1987 through March 1989, 1239 (2.5%) were diagnosed with extrapulmonary tuberculosis. Extrapulmonary tuberculosis was diagnosed in 1013 (2.3%) of the US-born persons with AIDS, compared with 26 (8%) of the Mexican-born, 82 (13%) of the Haitian-born, and 4 (1%) of the Cuban-born. Patients with AIDS with and without extrapulmonary tuberculosis were similar in age, except that extrapulmonary tuberculosis was relatively rare in patients with AIDS under the age 10. Compared with white homosexual/bisexual men, black race (odds ratio, 2.7), intravenous drug use (odds ratio, 2.0), heterosexual AIDS transmission category (odds ratio, 1.9), and Hispanic ethnicity (odds ratio, 1.6) were independently associated with extrapulmonary tuberculosis. In 1988, extrapulmonary tuberculosis in persons known to be human immunodeficiency virus seropositive represented 21% of national extrapulmonary tuberculosis morbidity.

Tuberculosis and acquired immunodeficiency syndrome--Florida.

Florida reported 1858 cases of the acquired immunodeficiency syndrome (AIDS) and 8455 cases of tuberculosis from January 1, 1981, through October 31, 1986. Of the patients with AIDS, 159 (8.6%) also had tuberculosis, and 154 (1.8%) of the patients with tuberculosis also had AIDS. Among patients with both diagnoses, tuberculosis was diagnosed before AIDS by more than 1 month in 50%, was diagnosed within 1 month before or 1 month after the diagnosis of AIDS in 30%, and was diagnosed more than 1 month after the AIDS diagnosis in 20%. Compared with patients with AIDS only, patients with both diagnoses were also more likely to be Haitian, black (other than Haitian), or Hispanic. Compared with patients with tuberculosis only, patients with both diagnoses were more likely to be younger, male, Haitian, black (other than Haitian), and Hispanic, have extrapulmonary tuberculosis and negative tuberculin skin tests, and have noncavitary chest roentgenograms. These data suggest that patients with AIDS may have an increased risk of tuberculosis and that patients with both diagnoses differ in important demographic and clinical characteristics from patients with AIDS only or tuberculosis only.

Hepatotoxicity from isoniazid and rifampin among children treated for tuberculosis.

To estimate rates of hepatotoxicity in the United States among children treated for tuberculosis, we conducted a retrospective survey of health departments and individual practitioners. We received 874 reports suitable for analysis of children treated during 1977 to 1979. A total of 16 hepatotoxic reactions were reported; 14/430 (3.3%) children receiving isoniazid and rifampin had a hepatotoxic reaction, which approximates the rate seen in adults taking these drugs. Half of the reactions occurred during the first month of therapy, and all of the well-documented reactions were noted during the first 10 weeks. Because the likelihood of hepatotoxicity may be increased with higher drug doses, limiting the dose of isoniazid to 10 mg/kg and that of rifampin to 15 mg/kg may help minimize hepatotoxic reactions. Because more serious disease, especially disseminated tuberculosis, may further increase the risk of hepatotoxicity, close monitoring of such children receiving isoniazid and rifampin should help minimize serious hepatotoxicity. Routine biochemical monitoring may not be necessary for all children, eg, those with mild forms of disease and those with normal pretreatment liver function who are treated with lower drug doses.

Reactivation of tuberculosis in Oklahoma: 1970-1973.

The medical records of 53 patients who had reactivation of tuberculosis between 1970 and 1973 in Oklahoma were reviewed. Reactivation accounted for 4 percent of all cases reported in this period. No correlation was found between race or sex and risk of reactivation. The interval between original diagnosis and reactivation (median 14.0 years) was longer than has been reported in other series but was felt to be an encouraging finding. The most important factor influencing reactivation appeared to be inadequate chemotherapy. Minimal disease appeared to be particulary prone to undertreatment in the past. Patients with reactivation of tuberculosis responded to treatment almost as well as those with a recent diagnosis, as measured by sputum conversion rates. The paucity of patients presenting with reactivated cases after having been adequately treated supports recent recommendations to discharge patients from further followup when treatment is adequate and complete.

Tuberculosis diagnosed at death in the United States.

From 1985 through 1988, 5.1 percent of TB cases reported in the United States were diagnosed at death. Differences in the proportions diagnosed at death by race/ethnicity, sex, and place of birth (United States vs foreign-born) were relatively small. The proportion of cases diagnosed at death increased with age, from 0.7 percent in patients less than 5 years old to 18.6 percent among patients 85 years and older. Only 26.0 percent of cases diagnosed alive were among those 65 years and older, but 60.3 percent of those diagnosed at death were in this age group. Eighteen percent of cases with miliary, meningeal and peritoneal TB were diagnosed at death, compared with 4.8 percent among those with pulmonary TB. These data indicate that TB too often remains unrecognized and that, to prevent continuing deaths from this curable disease, a high index of suspicion of TB remains important, particularly among the elderly and among persons with extrapulmonary sites of disease.

