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.

Frequency, severity and duration of immune reconstitution events in HIV-related tuberculosis.

SETTING: Patients were enrolled in a prospective trial of rifabutin-based tuberculosis (TB) treatment for human immunodeficiency virus related TB. Antiretroviral therapy (ART) was encouraged, but not required. OBJECTIVE: To evaluate the frequency, risk factors and duration of immune reconstitution events. DESIGN: Patients were prospectively evaluated for immune reconstitution events, and all adverse event reports were reviewed to identify possible unrecognized events. RESULTS: Of 169 patients, 25 (15%) developed immune reconstitution events related to TB. All 25 were among the 137 patients who received ART during TB treatment, so the frequency in this subgroup was 18% (25/137). Risk factors for an immune reconstitution event in multivariate analysis were Black race, the presence of extra-pulmonary TB and a shorter interval from initiation of TB treatment to initiation of ART. The most common clinical manifestations were fever (64%), new or worsening adenopathy (52%) and worsening pulmonary infiltrates (40%). Twelve patients (48%) were hospitalized for a median of 7 days, six underwent surgery and 11 had needle aspiration. The median duration of events was 60 days (range 11-442). CONCLUSION: Immune reconstitution events were common among patients receiving ART during TB treatment, produced substantial morbidity and had a median duration of 2 months.

Mortality in a large tuberculosis treatment trial: modifiable and non-modifiable risk factors.

SETTING: North America. OBJECTIVES: Tuberculosis (TB) patients in North America often have characteristics that may increase overall mortality. Identifying modifiable risk factors would allow for improvements in outcome. DESIGN: We evaluated mortality in a large TB treatment trial conducted in the United States and Canada. Persons with culture-positive pulmonary TB were enrolled after 2 months of treatment, treated for 4 more months under direct observation, and followed for 2 years (total observation: 28 months). Cause of death was determined by death certificate, autopsy, and/or clinical observation. RESULTS: Of 1075 participants, 71 (6.6%) died: 15/71 (21.1%) HIV-infected persons, and 56/1004 (5.6%) non-HIV-infected persons (P < 0.001). Only one death was attributed to TB. Cox multivariate regression analysis identified four independent risk factors for death after controlling for age: malignancy (hazard ratio [HR] 5.28, P < 0.0001), HIV (HR 3.89, P < 0.0001), daily alcohol (HR 2.94, P < 0.0001), and being unemployed (HR 1.99, P = 0.01). The risk of death increased with the number of independent risk factors present (P < 0.0001). Extent of disease and treatment failure/relapse were not associated with an increased risk of death. CONCLUSIONS: Death due to TB was rare. Interventions to treat malignancy, HIV, and alcohol use in TB patients are needed to reduce mortality in this patient population.

Overall and cause-specific mortality in a cohort of homo-/bisexual men, injecting drug users, and female partners of HIV-infected men. Pulmonary Complications of Human Immunodeficiency Virus Infection Study Group.

OBJECTIVE: To study the overall and cause-specific HIV-related mortality in a cohort of HIV-seropositive subjects according to transmission category, race/ethnicity, sex and severity of immunosuppression. DESIGN: A cohort of 1129 HIV-seropositive homo-/bisexual men, injecting drug users, and female partners of HIV-infected men were enrolled at six centers in San Francisco, Los Angeles, Chicago, Newark, Detroit and New York between 1 November 1988 and 1 November 1989. Subjects were evaluated every 6 months at least until 31 March 1994. METHODS: The analyses of overall mortality for the subgroups of interest were performed with Kaplan-Meier plots and Cox proportional hazards models. Cause-specific analyses were performed on the primary cause of death using rates per 100 person-years of exposure. RESULTS AND CONCLUSIONS: Baseline severity of immunosuppression is the strongest predictor of mortality. There were no statistically significant differences in overall HIV-related mortality among transmission categories, race/ethnicity groups or sexes. There were differences, however, in cause-specific mortality among the different risk groups.

Bioavailability of a once daily-administered theophylline preparation. A comparison study.

