Epidemiologic link between tuberculosis and cigarette/biomass smoke exposure: Limitations despite the vast literature.

The geographic overlap between the prevalence of cigarette smoke (CS) exposure and tuberculosis (TB) in the world is striking. In recent years, relatively large number of studies has linked cigarette or biomass fuel smoke exposure and various aspects of TB. Our goals are to summarize the significance of the known published studies, graphically represent reports that quantified the association and discuss their potential limitations. PubMed searches were performed using the key words 'tuberculosis' with 'cigarette', 'tobacco', 'smoke' or 'biomass fuel smoke.' The references of relevant articles were examined for additional pertinent papers. A large number of mostly case-control and cross-sectional studies significantly associate both direct and second-hand smoke exposure with tuberculous infection, active TB, and/or more severe and lethal TB. Fewer link biomass fuel smoke exposure and TB. While a number of studies interpreted the association with multivariate analysis, other confounders are often not accounted for in these analyses. It is also important to emphasize that these retrospective studies can only show an association and not any causal link. We further explored the possibility that even if CS exposure is a risk factor for TB, several mechanisms may be responsible. Numerous studies associate cigarette and biomass smoke exposure with TB but the mechanism(s) remains largely unknown. While the associative link of these two health maladies is well established, more definitive, mechanistic studies are needed to cement the effect of smoke exposure on TB pathogenesis and to utilize this knowledge in empowering public health policies.

Patients with nontuberculous mycobacterial lung disease exhibit unique body and immune phenotypes.

RATIONALE: Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease. OBJECTIVES: To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically. METHODS: We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation. MEASUREMENTS AND MAIN RESULTS: Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-γ and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM. CONCLUSIONS: This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined.

Cooccurrence of free-living amoebae and nontuberculous Mycobacteria in hospital water networks, and preferential growth of Mycobacterium avium in Acanthamoeba lenticulata.

The incidence of lung and other diseases due to nontuberculous mycobacteria (NTM) is increasing. NTM sources include potable water, especially in households where NTM populate pipes, taps, and showerheads. NTM share habitats with free-living amoebae (FLA) and can grow in FLA as parasites or as endosymbionts. FLA containing NTM may form cysts that protect mycobacteria from disinfectants and antibiotics. We first assessed the presence of FLA and NTM in water and biofilm samples collected from a hospital, confirming the high prevalence of NTM and FLA in potable water systems, particularly in biofilms. Acanthamoeba spp. (genotype T4) were mainly recovered (8/17), followed by Hartmannella vermiformis (7/17) as well as one isolate closely related to the genus Flamella and one isolate only distantly related to previously described species. Concerning mycobacteria, Mycobacterium gordonae was the most frequently found isolate (9/17), followed by Mycobacterium peregrinum (4/17), Mycobacterium chelonae (2/17), Mycobacterium mucogenicum (1/17), and Mycobacterium avium (1/17). The propensity of Mycobacterium avium hospital isolate H87 and M. avium collection strain 104 to survive and replicate within various FLA was also evaluated, demonstrating survival of both strains in all amoebal species tested but high replication rates only in Acanthamoeba lenticulata. As A. lenticulata was frequently recovered from environmental samples, including drinking water samples, these results could have important consequences for the ecology of M. avium in drinking water networks and the epidemiology of disease due to this species.

Patients with non-tuberculous mycobacterial lung disease have elevated transforming growth factor-beta following ex vivo stimulation of blood with live Mycobacterium intracellulare.

We previously found that a subset of patients with pulmonary non-tuberculous mycobacterial (pNTM) disease were taller, leaner, and had a higher prevalence of pectus excavatum and scoliosis than uninfected controls. Additionally, whole blood of pNTM patients stimulated ex vivo with live Mycobacterium intracellulare produced significantly less interferon-gamma (IFNγ) compared to that of uninfected controls. Since IFNγ production can be suppressed by transforming growth factor-beta (TGFß), an immunosuppressive cytokine, we measured basal and M. intracellulare-stimulated blood levels of TGFß in a group of 20 pNTM patients and 20 uninfected controls. In contrast to the IFNγ findings, we found that stimulated blood from pNTM patients produced significantly higher levels of TGFß compared to controls. Since pNTM patients frequently possess body features that overlap with Marfan syndrome (MFS), and increased TGFß expression is important in the pathogenesis of MFS, we posit that a yet-to-be-identified syndrome related to MFS predisposes certain individuals to develop pNTM disease.

Underlying host risk factors for nontuberculous mycobacterial lung disease.

