Lee B. Reichman

INCIDENCE OF TUBERCULOSIS IN THE UNITED STATES AMONG HIV-INFECTED PERSONS. THE PULMONARY COMPLICATIONS OF HIV INFECTION STUDY GROUP

Among opportunistic pathogens associated with the acquired immunodeficiency syndrome (AIDS), Mycobacterium tuberculosis is distinguished by its relative virulence and potential for person-to-person transmission. Persons infected with human immunodeficiency virus (HIV) are particularly susceptible to tuberculosis, both from the reactivation of latent infection and from new infection with rapid progression to active disease [1-4]. The annual incidence of tuberculosis in the United States was 8.7 per 100 000 persons in 1995 [5], but rates 1000-fold higher have been reported in some HIV-seropositive populations [6-14]. Most studies have been restricted by geography, HIV-risk group, or specific high-prevalence settings; such restrictions have resulted in an inaccurate assessment of the overall effect of the HIV epidemic on the incidence of tuberculosis in the United States [15, 16]. The Pulmonary Complications of HIV Infection Study (PCHIS) [17] prospectively followed HIV-seropositive patients who had demographic variables similar to those of patients with AIDS in the United States. Participants with asymptomatic or symptomatic HIV infection were recruited from sites in the eastern, midwestern, and western United States. A previous report on this cohort [18] identified determinants of delayed-type hypersensitivity response and risk factors for tuberculin reactivity. We examined the incidence of tuberculosis among patients enrolled in the PCHIS for a median observation period of approximately 4.5 years. Methods Patients and Study Design The PCHIS was a multicenter, prospective study of the frequency and spectrum of pulmonary disorders in persons infected with HIV. From November 1988 through February 1990, 1171 HIV-seropositive persons and 182 HIV-seronegative persons were enrolled at centers in six U.S. cities: New York; Newark, New Jersey; Detroit; Chicago; San Francisco; and Los Angeles. Participants were followed through 31 March 1994. We report on 1130 HIV-infected persons from the PCHIS who were followed past baseline. Participants were recruited to represent a range of severity of HIV disease. Approximately half of the participants at each center had CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms, and half had CD4 lymphocyte counts of less than 400 cells/mm3 or symptomatic HIV infection. Both groups included persons from one of three HIV-transmission categories: homosexual men, male and female injection drug users, and women who had acquired HIV through heterosexual contact. Exclusion criteria were AIDS, as defined by the Centers for Disease Control and Prevention (CDC) [19]; acute pulmonary processes; use of immunosuppressive therapy in the past 6 months; and treatment of tuberculosis in the past 12 months. The study was approved by the institutional review board at each site, and participants gave informed consent. At baseline and at regular intervals, clinical monitoring (including T-lymphocyte subset analysis and chest roentgenography) was done, and participants were acutely evaluated if new pulmonary symptoms occurred. Centers used the same predetermined diagnostic algorithms that were initiated if specified criteria were met. Complete details of the study design have been described elsewhere [17]. Delayed hypersensitivity was tested at baseline and then annually using purified protein derivative (PPD) tuberculin at a strength of 5 TU per 0.1-mL dose and mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania). Tests were administered by intradermal injection of 0.1 mL of antigen by the Mantoux method and read by experienced nurses 48 to 72 hours later in most cases (the interval exceeded 4 days in 18 persons). A positive response to PPD was defined as an induration at least 5 mm in diameter. Any person who was not positive when first tested but who became positive on any subsequent test was considered to be a tuberculin converter. A positive response to mumps was defined as any degree of induration (>0 mm). The criteria for anergy was nonreactivity (0 mm) to both PPD and mumps antigen. Pulmonary tuberculosis was defined by the isolation of M. tuberculosis from a respiratory tract specimen or by improvement on chest radiography in response to specific multidrug antituberculous therapy. Patients who were diagnosed with extrapulmonary tuberculosis had clinically compatible disease and response to specific therapy, with or without the isolation of the organism from a site outside the lung. Patients who were considered to have both pulmonary and extrapulmonary tuberculosis met each set of criteria. These requirements are consistent with those of the CDC for reporting cases of tuberculosis [20], except that we did not require patients to be PPD positive if they had disease that was not mycobacteriologically confirmed. Statistical Analysis Tuberculosis rates were calculated as the number of cases divided by