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Since the 1990s the rising incidence of multiple drug resistant TB, particularly in the context of human immunodeficiency virus co-infected patients, has threatened global TB control. At that time funding agencies began to support formal investigation of aerosol therapy which until then had been the subject of case reports of individual investigators. Over the last decade, proponents of aerosol therapy have increased in number within the TB research community as the incidence of multiple and extremely drug resistant TB has increased dramatically around the world. Aerosol therapy offers the potential to deliver drug at target concentrations directly into the lungs, use the alveolar-capillary interface to achieve systemic levels, while reducing the risk of systemic toxicity seen with parentally administered doses. In addition, there are insufficient new drugs in the pipeline to anticipate the appearance of a new regimen in time to assure future control of drug resistance. Consequently, alternative strategies are critical to achieving global TB control, and inhaled therapies should be considered as one such strategy., (Copyright © 2015. Published by Elsevier B.V.)

The threshold limit value (TLV) guideline for ultraviolet (UV) radiation specifies that irradiance measurements to ensure occupant safety be taken over an angle of 80° at the sensor. The purpose of this study was to evaluate the effect of an 80° field of view (FOV) tube on lower room UV-C irradiation measurements. Measurements were made in an experimental chamber at a height of 1.73m with and without an FOV tube. The FOV tube reduced the lower room irradiance readings by 18-34%, a statistically significant reduction compared to the bare sensor. An 80° FOV tube should be used for lower room irradiance measurements to comply with the TLV guideline. The resulting lower readings would allow more UV-C radiation in the upper room without compromising occupant safety. More UV-C radiation in the upper room could increase efficacy of UVGI systems for reducing transmission of airborne infectious diseases. In addition, recommendations are made to standardize lower room irradiance measurement techniques., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Multidrug-resistant (MDR) tuberculosis, "Ebola with wings," is a significant threat to tuberculosis control efforts. Previous prevailing views that resistance was mainly acquired through poor treatment led to decades of focus on drug-sensitive rather than drug-resistant (DR) tuberculosis, driven by the World Health Organization's directly observed therapy, short course strategy. The paradigm has shifted toward recognition that most DR tuberculosis is transmitted and that there is a need for increased efforts to control DR tuberculosis. Yet most people with DR tuberculosis are untested and untreated, driving transmission in the community and in health systems in high-burden settings. The risk of nosocomial transmission is high for patients and staff alike. Lowering transmission risk for MDR tuberculosis requires a combination approach centered on rapid identification of active tuberculosis disease and tuberculosis drug resistance, followed by rapid initiation of appropriate treatment and adherence support, complemented by universal tuberculosis infection control measures in healthcare facilities. It also requires a second paradigm shift, from the classic infection control hierarchy to a novel, decentralized approach across the continuum from early diagnosis and treatment to community awareness and support. A massive scale-up of rapid diagnosis and treatment is necessary to control the MDR tuberculosis epidemic. This will not be possible without intense efforts toward the implementation of decentralized, ambulatory models of care. Increasing political will and resources need to be accompanied by a paradigm shift. Instead of focusing on diagnosed cases, recognition that transmission is driven largely by undiagnosed, untreated cases, both in the community and in healthcare settings, is necessary. This article discusses this comprehensive approach, strategies available, and associated challenges., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Airborne transmitted pathogens such as Mycobacterium tuberculosis (Mtb) cause serious, often fatal infectious disease with enormous global health implications. Due to their unique cell wall and slow growth, mycobacteria are among the most resilient microbial forms. Herein we evaluate the ability of an emerging, chemical-free, nanotechnology-based method to inactivate M. parafortuitum (Mtb surrogate). This method is based on the transformation of atmospheric water vapor into engineered water nano-structures (EWNS) via electrospray. We demonstrate that the EWNS can interact with and inactivate airborne mycobacteria, reducing their concentration levels significantly. Additionally, EWNS can inactivate M. parafortuitum on surfaces eight times faster than the control. The mechanism of mycobacteria inactivation was also investigated in this study. It was demonstrated that the EWNS effectively deliver the reactive oxygen species, encapsulated during the electrospray process, to the bacteria oxidizing their cell membrane resulting into inactivation. Overall, this is a method with the potential to become an effective intervention technology in the battle against airborne infections., From the Clinical Editor: This study demonstrates the feasibility of mycobacterium inactivation in airborne form or on contact surfaces using electrospray activated water nano-structures. Given that the method is free of toxic chemicals, this might become an important tool in the prevention of mycobacterial infections, which are notoriously hard to treat., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Upper-room ultraviolet germicidal irradiation (UVGI) has several applications, its most important use is to reduce tuberculosis transmission in high-burden, resource-limited settings, especially those dealing with epidemics of drug-resistant disease. The efficacy of upper-room (UVGI) to reduce the transmission of airborne infection in real-world settings is no longer in question. International application (dosing) guidelines are needed, as are safety standards and commissioning procedures. A recent symposium to build consensus on guidelines discussed specifications for affordable UVGI fixture designs, safety, performance, computer-aided design (CAD) for UVGI, maintenance, dosimetry, gonioradiometric measurement and innovation using germicidal LEDs., (© 2013 The American Society of Photobiology.)