Nontuberculous mycobacteria (NTM) are environmental microbes that cause a variety of human diseases, particularly chronic lung infections. Despite the fact that NTM are widespread in the environment, relatively few people develop NTM lung disease, suggesting intrinsic vulnerability in some individuals. This paper reviews the evidence that underlying disorders predispose to NTM lung disease, in particular primary conditions that result in bronchiectasis, chronic obstructive pulmonary disease, α-1-antitrypsin anomalies, pneumoconiosis, pulmonary alveolar proteinosis, and frank immunosuppressive states such as that associated with the use of anti-tumor necrosis factor-α biologics, posttransplantation immunosuppression, and HIV infection. Over the past several decades, NTM lung disease has been increasingly identified in postmenopausal women with slender body habitus. Thus we will also review the clinical and experimental evidence which supports the observation that such individuals are predisposed to NTM lung disease.

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

BACKGROUND: Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB. METHODS AND FINDINGS: Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1-6.0]), ofloxacin (aOR: 2.5 [1.6-3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3-2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7-4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7-4.3]), ofloxacin (aOR: 2.3 [1.3-3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4-2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9-3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4-6.0]). CONCLUSIONS: In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment. Please see later in the article for the Editors' Summary.

Cigarette smoke increases susceptibility to tuberculosis--evidence from in vivo and in vitro models.

BACKGROUND: Cigarette smoke (CS) exposure is an epidemiological risk factor for tuberculosis, although the biological basis has not been elucidated. METHODS: We exposed C57BL/6 mice to CS for 14 weeks and examined their ability to control an aerosol infection of Mycobacterium tuberculosis Erdman. RESULTS: CS-exposed mice had more M. tuberculosis isolated from the lungs and spleens after 14 and 30 d, compared with control mice. The CS-exposed mice had worse lung lesions and less lung and splenic macrophages and dendritic cells (DCs) producing interleukin12 and tumor necrosis factor α (TNF-α). There were significantly more interleukin 10-producing macrophages and DCs in the spleens of infected CS-exposed mice than in non-CS-exposed controls. CS-exposed mice also showed a diminished influx of interferon γ-producing and TNF-α-producing CD4(+) and CD8(+) effector and memory T cells into the lungs and spleens. There was a trend toward an increased number of viable intracellular M. tuberculosis in macrophages isolated from humans who smoke compared with nonsmokers. THP-1 human macrophages and primary human alveolar macrophages exposed to CS extract, nicotine, or acrolein showed an increased burden of intracellular M. tuberculosis. CONCLUSION: CS suppresses the protective immune response to M. tuberculosis in mice, human THP-1 cells, and primary human alveolar macrophages.

Effects of gender and age at diagnosis on disease progression in long-term survivors of cystic fibrosis.

RATIONALE: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. OBJECTIVES: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. METHODS: Retrospective analysis of the Colorado CF Database (1992-2008), CF Foundation Registry (1992-2007), and Multiple Cause of Death Index (1992-2005). MEASUREMENTS AND MAIN RESULTS: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV(1) decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV(1) declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV(1) decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV(1) improvement in response to CF center care. CONCLUSIONS: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

Multidrug-resistant tuberculosis (TB) resistant to fluoroquinolones and streptomycin but susceptible to second-line injection therapy has a better prognosis than extensively drug-resistant TB.

Multidrug-resistant tuberculosis (TB) strains resistant to the fluoroquinolones and streptomycin but susceptible to second-line injection treatment would not be defined as extensively drug-resistant TB. In a cohort of 174 patients with multidrug-resistant TB, we demonstrated that 12 patients with multidrug-resistant TB strains resistant to the fluoroquinolones and streptomycin had significantly better initial and long-term outcomes, compared with 10 patients with extensively drug-resistant TB.

Multidrug-resistant and extensively drug-resistant tuberculosis: a review.

PURPOSE OF REVIEW: The spread of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) is a major medical and public health concern for the world. These two forms of highly drug-resistant TB threaten to make TB into an untreatable and highly fatal disease, particularly in resource-poor countries with a high prevalence of AIDS. The focus of this review is to highlight the current extent of the problem. RECENT FINDINGS: There is a great variability in clinical outcomes for MDR-TB, in part due to differences in the definitions of outcome measures and retrospective nature of the studies. Outcomes for XDR-TB are uniformly worse than those for MDR-TB. SUMMARY: A multifaceted approach is needed to prevent a more widespread epidemic of MDR-TB and XDR-TB. Rapid diagnostic assays to detect highly drug-resistant TB are essential in preventing delays in treatment of MDR-TB and XDR-TB and curbing their spread. Development of new drugs to effectively treat all forms of TB in a shorter period of time is urgently needed.