the number of years that patients were followed multiplied by 100. Except as noted below, the length of time that patients were followed was calculated for each person starting from enrollment and continuing until one of the following occurred: diagnosis of tuberculosis, death from any cause, the last study visit, or 31 March 1994. Statistical significance for comparison of rates was determined by tests for person-time data done on the basis of binomial distribution [21]. P values were determined by an exact test when sample sizes were insufficient and by an asymptotic test when sizes were sufficient. All tests were two-sided, and a P value of 0.05 was considered significant. Exact 95% CIs were calculated for rates by assuming the numerator to be a Poisson variable [22] and for rate ratios using a modified binomial model [21]. Adjusted rate ratios for comparisons among groups defined by demographic variables were calculated by using a Mantel-Haenszel type estimator for incidence-rate data with approximate 95% confidence limits based on the tests [21]. Seventy-three participants, including women who had acquired HIV through heterosexual contact and persons were not black, white, or Hispanic, were excluded from some calculations of adjusted rates because of small sample sizes. Distributions of time to death among patients with tuberculosis were estimated using the Kaplan-Meier method, and comparisons were made using the log-rank test. To calculate tuberculosis rates by immunologic status, we divided the time each participant was followed into the number of years during which CD4 lymphocyte counts were 200 cells/mm3 or greater and the number of years after CD4 lymphocyte counts were less than 200 cells/mm3. Time for these CD4 groups was then summed for all participants. Rates were calculated as the number of tuberculosis cases in each group divided by the number of years followed. One participant who did not have CD4 measurements was omitted from these calculations. Twenty-three participants who were never tested for PPD response were excluded from PPD conversion rates and calculations of tuberculosis rates by PPD status. Participants who were tested for PPD response at least once were classified into one of three groups: positive at entry, newly positive (converted), or negative. One hundred seventy-two of 1107 participants were assigned to groups on the basis of only one test. Baseline PPD status was assigned for 66 participants who were not tested at study entry by using the first reported test and time followed calculated from the date of that test. For participants who developed tuberculosis, only the results of PPD tests done before diagnosis were considered. Tuberculin converters were considered to be part of the negative group before becoming PPD positive and to be part of the newly positive group after converting. Persons who reported a history of isoniazid use or tuberculosis before the study or who received isoniazid for at least 6 months during follow-up were considered to have completed prophylactic therapy. All others were considered to have not been given prophylaxis. Time before completion of isoniazid therapy was included with time followed in the untreated group. Restricted tuberculosis rates were calculated by PPD status for those considered to have not received prophylaxis. Results Patient Characteristics at Baseline Overall, 1171 HIV-seropositive persons entered the study. Follow-up was completed for 1130 persons (96%), whose baseline characteristics are shown in Table 1. Approximately 1% of patients reported a history of tuberculosis, 8% reported a previous positive result on a PPD test, and 4% reported previous use of isoniazid. The median CD4 T-lymphocyte count among HIV-seropositive patients was 410 cells/mm3: Thirty-six percent of patients had counts of at least 500 cells/mm3, 44% had counts between 200 and 499 cells/mm3, and 19% had counts of less than 200 cells/mm3. At study entry, 6% of patients were PPD positive, 42% were reactive to mumps antigen, and 54% were anergic. A cross-sectional analysis of skin-test results at baseline in this cohort has been described in detail elsewhere [18]. Table 1. Baseline Characteristics of the Study Chart* Patient Follow-up The median duration of follow-up was 53 months. By the end of the study, 655 persons had survived after a median follow-up of 57 months (range, 31 to 64 months), 354 had died after a median follow-up of 31 months (range, 1 to 63 months), and 121 withdrew or were lost to follow-up after a median of 25 months (range, 1 to 61 months). Participants received PPD skin tests a median of three times, and 1107 (98%) participants were evaluated at least once. Sixty-six (6%) participants were PPD positive when first tested. Among the 1041 patients who were PPD negative at first testing, 29 subsequently became PPD positive (0.8 conversions per 100 person-years). During follow-up, isoniazid prophylaxis was prescribed for 110 persons (10%), but only 53 (5%) received therapy for 6 months or more. Inc

