Antibody markers of incident tuberculosis among HIV-infected adults in the USA: a historical prospective study.

OBJECTIVE: To assess whether serum levels of antibodies against Mycobacterium tuberculosis antigens increase before diagnosis of active tuberculosis (TB). DESIGN: Serial serum samples were obtained from 30 human immunodeficiency virus (HIV) co-infected individuals who developed active TB during a multicenter prospective study on pulmonary complications of HIV/AIDS conducted among >1300 subjects in the USA in the 1980s. Multiple serum samples from 47 matched control individuals who did not develop TB in the same study were also tested. Immunoglobulin G (IgG) antibodies to 10 M. tuberculosis proteins were detected by enzyme-linked immunosorbent assay (ELISA), and data were analyzed by descriptive and inferential statistical techniques to assess patterns, trends and differences in antibody levels relative to time from TB diagnosis. RESULTS: Antibodies to five antigens (ESAT-6, 38 kDa Ag, 16 kDa Ag, malate synthase and MTSA-10/CFP-10), but not to five other antigens (Rv2626c, ferredoxin A, glutamine synthetase, alanine dehydrogenase and Ag85) increased before diagnosis of TB relative to control levels. The earliest increase in the TB group was detected for MTSA-10/CFP-10 (24-30 months pre-diagnosis). CONCLUSIONS: Levels of serum antibodies to particular proteins of M. tuberculosis increase before microbiological and clinical symptoms of active TB. The use of antibody biomarkers for prognostic purposes should therefore be feasible.

The tuberculosis taboo.

The treatment of latent tuberculous infection (TBI) is a productive and meaningful approach to tuberculosis (TB) control, and an important component of the World Health Organization's (WHO's) new End TB Strategy, especially in high-risk contacts. Unfortunately, although recognized and recommended by the WHO, it continues to be underutilized, and has even been ignored for decades in some high-risk groups, as though it were a taboo. Historical approaches to treating TBI in contacts of drug-susceptible and drug-resistant TB are presented and discussed as compelling experiences. In the United States, the Centers for Disease Control and Prevention have recently shown that a directly observed or even self-administered 12-month regimen to treat TBI with once-weekly isoniazid (INH) and rifapentine is as effective as 9 months of daily INH. Treating TBI in drug-susceptible cases and their contacts should not still be considered taboo-such a short, effective regimen is more akin to the Holy Grail. While not yet confirmed in a clinical trial, treating contacts of drug-resistant TB with the same drugs that are effective in the source case would be expected intuitively and practically to prevent TB in contacts and should be introduced now instead of waiting until clinical trials are completed.

Smoking and tuberculosis: the epidemiological association and immunopathogenesis.

There is increasing evidence of a link between tuberculosis and smoking. This paper reviews the epidemiological evidence from the UK, China, India and the USA, summarizing some of the main papers which indicate an association. Where an association has been found there seems to be an increase in tuberculosis case rates of between two- and four-fold for those smoking in excess of 20 cigarettes a day, but it may be difficult to control for other factors, particularly alcohol consumption. The final part of the paper reviews possible mechanisms. A likely possibility is that nicotine turns off the production of TNF-alpha by the macrophages in the lungs, rendering the patient more susceptible to the development of progressive disease from latent Mycobacterium tuberculosis infection.

Drug dependence, a possible new risk factor for tuberculosis disease.

A study was performed to assess the risk of drug-dependent persons for developing tuberculosis. Tuberculosis prevalence was 3,740/100,000 drug-dependent inpatients compared with 584/100,000 non-drug-dependent discharges. In another program, prevalence was 3,750/100,000; in the New York Methadone Program, prevalence was 2,652/100,000 patients in Harlem and 1,372/100,000 city-wide. The city-wide prevalence rate in the entire population was 86.7/100,000 in 1971 and 64.7/100,000 in 1973. Similar elevations in incidence also were found in drug-dependent vs non-drug-dependent populations. Our data show that disease rate is elevated in drug-dependent populations, suggesting that drug dependency reflects a high-risk situation for tuberculous infected individuals developing tuberculosis disease. We suggest that infected drug-dependent persons (tuberculin positive) be considered for preventive therapy with isoniazid, which can be piggybacked onto a drug treatment program.

Tuberculosis among patients with AIDS and a control group in an inner-city community.