To evaluate the bioavailability of a new theophylline preparation suitable for once-a-day (od) oral administration, we performed a nonrandomized crossover study in which the absorption of the OD and a standard twice-a-day (bid) preparation were compared. Eight stable asthmatic patients, after having achieved steady-state, received an average of 975 mg of OD preparation at 8 PM. The protocol was later repeated with the same subjects receiving 487.5 mg of the bid preparation at 8 PM and again at 8 AM using the same total dose. The maximal mean serum concentrations were 15.5 +/- 1.6 (SEM) micrograms/ml for the od preparation on the 8th hour and 12.7 +/- 2.2 for the bid regimen. The trough level was 7.4 +/- 1.2 micrograms/ml for the od regimen and 10.6 +/- 1.6 for the bid regimen. With either regimen, therapeutic theophylline levels could be observed throughout the 24-hour study period. Anhydrous theophylline may be administered as a single daily dose agent.

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.

Respiratory mechanical effects of abdominal distension.

We develop a theory to predict the partitioning of a change in volume of the abdominal contents into the end-expiratory volume changes of the lung, rib cage, and anterior abdominal wall. First, we calculate the distribution of such a volume change using the relative compliances of the three compartments. We then consider the inspiratory influence of abdominal pressure on the rib cage and its effect on the distribution of this volume. We test our theory by inducing gastric distension in three experienced laboratory personnel. We instilled and subsequently withdrew 1 liter of water from a gastric balloon and examined the effects of this change in gastric volume on the relaxation characteristics of the respiratory system. The distribution of the volume change that would be expected from the observed relative compliances of the three compartments would be approximately 66% into change in lung volume, 25% into change in rib cage volume, and 9% into change in abdominal volume. Instead, in line with our predictions for acute gastric distension, approximately 33% went into decrease in lung volume, 40% into increase in rib cage volume, and 26% into increase in abdominal volume. These results suggest that the interactions among the rib cage, abdomen, and diaphragm are such as to defend against large changes in end-expiratory lung volume in the face of abdominal distension.

An incentive in tuberculosis preventive therapy for an inner city population.

SETTING: Measures known to improve adherence such as short course chemoprophylaxis and directly observed therapy can be enhanced to a significant extent/by the use of incentives. Adherence to tuberculosis therapy is influenced by several factors, including the health care system, complexity of therapeutic regimens and patient's characteristics. Individual factors that negatively influence patient's adherence are the most difficult to counter. Preventive tuberculosis therapy is doubly challenging because the benefit of treatment is not felt, while toxicity from the medication, when it occurs, is experienced immediately. Ingenious incentives therefore have to make it worth the patient's while. During a study on preventive regimens, a request for an incentive, Sustacal, was observed to help completion of preventive regimens. Components of individual TB programs may help in patient adherence; it is important for health care staff to identify these aspects and, if they are successful, utilize these as an incentive to complete treatment.

Results of testing for human immunodeficiency virus infection among recent contacts of infectious tuberculosis cases in the United States.

CONTEXT: Persons with recently acquired latent tuberculosis (TB) infection and human immunodeficiency virus (HIV) co-infection are at high risk of rapid progression to TB disease. OBJECTIVES: To determine the proportion of close contacts of infectious TB patients tested for HIV, and the results of HIV testing for this group. DESIGN, SETTING AND SUBJECTS: Review of health department records for all close contacts of 349 patients with culture-positive pulmonary TB aged 15 years or older reported from five study areas in the United States in 1996. MAIN OUTCOME MEASURES: Proportion of close contacts of TB patients tested for HIV, and rate of HIV infection among close contacts of TB patients. RESULTS: A total of 1169 close contacts were identified for 349 patients with active pulmonary TB. HIV test results were available for 224 (64%) TB patients and 220 (19%) close contacts. Of the TB patients tested, 164 (73%) were HIV-negative and 60 (27%) were HIV-positive. An equal proportion of close contacts of HIV-positive and -negative TB patients were tested (21% vs. 24%). Of the close contacts tested, 201 (91%) were HIV-negative and 19 (9%) were HIV-positive. Compared with close contacts of HIV-negative TB patients, close contacts of HIV-positive TB patients were more likely to be HIV-positive (53% vs. 2%; P < 0.01). This association was observed for contacts residing in the TB patient household (70% vs. none; P < 0.01), not residing in the TB patient household (20% vs. 4%; P < 0.05), 25-44 years of age (88% vs. 8%; P < 0.01), and > 44 years of age (22% vs. 2%; P < 0.05). CONCLUSIONS: HIV-positive TB patients and their close contacts may share some of the same risk factors for HIV infection. These findings suggest that the HIV status of the TB patient, in addition to established risk factors for HIV infection, may be an important consideration for prioritizing voluntary HIV counseling and testing efforts among close contacts of infectious TB patients.