Central Nervous System Tuberculosis with the Acquired Immunodeficiency Syndrome and Its Related Complex

Central nervous system tuberculosis occurred in three patients with the acquired immunodeficiency syndrome (AIDS) and seven patients with AIDS-related complex who were evaluated for 48 months. Nine patients were intravenous drug abusers and one was Haitian. Five patients had cerebral-ring-enhancing lesions and three had hypodense areas. The clinical spectrum included meningitis in two patients, multiple cerebral abscesses in one, and tuberculomas in four. All Mycobacterium tuberculosis isolates were sensitive to standard antituberculous drugs. All patients received treatment with isoniazid, rifampin, and pyrazinamide; six patients also received streptomycin. Three patients with AIDS died of opportunistic infection preceded by central nervous system tuberculosis. Among the patients with the AIDS-related complex, three improved with treatment, three were lost to follow-up, and one died. Tuberculosis should be considered in the differential diagnosis of central nervous system mass lesions in intravenous drug abusers with AIDS or AIDS-related complex. Because patients with tuberculosis can be cured, biopsy of accessible brain mass lesions should be mandatory. Preventive therapy may be indicated in drug abusers without disease.

Tuberculin and Anergy Testing in HIV-Seropositive and HIV-Seronegative Persons

Human immunodeficiency virus (HIV) is playing a substantial role in the resurgence of tuberculosis in the United States. Particularly affected are people in urban areas, where there are large populations of HIV-infected persons [1-8]. Urban subpopulations with a high prevalence of HIV infection, such as intravenous drug users (a group already at increased risk for tuberculosis before the appearance of the acquired immunodeficiency syndrome [AIDS]), have the highest tuberculosis attack rates [3]. Unlike other AIDS-associated opportunistic pathogens, Mycobacterium tuberculosis is readily communicable among persons with all levels of immunity. Recently, tuberculosis outbreaks, some with multidrug-resistant strains, have occurred among HIV-positive patients with transmission to HIV-negative patients and health care workers [9-13]. Prevention strategies rely heavily on the use of tuberculin purified protein derivative (PPD) to identify persons harboring M. tuberculosis [14]. Anergy, a consequence of HIV infection, undermines these strategies in persons at the highest risk for tuberculosis infection and subsequent active disease [15-18]. A negative PPD test result in this setting could be attributable to a true lack of exposure to tuberculosis or simply to the incapacity of the patient to manifest an appropriate cell-mediated immune response. To reduce the measured prevalence of anergy and thereby increase the proportion of tuberculin nonreactors who can be considered truly PPD negative, the Centers for Disease Control and Prevention (CDC) has recommended the additional use of at least two delayed-type hypersensitivity control antigens (mumps antigen plus Candida antigen or tetanus toxoid) when screening HIV-infected patients. Thus, persons from populations with a prevalence of tuberculous infection of 10% or more and who are tuberculin negative but not anergic may be spared preventive therapy with isoniazid [19]. However, the ability of control antigens to predict the likelihood that a negative PPD test result is truly negative in this highly anergic population is unknown. To improve approaches to tuberculosis prophylaxis, more data are needed about the relations among delayed-type hypersensitivity responsiveness, the prevalence of tuberculosis, and the waning immunity associated with progressive HIV infection. In an ongoing multicenter study of the natural history of the pulmonary complications associated with HIV infection, we have been examining these factors prospectively in a cohort of 1353 persons in 6 U.S. geographic areas. Recently, we evaluated baseline delayed-type hypersensitivity responses in this cohort of HIV-seropositive and HIV-seronegative persons and identified variables associated with tuberculin reactivity and anergy. Methods Patients and Study Design The Pulmonary Complications of HIV Infection Study is a multicenter study designed to prospectively describe the frequency, types, and effect of pulmonary complications in HIV-infected persons, both before and after the development of AIDS. All diagnoses, treatments, and outcomes are recorded and monitored in a common database. Because our purpose was to evaluate longitudinally both the early and late pulmonary manifestations of HIV infection, each center attempted to recruit about 170 HIV-seropositive participants, half with CD4 lymphocyte counts of 400 cells/mm3 or more and no HIV-related symptoms and half with fewer than 400 CD4 cells/mm3 or symptomatic HIV-infection (defined by a temperature of 38 C or more for at least 2 weeks, involuntary weight loss of 10% or more from baseline, diarrhea of at least a 1-month duration, oral candidiasis, or oral hairy leukoplakia). Within each group, participants were drawn from one of three HIV transmission categories (homosexual men, male and female intravenous drug users, and women with heterosexually acquired HIV infection) to reflect their approximate distribution at each clinical site. About 30 HIV-seronegative homosexual men and intravenous drug users were also recruited at each site to serve as controls. Participants had to be willing and able to comply with the protocol and were required to give informed consent. The study was reviewed and approved by the institutional review board at each