Concomitant use of voriconazole and rifabutin in a patient with multiple infections.

Abstract Concomitant administration of azole antifungal agents and rifamycins is contraindicated because an interaction between these drugs results in subtherapeutic azole concentrations. We describe a 30-year-old woman with severe pulmonary disease associated with Mycobacterium xenopi and Aspergillus fumigatus, necessitating simultaneous antimycobacterial and antifungal therapy. She was treated with rifabutin-the rifamycin with the least cytochrome P450 (CYP) enzyme induction-and therapeutic drug monitoring was performed so that target serum concentrations of all antimicrobial agents could be achieved. As a result of this monitoring, the frequency of voriconazole 300 mg needed to be increased from twice/day to 3 times/day. The patient's clinical outcome improved dramatically. She was discharged from the hospital and continued treatment for her mycobacterial infection while remaining free of the Aspergillus infection. We believe that careful drug selection combined with therapeutic monitoring of antimicrobial drug serum concentrations is a practical model that clinicians can use to manage coexisting mycobacterial and fungal infections.

Mycobacterium avium in a shower linked to pulmonary disease.

Mycobacterium avium was isolated from hot and cold water samples and from sediment (biofilm) collected from the showerhead in the home of a woman with M. avium pulmonary disease lacking known M. avium risk factors. IS1245/IS1311 DNA fingerprinting demonstrated that M. avium isolates from the hot and cold water and showerhead sediment demonstrated a clonal relationship with the patient's M. avium isolate. The data provide evidence that showers may serve as sources of infection by waterborne M. avium.

Comparing the temporal colonization and microbial diversity of showerhead biofilms in Hawai'i and Colorado.

The household is a potential source of opportunistic pathogens to humans, a particularly critical issue for immunodeficient individuals. An important human-microbe interface is the biofilm that develops on showerhead surfaces. Once microbe-laden biofilms become aerosolized, they can potentially be inhaled into the lungs. Understanding how quickly a new showerhead becomes colonized would provide useful information to minimize exposure to potentially pathogenic environmental microbes. High school scientists sampled the inner surfaces of pre-existing and newly fitted showerheads monthly over a nine-month period and applied standard microbiologic culture techniques to qualitatively assess microbial growth. Water chemistry was also monitored using commercial test strips. Sampling was performed in households on Oahu, Hawai'i and Denver, Colorado, representing warm/humid and cold/arid environments, respectively. Pre-existing showerheads in Hawai'i showed more diverse microbial growth and significantly greater microbial numbers than a comparable showerhead from Colorado. New, chrome-plated or plastic showerheads in Hawai'i showed diverse and abundant growth one month after installment compared to new showerheads from Colorado. The pH, total chlorine and water hardness levels varied significantly between the Hawai'i and Colorado samples. Enthusiastic student and teacher participation allowed us to answer long-standing questions regarding the temporal colonization of microbial biofilms on pre-existing and new showerhead surfaces.

Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases.

Aminoglycoside use is limited by ototoxicity and nephrotoxicity. This study compared the incidences of toxicities associated with 2 recommended dosing regimens. Eighty-seven patients with tuberculosis or nontuberculous mycobacterial infections were prospectively randomized by drug to receive 15 mg/kg per day or 25 mg/kg 3 times per week of intravenous streptomycin, kanamycin, or amikacin. Doses were adjusted to achieve target serum concentrations. The size of the dosage and the frequency of administration were not associated with the incidences of ototoxicity (hearing loss determined by audiogram), vestibular toxicity (determined by the findings of a physical examination), or nephrotoxicity (determined by elevated serum creatinine levels). Risk of ototoxicity (found in 32 [37%] of the patients) was associated with older age and with a larger cumulative dose received. Vestibular toxicity (found in 8 [9%] of the patients) usually resolved, and nephrotoxicity (found in 13 [15%] of the patients) was mild and reversible in all cases. Subjective changes in hearing or balance did not correlate with objective findings. Streptomycin, kanamycin, and amikacin can be administered either daily or 3 times weekly without affecting the likelihood of toxicity.

Medical management of pulmonary disease caused by Mycobacterium avium complex.

The current medical therapy for Mycobacterium avium complex is controversial. American Thoracic Society recommendations advocate empiric therapy with drug susceptibility testing only for clarithromycin. At National Jewish, where we mainly see cases complicated by treatment failure and drug intolerance, we use in vitro susceptibility testing and therapeutic drug monitoring to optimize efficacy and reduce toxicity.