Multidrug-resistant tuberculosis (MDR-TB) threatens global TB control. The lengthy treatment includes one of the injectable drugs kanamycin, amikacin, and capreomycin, usually for the first 6 months. These drugs have potentially serious toxicities, and when given as intramuscular injections, dosing can be painful. Advances in particulate drug delivery have led to the formulation of capreomycin as the first antituberculosis drug available as a microparticle dry powder for inhalation and clinical study. Delivery by aerosol may result in successful treatment with lower doses. Here we report a phase I, single-dose, dose-escalating study aimed at demonstrating safety and tolerability in healthy subjects and measuring pharmacokinetic (PK) parameters. Twenty healthy adults (n = 5 per group) were recruited to self-administer a single dose of inhaled dry powder capreomycin (25-mg, 75-mg, 150-mg, or 300-mg nominal dose) using a simple, handheld delivery device. Inhalations were well tolerated by all subjects. The most common adverse event was mild to moderate transient cough, in five subjects. There were no changes in lung function, audiometry, or laboratory parameters. Capreomycin was rapidly absorbed after inhalation. Systemic concentrations were detected in each dose group within 20 min. Peak and mean plasma concentrations of capreomycin were dose proportional. Serum concentrations exceeded 2 μg/ml (MIC for Mycobacterium tuberculosis) following the highest dose; the half-life (t1/2) was 4.8 ± 1.0 h. A novel inhaled microparticle dry powder formulation of capreomycin was well tolerated. A single 300-mg dose rapidly achieved serum drug concentrations above the MIC for Mycobacterium tuberculosis, suggesting the potential of inhaled therapy as part of an MDR-TB treatment regimen.

Tuberculosis notification rates among South African miners range from 4,000 to 7,000 per 100,000 people. These rates far exceed national tuberculosis notification rates for the general population. Tuberculosis mortality also surpasses deaths caused by mining accidents. These extraordinarily high rates of disease are unambiguously linked to a series of contributing factors, including exposure to silica dust, HIV infection, and poor working and living conditions. We argue that the only way to stop the transmission of this airborne disease is to treat the mine and its living quarters as one should any other congregate setting with individuals who have high rates of infection with drug-susceptible and drug-resistant strains of tuberculosis. This means implementing interventions that have been demonstrated to stop the spread of tuberculosis over the last 60 years: immediate treatment of active tuberculosis, concurrent treatment of latent tuberculosis disease to reduce the burden of active cases, and appropriate management of patients infected with HIV. Because tuberculosis is also a social disease, biomedical interventions must be coupled with improved living and working conditions. Achieving zero deaths from tuberculosis in the mines is possible if a clear commitment is made to a strategy that recognizes and ameliorates the biological and social antecedents to this epidemic.