site. Exclusion criteria included Centers for Disease Control and Prevention (CDC)-defined AIDS [20], severe non-HIV-related disease likely to affect survival, lung disorders likely to interfere with the required evaluations, acute pulmonary processes, immunosuppressive therapies within the previous 6 months, and treatment for active tuberculosis within the past 12 months. From November 1988 through February 1990, we enrolled 1353 persons in the study, of whom 1171 were HIV seropositive and 182 were HIV seronegative. Human immunodeficiency virus serologic status was confirmed at study entry using a licensed enzyme-linked immunosorbent assay and a Western blot assay. Further baseline evaluation included a complete medical history, a physical examination, hematologic and biochemical studies, T-lymphocyte subset analysis, delayed-type hypersensitivity testing, a chest roentgenogram, and pulmonary function measurements. Measurement of Delayed-Type Hypersensitivity Response We tested delayed-type hypersensitivity with the following antigens: mumps antigen (Connaught Laboratories, Inc., Swiftwater, Pennsylvania); Dermatophytin 0 (Candida) at 1:100 dilution (Hollister-Stier, Spokane, Washington); Dermatophytin (trichophytin) at 1:100 dilution (Hollister-Stier); and tuberculin PPD at a strength of 5 tuberculin units per 0.1-mL dose (Connaught Laboratories, Ltd., Willowdale, Ontario, Canada). Tests were administered by intradermal injection of 0.1 mL of antigen (Mantoux method) and read by a trained observer 48 to 72 hours after application in most participants (the interval exceeded 4 days in 18 persons). Response was recorded as the greatest diameter of induration. We used the current standard operational criteria for a positive response: induration of at least 5 mm for all antigens except PPD, for which an induration of 10 mm was required among HIV-uninfected persons [19]. Anergy was defined as 0 mm of induration for all delayed-type hypersensitivity antigens administered in a given panel. Unless otherwise specified, a test battery of tuberculin PPD, mumps antigen, and Candida antigen was used to define anergy. At one site, however, the investigators did not distinguish between induration and erythema for the mumps, Candida, and trichophytin tests, documenting reactions to these antigens in terms of millimeters of erythema. When examined by zone diameter, their measurements were generally consistent with those from the other centers. Furthermore, the results of multivariate analyses with and without the data from this site were similar. Other investigators have shown a high degree of correlation between induration and erythema with these antigens [21]. Thus, for the purposes of our analysis, responses were recorded in millimeters of induration. Because trichophytin elicited a positive reaction in only 14.0% of those tested, it was dropped from the delayed-type hypersensitivity battery midway through the enrollment period. Although lot numbers varied, the skin tests used at the centers were supplied by the same manufacturers, with a single exception: At one site, investigators used a different Candida preparation. The Candida test results for this center (247 participants) were excluded from all analyses involving this antigen. Determination of Lymphocyte Subsets Lymphocyte subsets were determined for CD3, CD4, and CD8 receptor-bearing cells by the same laboratory at each site. All laboratories participated in the flow cytometry quality control program sponsored by the National Institute of Allergy and Infectious Diseases [22]. Statistical Analysis All analyses are based on data collected during the baseline evaluation. Statistical significance for comparisons of proportions was determined by chi-square or Fisher exact test [23]. For comparisons among nonindependent groups, repeated-measures analysis for categorical outcomes was used to determine statistical significance [24, 25]. Logistic regression models were used to study the relation between PPD positivity or anergy and potential risk factors [26]. Risk factors considered were HIV status; CD4 count among HIV-seropositive persons; intravenous drug use; race or ethnicity; a history of a positive PPD test result, tuberculosis, or BCG vaccination; age; gender; and socioeconomic status. Seventy-seven participants, including women with heterosexually acquired infection and persons who were not white, black, or Hispanic, were excluded from all multivariate analyses because of small sample sizes. Initial models included HIV status (positive or negative), intravenous drug use (presence or absence), race or ethnicity (white, black, or Hispanic), a history of a positive PPD test result, and age, as well as interaction terms, to determine whether the effect of HIV positivity varied among these groups or whether the effect of drug use varied by race. No statistically significant interactions were observed. All odds ratios presented were derived from subsequent models containing main effects only. A dichotomous variable indicating the 12% of the cohort who did not have a high school diploma was used as an index of socioeconomic status and was included in all final models. All tests were two sided. A P value of 0.05 was considered statistically significant. Ninety-five percent CIs are given when appropriate. Results Patient Characteristics During the 16-month enrollment period, 1171 HIV-seropositive and 182 HIV-seronegative persons entered the study. The two groups were similar with regard to age, sex, race, transmission category, and tuberculosis-associated history (Table 1). Of the 1165 men, 966 (82.9%) were homosexual; of the 188 women, 132 (70.2%) were intravenous drug users.