BACKGROUND: Tuberculosis, the largest single cause of death of any infectious disease worldwide, has undergone a startling resurgence in the United States, partially related to the acquired immunodeficiency syndrome (AIDS) epidemic. METHODS: To compare the clinical, roentgenographic, and bacteriologic characteristics of patients with AIDS and the general population, we retrospectively analyzed the clinical records of all patients with tuberculosis in an inner-city population over a 4-year period. Forty-six patients with AIDS (including 38 injecting drug users [83%]) were identified and matched with a control group of 46 patients with tuberculosis who did not have AIDS. RESULTS: Forty-one patients with AIDS (89%) had pulmonary tuberculosis; 10 (22%) had disseminated disease and 13 (28%) had concurrent extrapulmonary disease. Among the patients without AIDS, two (4%) had disseminated disease and four (9%) had extrapulmonary disease. Patients with AIDS were far more likely to be black. Thirty-seven patients with AIDS (80%) had negative purified protein derivative skin test results compared with eight controls (17%). Seventeen (41%) of 41 patients with AIDS presented with classic post-primary upper-lobe disease compared with 32 (73%) of 44 patients in the control group. Primary tuberculosis features occurred predominantly in the AIDS group. Four (10%) of 41 patients with AIDS presented with clear chest films despite positive smears and cultures. Nine patients with AIDS (20%) were drug-resistant compared with three controls (7%). Seven patients with AIDS with drug resistance were born in the United States (78%), while all controls with drug resistance were foreign-born. CONCLUSIONS: We found vast differences in the clinical, roentgenographic, and drug susceptibility characteristics of patients with tuberculosis who did and did not have AIDS.

Lack of usefulness of radiographic screening for pulmonary disease in asymptomatic HIV-infected adults. Pulmonary Complications of HIV Infection Study Group.

OBJECTIVE: To determine the use of chest radiographs in the screening of asymptomatic adults infected with the human immunodeficiency virus (HIV). METHODS: A prospective, multicenter study of the pulmonary complications of HIV infection in a community-based cohort of persons with and without HIV infection. The subjects included 1065 HIV-seropositive subjects without the acquired immunodeficiency syndrome at the time of enrollment: 790 homosexual men, 226 injection drug users, and 49 women with heterosexually acquired infection. Frontal and lateral chest radiographs were performed at 3-, 6-, and 12-month intervals, CD4 lymphocyte measurements at 3- and 6-month intervals, tuberculin and mumps skin tests at 12-month intervals, and medical histories and physical examinations at 3- and 6-month intervals. Pulmonary diagnoses that occurred within 2 months following each radiograph were analyzed and correlated with the radiographic results. RESULTS: Evaluable screening chest radiographs (5263) were performed in HIV-seropositive subjects while they were asymptomatic; of these, 5140 (98%) were classified as normal and 123 (2%) as abnormal. A new pulmonary diagnosis was identified within 2 months following a screening radiograph in 55 subjects. Only 11 of these subjects had abnormal radiographs; the sensitivity of the radiograph was 20%. The sensitivity was similarly low at baseline, within each transmission category, and in subjects whose CD4 lymphocyte counts were less than 0.2 x 10(9)/L (200/microL). The types of pulmonary diseases that occurred were similar in the subjects with normal and abnormal screening radiographs. CONCLUSION: Screening chest radiography in asymptomatic HIV-infected adults is unwarranted because the diagnostic yield is low.

Western Pacific Regional Green Light Committee: progress and way forward.

The Western Pacific Regional Green Light Committee (rGLC WPR) was established in 2011 to promote the rational scale-up of programmatic management of drug-resistant tuberculosis (PMDT). We reflect on its achievements, consider the challenges faced, and explore its potential future role. Achievements include the supervision and support of national PMDT action plans, increased local ownership, contextualized guidance, and a strong focus on regional capacity building, as well as a greater awareness of regional challenges. Future rGLC activities should include (1) advocacy for high-level political commitment; (2) monitoring, evaluation, and supervision; (3) technical support and contextualized guidance; and (4) training, capacity building, and operational research. Regional activities require close collaboration with both national and global efforts, and should be an important component of the new Global Drug-resistant TB Initiative.

Monitoring preventive therapy patients for liver disease as well as compliance.