Standard therapy for tuberculosis 1985.

PIP: Numerous clinical trials of chemotherapy for tuberculosis conducted throughout the world over the past 4 decades have established 2 basic principles of treatment: effective treatment requires the initial concomitant administration of at least 2 drugs to which the patient's organisms are susceptible; and cure of tuberculosis requires that treatment continue beyond the time of sputum conversion and amelioration of symptoms. The treatment of tuberculosis was revolutionized in the late 1960s with the introduction of rifampin. Shorter regimens of 6-9 months in duration became possible. Scores of trials of short-course chemotherapy have been conducted, and more are planned. The goals of the new treatment regimens are to achieve effective sterilization of the tuberculous lesion in the shortest time possible. A table lists drugs now in use in the US and Canada and gives the usual doses, common side effects, and important interactions among drugs. Chemotherapeutic regimens acceptable for use in the US and Canada are well-defined combinations of drugs which must be regularly administered in the recommended dosages and rhythm for a specific time period. Regimens should be highly effective, i.e., a relapse rate of less than 5%, and have a low risk of toxic effects. Regimens also should be acceptable to patients and applicable on a community-wide basis. The regimens recommended meet these criteria and are backed by well-conducted clinical trails. A 9-month regimen consisting of isoniazid and rifampin throughout, usually supplemented in the initial phase by ethambutol, streptomycin, or pyrazinamide, is a well-tolerated regimen which will cure virtually all patients with susceptible organisms. The initial daily phase may last 2-8 weeks; the continuation phase may be administered daily or twice weekly. These regimens have an overall bacteriologic relapse rate of between zero and 4%. When 4 drugs -- isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin -- are given under close during supervision during the initial 2 months of daily or "induction" therapy, followed by an additional 4 months of isoniazid and rifampin, the results have been excellent. Where primary resistance to isoniazid or streptomycin is suspected, the patient should be placed on 1 of the following 3 regimens: isoniazid, rifampin, and ethambutol; isoniazid, rifampin, pyrazinamide, and streptomycin; or isoniazid, rifampin, pyrazinamide, and ethambutol. Short-course chemotherapy for extrapulmonary tuberculosis and chemotherapy of tuberculosis in children are reviewed along with several conditions which affect therapy -- tuberculosis during pregnancy, renal and hepatic disease, cancer and other conditions associated with immunosuppression, and drug interaction.^ieng

Variations in national health care practices and behaviours and their influence on international research.

Multinational clinical trials are valuable to the understanding of global health problems, but they pose special problems. Our experience with a multinational trial of isoniazid (INH) preventive therapy for tuberculosis revealed marked variation among the seven participating countries in the amount of tuberculosis screening prior to the trial; this variation contributed to the observed differences in the risk of tuberculosis among the countries. The incidence of 'uncooperativeness' and drug side-effects, and the proportion of participants who complied with and completed treatment also varied significantly from country to country. These differences in completion and compliance served to differentially alter the expected risk of tuberculosis among the three regimens being studied. For all factors investigated, variation from country to country was greater than variation from dispensary to dispensary within a country. This suggests that cultural and other national characteristics are more potent determinants of health care practices and behaviours than patient and health care practitioner characteristics.

Tuberculin skin testing of hospital employees: infection, "boosting," and two-step testing.

The prevalence of tuberculous infection (i.e., reactions greater than or equal to 10 mm to 5 tuberculin units of purified protein derivative; Mantoux skin test) was determined among employees of 10 hospitals located throughout the United States. The risk of infection was strongly associated with age and race/ethnicity; nonwhites and older individuals were at higher risk. The prevalence of infection among hospitals varied threefold, from 7.0% to 21.4%. After adjusting for differences in the characteristics of employee groups (e.g., age, race/ethnicity, and sex), twofold differences among hospitals were still observed. The occurrence of "boosting" on retest was also studied. Among the different hospitals, the rate varied from 0% to nearly 10%. Race/ethnicity and age were the characteristics most closely associated with boosting. From our data and other data in the literature, we conclude that all hospitals should use two-step testing at least on a pilot basis. Our calculations suggest that two-step testing for employees over 35 years of age could be cost effective if the booster rate is greater than 1% of the employees retested.

Facilitating use of analytic methods at a federal agency.

Identification and application of appropriate analytic methods are critical pieces of the foundation of science. Because of the increasingly complex issues federal agencies face and the increasing importance of addressing those issues with multi-disciplinary teams that offer knowledge and skills in many methods areas, it is important that agencies foster coordinated integration of analytic methods. This report discusses the Centers for Disease Control and Prevention's (CDC's) evolving needs regarding analytic methods and includes activities that CDC has undertaken to facilitate a coordinated approach to the use of the statistical sciences. We introduce a new framework for facilitating coordination in analytic methods as a hybrid model, blending attributes of centralized and decentralized resource models. This coordinating focus approach offers assets of timeliness, efficiency, and effectiveness, as well as fosters strengthened relationships among scientists and increased collaboration among scientific disciplines.