Old ideas to innovate tuberculosis control: preventive treatment to achieve elimination

The introduction of new rapid diagnostic tools for tuberculosis (TB) and the promising TB drugs pipeline together with the development of a new World Health Organization Strategy post 2015 allows new discussions on how to direct TB control. The European Respiratory Society’s European Forum for TB Innovation was created to stimulate discussion on how to best take advantage of old and new opportunities, and advances, to improve TB control and eventually progress towards the elimination of TB. While TB control is aimed at reducing the incidence of TB by early diagnosis and treatment of infectious cases of TB, TB elimination requires focus on sterilising the pool of latently infected individuals, from which future TB cases would be generated. This manuscript describes the three core components that are necessary to implement the elimination strategy fully. 1) Improve diagnosis of latent TB infected individuals. 2) Improve regimens to treat latent TB infection. 3) ensure public health commitment to make both 1) and 2) possible. Old and new evidence is critically described, focusing on the European commitment to reach elimination and on the innovative experiences and best practices available. Diagnosis and treatment of latent TB infection is the core intervention to reach elimination http://ow.ly/mjW0R

Tuberculin Skin Testing

Tuberculin testing is the major method of diagnosing tuberculous infection. Although a significant degree of variability exists in reading reactions (1), the test continues to be the most reliable and available in diagnosis. It is used to diagnose tuberculous infection in contrast to tuberculous disease. Its reactivity separates the infected individual (class 2 — significant skin test with negative bacteriologic and roent-genographic studies) from the exposed individual without infection (class 1 — tuberculosis-exposed history with nonsignificant tuberculin skin test). The implication of a significant tuberculin test is infection with tubercle bacilli.

Successful Supervised Ambulatory Management of Tuberculosis Treatment Failures

Twenty-one patients with long histories of failed treatment for pulmonary tuberculosis, most of whom were recalcitrant in taking medications, were treated on a primarily ambulatory basis with various antituberculosis drugs. Supervision ensured that medication was taken. Convenient, personalized, comprehensive medical care and social services were provided without cost to patients during the early phase of treatment. Management during the continuation phase was unsupervised. Fourteen patients had drug-resistant tuberculosis and 16 were either alcohol or opiate abusers. Treatment success was achieved in 19 of 21 patients with a mean follow-up of 26 months. Two patients failed to achieve a sputum-negative status for Mycobacterium tuberculosis.