Ongoing transmission and re-infection, primarily in congregate settings, is a key factor fueling the global multidrug-resistant/extensively drug-resistant tuberculosis (MDR/XDR-TB) epidemic, especially in association with the human immunodeficiency virus. Even as efforts to broadly implement conventional TB transmission control measures begin, current strategies may be incompletely effective under the overcrowded conditions extant in high-burden, resource-limited settings. Longstanding evidence suggesting that TB patients on effective therapy rapidly become non-infectious and that unsuspected, untreated TB cases account for the most transmission makes a strong case for the implementation of rapid point-of-care diagnostics coupled with fully supervised effective treatment. Among the most important decisions affecting transmission, the choice of an MDR-TB treatment model that includes community-based treatment may offer important advantages over hospital or clinic-based care, not only in cost and effectiveness, but also in transmission control. In the community, too, rapid identification of infectious cases, especially drug-resistant cases, followed by effective, fully supervised treatment, is critical to stopping transmission. Among the conventional interventions available, we present a simple triage and separation strategy, point out that separation is intimately linked to the design and engineering of clinical space and call attention to the pros and cons of natural ventilation, simple mechanical ventilation systems, germicidal ultraviolet air disinfection, fit-tested respirators on health care workers and short-term use of masks on patients before treatment is initiated.

To evaluate the utility of the QuantiFERON-TB Gold assay for monitoring latent tuberculosis treatment efficacy, the assay was performed serially for healthcare workers receiving isoniazid therapy. After 9 months of isoniazid therapy, all of these healthcare workers remained QuantiFERON-TB Gold positive, and cellular proliferation assays revealed persistently strong purified protein derivative responses. These results do not support the use of the QuantiFERON-TB Gold assay to monitor therapy.

Objective: In late 2006, our hospital implemented use of the QuantiFERON-TB Gold (QFT-G) assay, a whole-blood interferon-gamma release assay, for detection of tuberculosis infection. All newly hired healthcare workers (HCWs) with positive Mantoux tuberculin skin test (TST) results were routinely tested with the QFT-G assay, to take advantage of its higher specificity. We then undertook a quality assurance review to evaluate the QFT-G test results in HCWs with multiple risk factors for latent tuberculosis infection (LTBI)., Methods: The clinical records for TST-positive HCWs tested with the QFT-G assay were reviewed. HCWs with 2 or more risk factors commonly associated with LTBI were classified as "increased risk" (IR). IR HCWs who had negative QFT-G test results underwent repeat QFT-G testing and were offered testing with a different interferon-gamma release assay (T-SPOT.TB) and with extended T cell stimulation assays., Results: Of 143 TST-positive HCWs tested with the QFT-G assay, 26 (18%) had positive results, 115 (81%) had negative results, and 2 (1%) had indeterminate results. Of 82 IR HCWs, 23 (28%) had positive QFT-G test results, and 57 (70%) had negative results. Of the 57 IR HCWs with negative results, 43 underwent repeat QFT-G testing: 41 had negative results again, and 2 had positive results. These 43 HCWs were also offered additional testing with the T-SPOT.TB diagnostic, and 36 consented: 31/36 tested negative, and 5/36 tested positive. Extended assays using the antigens ESAT-6 and CFP-10 confirmed the positive results detected by the overnight assays and yielded positive results for an additional 7/36 (19%) of individuals; strikingly, all 36 HCWs had strongly positive test results with assays using purified protein derivative., Conclusions: The extreme discordance between the results of our clinical diagnostic algorithm and the results of QFT-G testing raises concern about the sensitivity of the QFT-G assay for detection of LTBI in our HCWs. Results of extended stimulation assays suggest that many of our IR HCWs have indeed been sensitized to Mycobacterium tuberculosis. It is possible that the QFT-G assay identifies those at higher reactivation risk rather than all previously infected, but, in the absence of long-term follow-up data, we should interpret negative QFT-G results with some caution.