Directly observed therapy (DOT) is not the entire answer: an operational cohort analysis.

SETTING: New Jersey Medical School National Tuberculosis Center-Lattimore Clinic, a TB Clinic for an inner city population of Newark, New Jersey, USA. OBJECTIVE: Directly observed therapy (DOT) is the recommended standard of TB care. Recent reports suggest that DOT may not be any better than self-administered therapy (SAT). To quantify the impact of different levels of SAT, DOT, and active case management on outcomes of TB treatment at our location, we reviewed the outcomes of six TB patient-cohorts from Newark between 1 January 1994 and 31 December 1996. STUDY DESIGN: A retrospective cohort study of the outcomes of 343 tuberculosis patients treated during the years 1994-1996. The three treatment strategies were 1) self-administered with occasional selective directly observed therapy, 2) universal directly observed therapy alone (universal DOT), and 3) universal DOT with nurse case management (NCM). RESULTS: The first two cohorts who began treatment during the transition may have received more than one treatment strategy. However, universal DOT did not significantly improve the TB treatment completion rates of Cohort 2 over SAT therapy with selective DOT given to Cohort 1. Universal DOT with NCM, Cohorts 3, 4, 5, and 6, significantly increased the TB treatment completion rates by three to six times. A cohort-specific step-wise reduction in duration of treatment from a median of 11.6-7.5 months and an increase in completion rates from 57-81% resulted. The most desirable and optimal (shortest) duration of treatment completion coincided with the application of universal DOT combined with NCM.

Outcomes of contact investigation among homeless persons with infectious tuberculosis.

SETTING: Homelessness is an important risk factor for tuberculosis (TB). Health departments often fail to identify contacts for homeless TB cases, but little else is known about the outcome of contact investigations for these cases. OBJECTIVE: To describe the outcomes of identification, tuberculin skin testing (TST), clinical evaluation and treatment for contacts of infectious homeless TB cases. DESIGN: Retrospective multicenter review of data of contact investigations conducted in 1996 by five health departments in the United States. RESULTS: Twenty-seven (8%) of 349 TB cases were homeless. Failure to identify contacts occurred in six (50%) of 12 cases residing in shelters vs. one (7%) of 15 non-shelter cases. Of 479 contacts identified, 297 (62%) were fully evaluated, 97 (20%) had only initial testing, and 85 (18%) were not evaluated. Of the 394 evaluated contacts, 13 (3%) had a prior positive TST. Of the remaining 381 contacts, six (1.6%) had active TB and 67 (17.6%) were TST-positive. Only 27 (44%) of 61 contacts completed treatment for latent TB infection. CONCLUSION: Despite the failure to identify contacts for some cases, contact investigations for homeless TB cases identified large numbers of contacts for whom evaluation and treatment were often not completed. Prospective studies with more complete documentation are needed to improve contact investigations for homeless TB cases.

Workplace contact investigations in the United States.

SETTING: Five state tuberculosis (TB) control programs in the United States. OBJECTIVES: To determine the prevalence of and treatment for latent TB infection (LTBI) among contacts of active TB cases identified in the workplace, and to describe TB control program policies for the initiation and conduct of workplace investigations. DESIGN: Retrospective review of health department records for all culture-positive pulmonary tuberculosis cases aged > or = 15 years reported in 1996, and their contacts. RESULTS: There were 349 cases of active TB, of whom 134 (38%) were employed. Workplace contact investigations were conducted for 42 cases, resulting in the identification of 724 contacts. The rate of LTBI was 29% overall, varying by worksite from a low of 16% to a high of 51%. LTBI estimates were higher for fully-screened contacts of smear-positive rather than of smear-negative index cases. However, fully-screened contacts of index patients with cavitary disease had lower LTBI estimates than those of index patients without cavitation. Treatment for LTBI was initiated in 45% of infected contacts. The five programs had somewhat variable policies regarding workplace contact investigations. Data on HIV co-infection and place of birth of contacts were largely missing. CONCLUSION: Factors contributing to LTBI among workplace contacts may include the presence of persons with pre-existing LTBI or a positive skin test as a result of BCG vaccination, clinical characteristics of the index case, and workplace environmental characteristics conducive to transmission. Standard guidelines for workplace investigations, written workplace investigation policies, and standard data collection practices are needed to better apportion the causes of observed infection rates in the workplace.