Enhancing patient compliance with tuberculosis therapy.

A major determinant of the outcome of tuberculosis treatment is patient compliance; nevertheless, 20 to 50 per cent of patients fail to complete therapy. The consequences of failure to complete therapy include prolonged communicability, relapse, prolonged and more expensive therapy, development of drug resistance, and death. Noncompliance is a significant factor leading to the persistence of tuberculosis in the United States. Although one-to-one counseling offers the greatest impact for improving compliance, other strategies, such as the use of enablers, incentives, and directly observed therapy, are important as well.

The epidemiology of tuberculosis in the United States. Implications for diagnosis and treatment.

Tuberculosis in the United States is primarily and increasingly a disease of minorities and the foreign-born. Tuberculosis among non-Hispanic whites is predominantly a disease of the elderly, whereas among minorities and the foreign-born, it is primarily concentrated in young adults. In the past few years, tuberculosis has increased among young adults, especially those who are black or Hispanic. Available data support the hypothesis that the spread of human immunodeficiency virus infection has increased the risk of tuberculosis. A substantial proportion of tuberculosis in the United States is potentially preventable through the administration of preventive therapy to high-risk populations.

Behavioral and social sciences at the Centers for Disease Control and Prevention. Critical disciplines for public health.

The mission of the Centers for Disease Control and Prevention (CDC) is to promote health and quality of life by preventing and controlling disease, injury, and disability. Fifty years ago, CDC's efforts were focused on epidemiologic and laboratory studies of malaria, typhus, and plague. Today, CDC's activities cover a broad range of diseases and conditions, and a broader range of disciplines are required to address these diverse public health problems. The behavioral and social sciences have a critical role to play in helping the public understand risk group characteristics and the frequency, context, and determinants of risky behaviors and in developing, implementing, and assessing prevention programs. CDC is taking steps to foster an environment in which behavioral and social sciences can flourish and to integrate these sciences into all of CDC's prevention activities. Other articles in this section describe the breath and nature of the contributions of behavioral and social sciences at CDC.

Tuberculosis: an increasing problem among minorities in the United States.

Although the number of tuberculosis cases reported annually in the United States has decreased markedly during the past three and a half decades, the decrease among whites has been considerably greater than among nonwhites. As a result of this widening gap, nearly two-thirds of the cases reported in 1987 occurred in minority populations and, for the first time in history, the number of cases among blacks exceeded the number of cases among non-Hispanic whites. From 1985 to 1987, tuberculosis among blacks increased 6.3 percent and among Hispanics, by 12.7 percent, but it decreased 4.8 percent among non-Hispanic whites. Much of the increase appears attributable to tuberculosis occurring among persons infected with the human immunodeficiency virus (HIV). Although there are many obstacles to the elimination of the disease in minority populations, numerous strategies have been developed and are being implemented to address this situation.

Isoniazid hepatitis among pregnant and postpartum Hispanic patients.

On request of local health officials, the authors investigated isoniazid (INH) hepatitis morbidity and mortality among patients attending an Hispanic prenatal clinic. Among 3,681 women treated with INH during and after pregnancy to prevent tuberculosis (TB), 5 developed INH hepatitis, and 2 of the 5 women died. Comparison with previously collected Public Health Service data concerning 3,948 nonpregnant women, using the Cox proportional hazards model, revealed a 2.5-fold increased risk of INH hepatitis in the prenatal clinic group. The mortality rate was four times higher in the prenatal clinic group. However, statistical power was low because of the small number of cases, and neither of these findings was statistically significant (P greater than 0.05). In the absence of controlled studies, the issue of INH safety during the perinatal period remains unresolved. Nevertheless, current American Thoracic Society-Centers for Disease Control recommendations regarding TB screening, implementation of INH chemoprophylaxis programs, and adequate monitoring of individuals on INH should be adhered to. The results of this investigation raise concern that deviations from existing policy may contribute to unnecessary morbidity and mortality.

The need for epidemic intelligence.

The past decade has witnessed an unprecedented upturn in tuberculosis morbidity and outbreaks of difficult- to-treat and highly lethal multidrug-resistant tuberculosis. In the early 1990s, a national consensus developed among public health officials to define more comprehensively the problem, and in January 1993, expanded tuberculosis surveillance was implemented nationwide. Carefully selected epidemiologic and case management variables were added to the Report of Verified Case of Tuberculosis form. Information is collected on the health status and treatment of patients, including human immunodeficiency virus status, drug susceptibility test results, and the initial drug regimen. Completion of therapy and use of directly observed therapy are also monitored. The new surveillance system allows a comparison of the quality of care of patients in the public and private sectors. Additional epidemiologic variables include membership in high-risk groups (the homeless, residents of correctional or long-term care facilities, migrant workers, health care workers, and correctional employees) and substance abuse (injecting drug use, non-injecting drug use, and excess alcohol use). The additional information derived from expanded tuberculosis surveillance is crucial to optimal patient management, policy development, resource allocation, as well as program planning, implementation, and evaluation at Federal, State, and local levels.