The opportunities for human immunodeficiency virus (HIV) care and treatment created by new treatment initiatives promoting universal access are also creating unprecedented opportunities for persons with HIV-associated immunosuppression to be exposed to patients with infectious tuberculosis (TB) within health care facilities, with the attendant risks of acquiring TB infection and developing TB disease. Infection control measures can reduce the risk of Mycobacterium tuberculosis transmission even in settings with limited resources, on the basis of a 3-level hierarchy of controls, including administrative or work practice, environmental controls, and respiratory protection. Further research is needed to define the most efficient interventions. The importance of preventing transmission of M. tuberculosis in the era of expanding HIV care and treatment in resource-limited settings must be recognized and addressed.

Setting: University hospital and university campus in Lima, Peru., Objective: To demonstrate the risk of latent tuberculosis infection (LTBI) in the hospital relative to the community., Design: Prospective cohort study of university students measuring prevalence, boosting, and conversion of tuberculin skin tests (TSTs) among health care students (HCS) and non-health care students (NHCS)., Results: Among the HCS relative to NHCS, prevalence of initial positive TST was 20.9% vs. 12.2% (P < 0.001), and conversion rate was 1.1% vs. 0% (P = 0.423) at the 10 mm cut-off and 11.8% vs. 0% at the 6 mm cut-off (P = 0.00005). Multivariate analysis showed that the HCS group had a higher risk of baseline positive TST compared with the NHCS group after controlling for confounding factors (OR 1.7, 95% CI 1.1-2.6)., Conclusion: HCS are at greater risk than NHCS for having positive baseline TSTs and for TST conversion at the 6 mm cut-off. We conclude that the hospital we studied in Lima, Peru, poses a greater risk than the surrounding community for tuberculosis infection, and greater attention to hospital infection control measures is warranted. A higher rate of skin test boosting among the HCS cohort suggests the possibility of transient, non-progressive LTBI, which merits further study.

Background: There is no gold standard on how national tuberculosis programs should design retreatment regimens. Often drug susceptibility testing (DST) is not available for all patients, and representative DST patterns in patient populations are used to guide therapy., Objectives: To examine DST patterns in different patient populations based on previous treatment and to estimate the number of effective anti-tuberculosis agents in several retreatment regimens., Methods: We reviewed DST results from patients treated with individualized regimens in Peru between January 1998 and July 2004. We stratified patients into four groups based on previous treatment exposure from Group 1 who had failed only one regimen to Group 4 who had failed three regimens. We compared resistance frequencies across the four groups. In Groups 1 and 3, the number of likely effective agents under six possible retreatment regimen scenarios was estimated., Results: Resistance to second-line drugs was significantly higher in groups with more previous courses of treatment. A few retreatment regimens could be identified that would allow at least 80% of patients to receive at least four likely effective drugs., Conclusion: Because it is associated with resistance frequencies, previous treatment exposure can serve to guide the design of non-individualized MDR-TB regimens.

Setting: Lima, Peru., Objective: To describe drug resistance profiles of TB isolates from patients at risk for multidrug-resistant tuberculosis (MDR-TB), and to consider the implications of these findings for treatment., Design: Descriptive study of drug susceptibility testing (DST) results for TB isolates from 1680 patients referred for suspicion of MDR-TB between 1996 and 2001., Results: Of 1680 isolates tested, 1144 (68%) were resistant to at least one anti-tuberculosis drug and 926 (55%) were MDR-TB strains. Of 926 MDR isolates, 50 (5%) were resistant to INH and RMP alone, while 367 (40%) were resistant to at least five first-line drugs. We identified 146 unique drug resistance profiles, the most common of which accounted for 11% of drug-resistant isolates. The annual prevalence of isolates with resistance to at least five first-line drugs rose significantly during the study period, from 29% to 37% (P = 0.00086)., Conclusions: This is a group of patients with TB disease among whom the prevalence of a broad spectrum of often highly drug-resistant strains appears to be increasing over time. A single standardized retreatment regimen may be inadequate to cure most patients. Capacity for drug sensitivity testing is essential for development of multiple standardized retreatment or individualized treatment regimens and epidemiological surveillance for planning.