Tuberculosis and the atypical pneumonia syndrome.

Literature over the last 30 years has warned of the atypical or unusual characteristics of pulmonary TB. Shifts in the demographic distribution of the disease in the US are ascribed in part to the occurrence of HIV disease outbreaks in group settings, and to recent influxes of immigrants from developing countries. Unsuspected pulmonary TB is particularly common among the elderly. Socioeconomic categories not traditionally thought of as being high risk also are affected. In the low-risk setting, TB can be treacherous because misdiagnosis is likely. Tuberculosis is a great mimicker, and it can appear to be any acute community-acquired pneumonia such as atypical pneumonia. Symptoms and signs are few. A high index of awareness is therefore essential. The approach to atypical pneumonia emphasizes the need to include TB in the differential diagnosis to be aware of the total disease spectrum of TB and understand the risk factors. The atypical pneumonia syndrome is only a portion of the clinical spectrum of TB.

Rib cage and abdominal volume displacements during breathing in pregnancy.

To examine the effect of abdominal distension upon the actions of both rib cage and abdomen, we made serial determinations of tidal volume with a chest wall volume-displacement method in 8 pregnant women. Enhancement of tidal volume, long recognized in pregnancy, was achieved usually by augmentation of rib cage volume displacement. By contrast, abdominal volume displacement during quiet breathing is not altered in a predictable fashion by the gravid state. Given these findings, we hypothesize that the increased diaphragmatic contraction of pregnancy is accompanied by the transmission of that force to the lower rib cage via the area of apposition and that diaphragmatic contraction accounts for enhancement of the tidal breath. Diminished abdominal compliance might contribute to the augmentation of rib cage volume displacement as well. Konno-Mead diagrams suggest that this hypothesis is true in some, but not all, subjects.

Management after exposure to tuberculosis.

The increased incidence of tuberculosis-coupled with the emergence of mycobacterial strains resistant to the most effective drugs-has highlighted the importance of identifying transmission and preventing active disease. Skin test conversion can document infection, except in most patients vaccinated with bacille Calmette-Guérin. Prophylactic medication is effective, but not without complications.

Minute ventilation in asthma. Enhancement by mouthpiece and depression by oxygen administration.

To evaluate independently the effects of an inspiratory stimulus (a mouthpiece) and a ventilatory depressant (oxygen) on minute ventilation (VE) in asthma, we measured VE with magnetometers in 18 asthmatic subjects. When room air was inspired from a loose-fitting mask, VE was 10.2 +/- 0.6 L/min. When oxygen was substituted for room air, VE decreased (8.4 +/- 0.6). In contrast, when oxygen was given by mouthpiece, VE increased (12.9 +/- 0.7). We conclude that in the clinical setting, the mouthpiece artifact may operate either to exaggerate the tidal breath or to obscure the effect of a respiratory depressant (e.g., oxygen) upon the measurement of resting ventilation.

The HLA-A, -B, and -DR phenotypes and tuberculosis.

The HLA-A, -B, and -DR antigens were studied in black Americans to analyze deviation in phenotype distribution between ATS Class 3 patients with tuberculosis disease and ATS Class 2 healthy persons with significant tuberculin reaction, but no tuberculosis. Statistical analyses with Fisher's exact test revealed a significant difference in frequency distribution of HLA-B5 (p = 0.046), HLA-DR5 (p = 0.0276), and HLA-DR6y (p = 0.0095) between ATS Class 2 and ATS Class 3 patients. There was a significant decrease in HLA-DR6y (p = 0.01) but increase in HLA-B5 and HLA-DR5 phenotypes in ATS Class 3 patients.