An apparently increasing incidence of isoniazid-associated hepatitis concurrent with interest in the problem has led to the universal teaching that patients on isoniazid preventive therapy must be carefully monitored for liver disease. This teaching has been reinforced and endorsed in a recent report of the tuberculosis advisory committee and special consultants to the director of the Center for Disease Control; this report, in turn, led to an American Thoracic Society statement concluding that the use of isoniazid with appropriate safeguards must be based on a comparison of the benefit of preventive therapy with the risk of hepatic injury and, therefore, should be used when necessary, under careful control and follow-up. In New York City, with increasing use of the tuberculin skin test leading to increased numbers of patients receiving this treatment in nurse-operated clinics, a new control form and protocol were designed. These insure that all individuals on preventive therapy are carefully monitored for liver disease as well as compliance in taking the drug. This system also insures the safeguards alluded to, as well as increasing concern and awareness among the health professionals in prescribing the treatment.

Long-term follow-up of tuberculoma of the brain in an AIDS patient.

Human immunodeficiency virus infection and extrapulmonary TB are defined as AIDS. The clinical manifestations of the TB are related to the interplay of the organism and the host's immune system. A seven-year follow-up of a woman successfully treated for biopsy- and culture-documented tuberculous brain abscess is described. Antibodies to HIV have been positive on repeated testing, yet CD4 counts remain over 500. Aggressive diagnostic and therapeutic maneuvers for all forms of TB in AIDS are warranted since long-term prognosis may be good.

Preventive therapy for contacts of multidrug-resistant tuberculosis. A Delphi survey.

OBJECTIVE: Several outbreaks of multidrug resistant tuberculosis (MDR-TB) have recently occurred in which healthcare workers and others have become infected. Given the lack of clinical data to guide preventive therapy for such contacts, a Delphi survey of a panel of 31 TB therapy experts was undertaken to identify a consensus regimen. DESIGN: An initial questionnaire presented three scenarios describing persons with significant exposure to MDR-TB and with new tuberculin skin test reactions > 15 mm (except one anergic patient) without evidence of disease. Panelists were asked to suggest possible preventive therapy regimens. METHODS: During a second round survey, the panel members were asked to review the suggested regimens provided for each scenario and to rank them from one to nine as extremely inappropriate to extremely appropriate. Results of this second survey were tabulated and shared with the members of the panel who were then asked to rerank each regimen in light of the previous cumulative panel responses. RESULTS: No specific regimen achieved initial positive consensus by predefined criteria. In two of the three scenarios the no treatment option, however, was deemed clearly inappropriate. The data were also analyzed by what percentage of respondents who ranked a regimen as at all appropriate (ie, six or more on the nine point scale). For scenarios involving a nurse, an HIV-positive tuberculin reactor, and a patient who was anergic HIV-positive, treatment with pyrazinamide 1,500 mg daily with ciprofloxacin 750 mg twice a day for 4 months received a somewhat appropriate rating from more than 50 percent of respondents. CONCLUSIONS: The management of persons exposed to and infected by patients with MDR-TB has become a serious problem in the context of MDR-TB outbreaks. This panel of experts agreed that some form of preventive therapy was warranted; however, they were not able to reach defined consensus on what regimen should be used, although a regimen of pyrazinamide 1,500 mg daily with ciprofloxacin 750 mg twice a day for 4 months was considered somewhat appropriate. Clinical data on the efficacy of alternative preventive therapy regimens for such contacts are urgently needed.

Tuberculin reaction size measurement by the pen method compared to traditional palpation.

A prospective, double blind study was conducted to determine the degree of concordance of pen and palpation methods of measuring skin induration to Mantoux tuberculin tests. One hundred thirty-five skin tests were performed in patients with previously bacteriologically proved tuberculous disease. An experienced reader who was only able to see the forearm of the patient measured the induration by the palpation technique. The measurement was then repeated by the pen method under the same conditions, on the same day. Results of the study indicated that the pen method yielded statistically the same frequency distribution of indurations as the palpation method and the pen method appeared to be more sensitive.

Oat cell carcinoma with multiple tracheobronchial papillomatous tumors.

Multiple papillomas of the tracheobronchial tree are rare in children and adults. We describe a 42-year-old woman with multiple papillomatous-like tumors involving the trachea and bronchi. The limited tissue samples obtained during fiberoptic bronchoscopy initially lead to a benign histopathologic diagnosis; concurrent cytology studies strongly suggested oat cell carcinoma. The biopsy specimen obtained by rigid bronchoscopy ultimately demonstrated unequivocal oat cell carcinoma. This case illustrates an unusual and previously unreported manifestation of oat cell carcinoma--an endoscopic presentation in a papillary form suggesting benign tracheobronchial papillomatosis. Cytology studies were of increased diagnostic significance in this clinicopathologic setting.