Humans commonly exhale aerosols comprised of small droplets of airway-lining fluid during normal breathing. These "exhaled bioaerosols" may carry airborne pathogens and thereby magnify the spread of certain infectious diseases, such as influenza, tuberculosis, and severe acute respiratory syndrome. We hypothesize that, by altering lung airway surface properties through an inhaled nontoxic aerosol, we might substantially diminish the number of exhaled bioaerosol droplets and thereby provide a simple means to potentially mitigate the spread of airborne infectious disease independently of the identity of the airborne pathogen or the nature of any specific therapy. We find that some normal human subjects expire many more bioaerosol particles than other individuals during quiet breathing and therefore bear the burden of production of exhaled bioaerosols. Administering nebulized isotonic saline to these "high-producer" individuals diminishes the number of exhaled bioaerosol particles expired by 72.10 +/- 8.19% for up to 6 h. In vitro and in vivo experiments with saline and surfactants suggest that the mechanism of action of the nebulized saline relates to modification of the physical properties of the airway-lining fluid, notably surface tension.

Store-and-forward telemedicine, using e-mail to send clinical data and digital images, offers a low-cost alternative for physicians in developing countries to obtain second opinions from specialists. To explore the potential usefulness of this technique, 91 chest X-ray images were photographed using a digital camera and a view box. Four independent readers (three radiologists and one pulmonologist) read two types of digital (JPEG and JPEG2000) and original film images and indicated their confidence in the presence of eight features known to be radiological indicators of tuberculosis (TB). The results were compared to a "gold standard" established by two different radiologists, and assessed using receiver operating characteristic (ROC) curve analysis. There was no statistical difference in the overall performance between the readings from the original films and both types of digital images. The size of JPEG2000 images was approximately 120KB, making this technique feasible for slow internet connections. Our preliminary results show the potential usefulness of this technique particularly for tuberculosis and lung disease, but further studies are required to refine its potential.

We used molecular genotyping to further understand the epidemiology and transmission patterns of tuberculosis (TB) in Massachusetts. The study population included 983 TB patients whose cases were verified by the Massachusetts Department of Public Health between July 1, 1996, and December 31, 2000, and for whom genotyping results and information on country of origin were available. Two hundred seventy-two (28%) of TB patients were in genetic clusters, and isolates from U.S-born were twice as likely to cluster as those of foreign-born (odds ratio [OR] 2.29, 95% confidence interval [CI] 1.69 to 3.12). Our results suggest that restriction fragment length polymorphism analysis has limited capacity to differentiate TB strains when the isolate contains six or fewer copies of IS6110, even with spoligotyping. Clusters of TB patients with more than six copies of IS6110 were more likely to have epidemiologic connections than were clusters of TB patients with isolates with few copies of IS6110 (OR 8.01, 95%; CI 3.45 to 18.93).

We estimated direct medical and nonmedical costs associated with a false diagnosis of tuberculosis (TB) caused by laboratory cross-contamination of Mycobacterium tuberculosis cultures in Massachusetts in 1998 and 1999. For three patients who received misdiagnoses of active TB disease on the basis of laboratory cross-contamination, the costs totaled U.S. dollars 32618. Of the total, 97% was attributed to the public sector (local and state health departments, public health hospital and laboratory, and county and state correctional facilities); 3% to the private sector (physicians, hospitals, and laboratories); and <1% to the patient. Hospitalizations and inpatient tests, procedures, and TB medications accounted for 69% of costs, and outpatient TB medications accounted for 18%. The average cost per patient was dollars 10873 (range, dollars 1033-dollars 21306). Reducing laboratory cross-contamination and quickly identifying patients with cross-contaminated cultures can prevent unnecessary and potentially dangerous treatment regimens and anguish for the patient and financial burden to the health-care system.