Impact of Bacterial Pneumonia and Pneumocystis carinii Pneumonia on Human Immunodeficiency Virus Disease Progression

The course of pneumonia caused by pyogenic bacteria and Pneumocystis carinii was examined in a multicity cohort study of HIV infection. The median duration of survival among 150 individuals following initial bacterial pneumonia was 24 months, compared with 37 months among 299 human immunodeficiency virus (HIV)-infected control subjects matched by study site and CD4 lymphocyte count (P<.001). For 152 subjects with P. carinii pneumonia, median survival was 23 months, compared with 30 months for 280 matched control subjects (P = .002). Median durations of survival associated with the two types of pneumonia differed by only 47 days, despite a higher median CD4 lymphocyte count associated with bacterial pneumonia. These results suggest that both P. carinii pneumonia and bacterial pneumonia are associated with a significantly worse subsequent HIV disease course. The similarity of prognosis after one episode of bacterial pneumonia vs. an AIDS-defining opportunistic infection and the proportion of cases occurring in association with a CD4 lymphocyte count of >200 suggest that measures to prevent bacterial pneumonia should be emphasized.

Rethinking the Socioeconomics and Geography of Tuberculosis Among Foreign-Born Residents of New Jersey, 1994–1999

OBJECTIVES This study investigated the socioeconomic profile of foreign-born tuberculosis patients in New Jersey. METHODS Foreign- and US-born tuberculosis patients in 1994-1999 were compared using various measures of socioeconomic status. RESULTS Out of 4295 tuberculosis patients, 2005 (47%) were foreign-born. Foreign-born patients resided in more affluent, more educated, and less crowded areas than did US-born patients (P <.005). They were also more likely to have been employed during the 2 years before diagnosis (62% vs 41%, P <.001). Private physicians treated the majority of South Asian-born patients. CONCLUSIONS Substantial numbers of employed foreign-born tuberculosis patients now reside in affluent New Jersey locations. Changes in tuberculosis control programs may be required when the socioeconomic status and place of residence of foreign-born populations diverge from traditional assumptions linking poverty with tuberculosis.

Presenting the European Forum for TB Innovation: innovative thinking in progressing towards TB elimination in Europe

On March 9, 2012 the European Respiratory Society (ERS) launched its first ever think tank on tuberculosis (TB): the European Forum for TB Innovation. When we, as prospective authors, sat down to tackle the content layout of this short editorial, we realised that we could not just use the academic tone that commonly characterises scientific articles. The principles that have led the ERS to embrace the discussion surrounding TB innovation transcend science and academic discussion. They are principles originating from the need to re-think TB control in Europe and beyond. We therefore felt that our personal account on how we came to agree to contribute to this new initiative was the only acceptable way of bringing this editorial to life. I will admit it. I am not a TB expert. I started my career as a cardiologist, to later embrace the field of respiratory care with a keen interest in pneumonia. I am, in other words, not a usual suspect. But even while immersed in my clinical practice in one of the major Italian cities, Milan, I was alarmed by the subtle and ominous presence of TB. I am not referring to the persistent and tireless reminding by ERS colleagues from the TB Assembly, that TB is everywhere and well rooted among our population. That played a role, too. But my awakening came with the realisation that TB and multidrug-resistant (MDR)-TB in Europe, in Italy and in my city were and are besieging the life of the most vulnerable and anchoring their roots among the general population again [1–8]. Silently, but relentlessly. The realisation that, in the 21st century, the tools to control the disease and alleviate patient suffering are still those described in the textbook I used throughout medical school has led me to commit …

A Summary of Meeting Proceedings on Addressing Variability around the Cut Point in Serial Interferon-γ Release Assay Testing

On June 13, 2012, a group of key stakeholders, leaders, and national experts on tuberculosis (TB), occupational health, and laboratory science met in Atlanta, Georgia, to focus national discussion on the higher than expected positive results occurring among low-risk, unexposed healthcare workers undergoing serial testing with interferon-γ release assays (IGRAs). The objectives of the meeting were to present the latest clinical and operational research findings on the topic, to discuss evaluation and treatment algorithms that are emerging in the absence of national guidance, and to develop a consensus on the action steps needed to assist programs and physicians in the interpretation of serial testing IGRA results. This report summarizes its proceedings.