Preventive therapy for the patient with both universal indication and contraindication for isoniazid.

BACKGROUND: The delphi method of decision making was used to address an unusual clinical case in which various aspects of the case required opposing management strategies. METHODS: A panel of 30 pulmonary experts was surveyed repeatedly until a convergence of treatment approaches was reached for a patient who was considered to have both a universal indication for and a universal contraindication against prevention therapy. Participants were asked to evaluate the appropriateness of proposed treatments on a scale from 1 to 9, with 1 being extremely inappropriate, 5 being equivocal, and 9 being extremely appropriate. The delphi survey data responses were compared using measures of central tendency (ie, the mean and median) and measures of variability (ie, the standard deviation and interquartile range). RESULTS: Although no treatment was wholeheartedly supported by the experts, analysis of the three-round delphi survey responses resulted in two possible treatments: rifampin, 600 mg daily, for four months, or no treatment with close observation. Interestingly, the experts working in a non-university setting favored the rifampin treatment, and those working in a university setting favored no treatment with close observation. CONCLUSIONS: The delphi method has the potential to be used for clinical decision making.

Mycobacterium tuberculosis miniepidemic in a church gospel choir.

BACKGROUND: Conventional contact investigation and molecular fingerprinting of Mycobacterium tuberculosis isolates in tuberculosis (TB) outbreaks have facilitated recognition as well as application of public health control activities. Singing in a choir as an activity that promotes TB transmission has been occasionally recognized. Such avocational transmission in a middle class community can occur with attendant difficulties encountered in contact investigation. METHODS: Five cases of TB (one index case; three secondary cases; one unassociated case) were identified among members of a famous church gospel choir in Newark, NJ. DNA fingerprinting and susceptibility testing were done on all retrieved strains. Of 306 choir members who had tuberculin tests, 19% were reactors. The presumed outbreak site was investigated. RESULTS: Four of the five patients were tenors, and one was an alto. Tenors were approximately twice as likely to be tuberculin reactors than subjects with other vocal ranges combined (relative risk, 2.04; 95% confidence interval, 1.17 to 3.56). An air ventilation outlet was directly in front of the tenor section. Some limited extra-church activity between choir members may have contributed to transmission. CONCLUSION: Conventional contact investigation must be supplemented by newer techniques, such as DNA fingerprinting, in identifying possible outbreak transmission. Singing, location of a ventilation outlet, and exposure time may have contributed to TB transmission in this outbreak. Transmission need not only be in congregate settings among well-defined socioeconomic groups but may occur unexpectedly in middle class communities.

Performance of an algorithm to detect Pneumocystis carinii pneumonia in symptomatic HIV-infected persons. Pulmonary Complications of HIV Infection Study Group.

STUDY OBJECTIVES: To determine whether an algorithm consisting of a chest radiograph and the diffusing capacity of the lung for carbon monoxide (D(LCO)) is effective in detecting Pneumocystis carinii pneumonia (PCP) in symptomatic HIV-infected persons; and to establish a benchmark for future comparisons of alternative algorithms. DESIGN: Prospective, 64-month study. SETTING: Multicenter, ambulatory care. PATIENTS: 306 HIV-infected subjects enrolled in the Pulmonary Complications of HIV Infection Study who developed 467 episodes of new or worsening respiratory symptoms. MEASUREMENTS: Chest radiography followed by D(LCO) measurement, if the radiograph was normal or unchanged. RESULTS: An algorithm combining a chest radiograph followed by a D(LCO) measurement, if the radiograph was normal or unchanged, was effective and detected abnormalities that led to a diagnosis of PCP in 78 of 80 evaluable episodes (97.5%). The radiograph (specific parenchymal abnormality, number of lung zones involved) and the D(LCO) (degree of decrease, degree of decrease from baseline) also provided additional information on the probability of PCP. CONCLUSIONS: In symptomatic HIV-infected patients suspected of having PCP, the diagnostic evaluation should begin with a chest radiograph, followed by a D(LCO) measurement, if the radiograph is normal or unchanged. If both of these tests are normal, it may be reasonable to conclude the evaluation rather than to proceed on to additional testing. This algorithm can serve as a benchmark for future comparisons.

Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease. Pulmonary Complications of HIV Infection Study Group.