Setting: An outbreak of tuberculosis caused by Mycobacterium tuberculosis resistant to isoniazid and streptomycin (HS-resistant) was documented in Boston's homeless population in 1984. Isolate relatedness was confirmed at the time by phage typing. In the late 1990s, cases of HS-resistant tuberculosis in the homeless were also documented, confirmed by RFLP typing using IS6110. None of the phage typed isolates from the 1980s were viable for performing RFLP analysis. We attempted to determine, using mixed-linker PCR (M-L PCR) finger-printing, whether or not these cases were all due to the same strain of M. tuberculosis., Design: Isolates from 10 HS-resistant patients-four non-viable isolates from the 1980s and six viable isolates from 1996-1997-were sent to the Centers for Disease Control and Prevention for M-L PCR fingerprinting. These results were combined with record reviews of older cases and an ongoing epidemiologic investigation., Results: Eight of 10 of the isolates were clonal, and the other two were strongly suspected matches. Epidemiologic investigation determined that transmission continued to occur after the initial outbreak in 1984-1985, and that a streptomycin-monoresistant variant of the strain was also circulating., Conclusion: M-L PCR fingerprinting combined with epidemiology was able to document links between cases across 15 years.

Over the past 10 years, molecular methods have become available with which to strain-type Mycobacterium tuberculosis. They have allowed researchers to study certain important but previously unresolved issues in the epidemiology of tuberculosis (TB). For example, some unsuspected microepidemics have been revealed and it has been shown that the relative contribution of recently acquired disease to the TB burden in many settings is far greater than had been thought. These findings have led to the strengthening of TB control. Other research has demonstrated the existence and described the frequency of exogenous reinfection in areas of high incidence. Much recent work has focused on the phenotypic variation among strains and has evaluated the relative transmissibility, virulence, and immunogenicity of different lineages of the organism. We summarize the recent achievements in TB epidemiology associated with the introduction of DNA fingerprinting techniques, and consider the implications of this technology for the design and analysis of epidemiological studies.

Environmental control measures (ventilation, high-efficiency particulate air filtration, and upper room ultraviolet germicidal irradiation [UVGI]) are recommended to effectively control tuberculosis (TB) transmission from unsuspected TB patients in high-risk settings, but the effectiveness of their use is not often clear. This study presents a simulation model for a hypothetical hospital waiting room, in which the number of susceptible immunocompetent people in the waiting room follows a Poisson distribution (M = 5) in either low (annual number of TB patients = 5) or high TB risk settings (annual number of TB patients = 50), and used the model to evaluate the reduction of TB transmission risk by upper room UVGI. An exponential dose-response model was used for TB transmission and a two-zone model was used for evaluating the effect of upper room UVGI. Upper room UVGI reduced TB risk by 1.6-fold at 3 microW/cm2 UV irradiance in the upper room in the low TB risk setting and by 4.1-fold at 15 microW/cm2 UV irradiance in the upper room in the high TB risk setting. Use of upper room UVGI also reduced the mean annual new infection rate from 2.2 to 1.3 infections per year at 3 microW/cm2 and to 0.6 infections per year at 15 microW/cm2 in our hypothetical high-risk settings. The effect of upper room UVGI was sensitive to both vertical air velocity (air mixing) and UV irradiance level. Results from partitioning variability indicate that most variability of TB transmission risk came from waiting time in our hypothetical hospital.

Objectives: To evaluate the relative efficacy of personal respiratory protection as the concentrations of infectious aerosols increase or as room ventilation rates decrease., Methods: We modified the Wells-Riley mathematical model of airborne transmission of disease by adding a variable for respirator leakage. We modeled three categories of infectiousness using various room ventilation rates and classes of respirators over a 10-hour exposure period., Results: The risk of infection decreases exponentially with increasing room ventilation or with increasing personal respiratory protection. The relative efficacy of personal respiratory protection decreases as room ventilation rates increase or as the concentrations of infectious aerosols decrease., Conclusions: These modeling data suggest that the risk of occupational tuberculosis probably can be lowered considerably by using relatively simple respirators combined with modest room ventilation rates for the infectious aerosols likely to be present in isolation rooms of newly diagnosed patients. However, more sophisticated respirators may be needed to achieve a comparable risk reduction for exposures to more highly concentrated aerosols, such as may be generated during cough-inducing procedures or autopsies involving infectious patients. There is probably minimal benefit to the use of respirators in well-ventilated isolation rooms with patients receiving appropriate therapy.

The premise of this article is that it is possible to reduce but not eliminate the risk of TB infection in many institutional settings through environmental interventions--as supplements to conventional public health TB control efforts. Of the environmental means available to reduce the concentration of infectious droplet nuclei, ventilation, isolation strategies, and personal respirators have received the most attention, but each has inherent limitations. Ventilation and other air-moving strategies (i.e., fan-filter and fan-UV room units) are limited by the large volume of air that must be moved to dilute and remove already dilute droplet nuclei. Isolation assumes that potential transmitters are suspected, whereas negative pressure in isolation rooms is difficult to achieve and maintain in many hospitals. The use of well-designed small enclosures for sputum induction and other high-risk procedures, however, should provide highly effective source control. Personal respirators have a limited protective role because they cannot be worn by all workers at all times, and cannot reasonably be issued to other patients and visitors. Germicidal UV irradiation of upper room air is widely misunderstood, but offers practical air disinfection that can be safely and efficiently deployed in a variety of high-risk environments. Although there are theoretical and experimental bases for these recommendations, there are no clinical field trials preventing TB using any of the available environmental interventions, primarily because of the highly variable nature of TB transmission.

For most patients with tuberculosis (TB), treatment has never been shorter or cure more certain than with current drug regimens. However, in Massachusetts and elsewhere in the United States there is a growing minority of patients who are not easily cured with the best available outpatient regimens. Close treatment supervision through culturally appropriate outreach workers has been successful for some foreign-born TB patients in whom therapy might otherwise fail. Full supervision of outpatient therapy, sometimes with incentives, has also been used successfully to treat selected homeless patients. However, a growing number of hard-to-treat homeless patients are addicted to illicit drugs, human immunodeficiency virus (HIV) infected, or have major behavioral problems. These patients often do not cooperate with fully supervised therapy and acquire drug resistance as a result of erratic drug taking. They can then transmit these dangerous organisms to others, especially to other HIV-infected persons within shelters, jails, prisons, detoxification centers, clinics, and hospitals, infecting institutional workers at the same time. In Massachusetts these hard-to-treat TB patients are increasingly being legally committed to involuntary, long-term, inpatient therapy. Although long-term inpatient TB treatment is expensive, it is likely to be cost effective when it successfully breaks the chain of transmission within institutions, and achieves cures not otherwise possible. A new model of lower-cost inpatient care that incorporates psychosocial rehabilitation techniques to modify the behavior of the hardest-to-treat patients is briefly described. Ultimately, however, the reversal of the current upsurge in hard-to-treat TB cases in Massachusetts and elsewhere depends not on inpatient care but on substantial changes in the socioeconomic order that perpetuates homelessness, substance abuse, crime, and the transmission of both TB and HIV infections.

Of 67 office workers 27 (40%) had documented tuberculin skin test conversions after an estimated 4-wk exposure to a coworker with cavitary tuberculosis. Worker complaints for more than 2 yr before the tuberculosis exposure prompted investigations of air quality in the building before and after the tuberculosis exposure. Carbon dioxide concentrations in many parts of the building were found to be above recommended levels, indicating suboptimal ventilation with outdoor air. We applied a mathematical model of airborne transmission to the data to assess the role of building ventilation and other transmission factors. We estimated that ventilation with outside air averaged about 15 feet 3/min (cfm) per occupant, the low end of acceptable ventilation, corresponding to CO2 levels of about 1,000 ppm. The model predicted that at 25 cfm per person 18 workers would have been infected (a 33% reduction) and at 35 cfm, a level considered optimal for comfort, that 13 workers would have been infected (an additional 19% reduction). Further increases in outdoor air ventilation would be impractical and would have resulted in progressively smaller increments in protection. According to the model, the index case added approximately 13 infectious doses (quanta) per hour (qph) to the office air during the exposure period, 10 times the average infectiousness reported in a large series of tuberculosis cases. Further modeling predicted that as infectiousness rises, ventilation would offer progressively less protection. We conclude that outdoor air ventilation that is inadequate for comfort may contribute to airborne infection but that the protection afforded to building occupants by ventilation above comfort levels may be inherently limited, especially when the level of exposure to infection is high.