STUDY OBJECTIVES: To examine the significance of previously suggested risk factors and assess outcomes associated with Aspergillus identification in respiratory specimens from HIV-seropositive individuals. DESIGN: This was a nested case-control study. Patients who had Aspergillus species identified in respiratory specimens were matched at the time of study entry 1:2 with control subjects according to study center, age, gender, race, HIV transmission category, and CD4 count. SETTING: The multicenter Pulmonary Complications of HIV Infection Study. PARTICIPANTS: HIV-seropositive study participants. MEASUREMENTS AND RESULTS: Between November 1988 and March 1994, Aspergillus species were detected in respiratory specimens from 19 (1.6%) participants. The rate of Aspergillus identification among participants with CD4 counts <200 cells per cubic millimeter during years 2 through 5 after study entry ranged from 1.2 to 1.9%. Neutropenia, a CD4 count <30 cells per cubic millimeter, corticosteroid use, and Pneumocystis carinii infection were associated with subsequent identification of Aspergillus in respiratory specimens. Cigarette and marijuana use, previously suggested risk factors, were not associated with Aspergillus respiratory infection. A substantially greater proportion of patients with Aspergillus compared with control subjects died during the study (90% vs 21%). Excluding four cases first diagnosed at autopsy, 67% died within 60 days after Aspergillus was detected. CONCLUSIONS: Although Aspergillus is infrequently isolated from HIV-infected persons, the associated high mortality would support serious consideration of its clinical significance in those with advanced disease and risk factors.

Nonspecific airway hyperresponsiveness in HIV disease. Pulmonary Complications of HIV Infection Study Group.

OBJECTIVES: HIV disease is frequently complicated by episodic acute bronchitis, suggesting the presence of chronic bronchial inflammation. To further examine this concept, we investigated the possible association of nonspecific airway hyperresponsiveness (AHR) and HIV disease. DESIGN: Methacholine inhalation challenge studies were performed on 66 HIV-seropositive and 8 HIV-seronegative members of the Pulmonary Complications of HIV Infection Study Cohort. AHR was defined as 20% or more decline in FEV1 from the postdiluent value after inhalation of 125 or less cumulative breath units. The prevalence of AHR in HIV-seropositive cohort members was compared with that in matched control subjects who had undergone methacholine challenge testing for two unrelated studies. Demographic, behavioral, and clinical features in HIV cohort members with and without AHR were contrasted. The relationship between AHR and the occurrence of episodic airway disease or symptoms suggestive of airway disease was examined. RESULTS: AHR was not more prevalent in HIV-seropositive cohort members than control subjects (19.3% vs 12.9%; p > 0.1). Within the cohort, AHR was detected more frequently in members with than without a history of asthma (60% vs 16%; p < 0.05). A greater proportion with than without AHR had 1 or more episode of pneumonia within 2 years (46% vs 9%; p < 0.01), 1 or more asthma episode during the study period (39% vs 1.9%; p < 0.001), or wheeze noted during clinic visits (62% vs 17%; p < 0.01). The proportion that experienced acute bronchitis did not differ in the two groups. CONCLUSIONS: This study suggest that HIV-infected persons do not have increased prevalence of nonspecific AHR. In HIV disease, AHR is associated asthma, but not episodic acute bronchitis. Thus, the possibility that airway injury without demonstrable AHR might complicate HIV disease remains.

Antilung antibodies in asthma.

Twenty-four asthmatic patients were evaluated for the presence of circulating cytotoxic lung antibodies. These patients were further classified as either extrinsic or intrinsic asthmatics on the basis of skin testing, age of onset, and atopic history. Of the 12 patients considered to have extrinsic asthma, 10 had positive titers, one borderline, and one negative for cytotoxic lung antibodies. In the group of 12 patients classified as intrinsic asthmatics, eight had negative titers, two borderline, and two positive for cytotoxic lung antibodies. Adsorption studies indicated that these antibodies were organ-specific. Twenty normal non-smoking controls were also tested, all of whom were negative. Five patients with allergic rhinitis, positive intradermal skin tests, and no history of asthma were found to be negative for cytotoxic lung antibodies.

Pulmonary tuberculosis in the HIV-positive patients.

Tuberculosis associated with human immunodeficiency virus (HIV) infection continues to represent a serious medical and public health problem. Physicians' awareness of this entity is important because the diagnosis requires a high index of suspicion. A continuing increase in the cases of tuberculosis associated with HIV infection is predicted unless extensive efforts are directed toward detection of this dual infection and implementation of effective tuberculosis preventive therapy and treatment programs.