In developed countries where tuberculosis is increasing in association with HIV infection, nosocomial transmission among patients and from patients to health care workers is being increasingly reported. Nosocomial tuberculosis among HIV-infected patients is difficult to prevent by conventional control measures because the clinical presentation of the disease may be atypical and confused with other respiratory infections, because the tuberculin skin test is less reliable, because cough generating procedures may increase the probability of transmission, because HIV-infected patients may progress rapidly from infection to disease, and because the organisms are increasingly drug resistant, making preventive therapy difficult. Substandard ventilation and the recirculation of air in many contemporary buildings has also been implicated in widespread nosocomial transmission. Source control through isolation and effective treatment of known or suspected cases remains the most effective strategy for preventing transmission. Dilution of infectious droplet nuclei through ventilation with outside air is important, but incompletely protective. Like ventilation with outside air, filtration of recirculated air may reduce the chance of infection by dilution, but it is expensive. Traditional surgical masks offer the wearer little or no protection. Finally, ultraviolet air disinfection may augment ventilation by inactivating organisms in the upper room air, or in ventilation ducts.

Tuberculosis (TB) is a problem in some institutions, but not in others. Six factors may be used to assess the risk of TB in an institution: the entrance-point prevalence of infection among institutional residents and staff, the potential for reactivation, the role of transmission within the institution, the potential for detection of infection and disease, the potential for prevention and treatment of disease, and the potential of the building environment to favor transmission. The aging of the population, the crowding of prisons and the high prevalence of human immunodeficiency virus (HIV) infection are factors currently increasing the likelihood of TB in nursing homes, prisons, drug detoxification centers, and acute hospitals. Entrance-point skin testing, contact testing, periodic retesting, supervised preventive therapy, effective treatment of disease, and the selective application of ultraviolet air disinfection for certain high-risk areas are the suggested control strategies for hospitals, nursing homes, prisons, and chronic care facilities. However, for inner-city shelters and jails skin testing and preventive treatment are usually not possible, and the control strategy shifts to disease detection, isolation, effective long-term treatment, reduced crowding, ultraviolet air disinfection, and periodic testing and treatment of staff.

To study regulation of CSF [HCO-3] in metabolic acidosis and in particular the role of CSF PCO2 in establishing CSF bicarbonate level, acute metabolic acidosis was induced by the intravenous infusion of HCl in three groups of anesthetized dogs for six hours when PaCO2 was changed at different rates. Plasma [HCO-3] was lowered to 12 +/- 2 meq/L within one hour and maintained at that level thereafter in all groups. (I) Seven dogs were kept isocapnic while metabolic acidosis was induced. The cisternal CSF [HCO-3] fell by only 2.6 meq/L after six hours and was not significantly different from control. (II) In 11 dogs metabolic acidosis was induced while the dogs breathed spontaneously. There was a gradual drop in PaCO2 accompanied by a similar drop in CSF PCO2 of 14.5 torr. CSF [HCO-3] fell significantly by 6.1 meq/L at 6 hours and in parallel with the fall in CSF PCO2. (III) In order to show interdependence of the rate of fall in CSF [HCO-3] with rate of fall in cisternal PCO2 six dogs were mechanically hyperventilated and PaCO2 reduced to 21 torr rapidly and maintained there for six hours. CSF PCO2 followed PaCO. CSF bicarbonate fell rapidly and by 5 meq/L. In groups II and III the fall in cisternal [HCO-3] paralleled the drop in PCO2. Therefore, in metabolic acidosis the rate of the fall in cisternal bicarbonate appears to be a function of the rate of fall in CSF PCO2. It is speculated that the coupling of CSF [HCO-3] reduction in metabolic acidosis to CSF PCO2 fall is primarily for the benefit of CNS H+ homeostasis.