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12/2012: pages 25-37; , ISBN: 978-1-84984-027-9
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ABSTRACT: Over the last 30 years it has become increasingly clear that nontuberculous mycobacterial (NTM) lung infections and bronchiectasis are closely related disorders. Although incontrovertible proof is lacking, there is a growing consensus of opinion that NTM lung disease characterized by nodules and bronchiectasis (nodular/bronchiectatic NTM lung disease) may be a consequence of preexisting bronchiectasis that predisposes to NTM infection and disease. To use published diagnostic guidelines effectively, physicians must become familiar with the disease-causing potential of individual NTM species. Essentially all NTM patients have bronchiectasis, so optimal overall patient management requires successful therapeutic strategies for both NTM infection and bronchiectasis.
Clinics in chest medicine 06/2012; 33(2):283-95. · 2.51 Impact Factor
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ABSTRACT: The prevalence of nontuberculous mycobacterial (NTM) lung disease is increasing in the USA. Clinicians are therefore encountering these patients with increasing frequency, with the attendant multiple therapeutic challenges presented by NTM lung disease including relatively frequent (compared with tuberculosis) treatment failure.
Critical elements for the successful treatment of Mycobacterium avium complex (MAC) lung disease include aggressive first therapeutic attempts and avoidance of the emergence of macrolide-resistant MAC strains, which are associated with worse treatment response and increased mortality. Reliably effective therapy for M. abscessus lung disease remains elusive but still usually requires parenteral agents. Lung resection surgery for selected patients is an important adjunct for both MAC and M. abscessus lung disease. Aside from surgery and parenteral antibiotics, there are very few data to support the efficacy of other drugs or interventions for patients who have failed the first-line therapy.
Clinicians who manage NTM lung disease will inevitably encounter patients who fail the first-line therapy. The choices for effective treatment of these patients are depressingly sparse. It is critically important to avoid creation of macrolide-resistant MAC strains and to carefully choose those NTM lung disease patients who will benefit from surgery.
Current Opinion in Infectious Diseases 04/2012; 25(2):218-27. · 4.93 Impact Factor
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David E Griffith
Clinical Infectious Diseases 03/2011; 52(5):572-4. · 9.15 Impact Factor
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David E Griffith
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ABSTRACT: There is increasing awareness that nontuberculous mycobacteria (NTM) lung diseases are becoming more prevalent. Nontuberculous mycobacterial diseases could legitimately be seen as an emerging public-health threat.
Nontuberculous mycobacterial lung disease associated radiographically with nodules and bronchiectasis occurs primarily in women. These patients are associated with a specific morphotype, including low BMI, tall stature, scoliosis, pectus excavatum and mitral valve prolapse. The pathophysiologic link between these findings and the development of bronchiectasis and NTM disease remains unclear. As with tuberculosis, the tumor-necrosis factor alpha (TNF-alpha) blockers also predispose to NTM infection that can be severe. The most frustrating aspect of NTM therapy remains the generally poor correlation between in-vitro antibiotic susceptibility and in-vivo response to antimicrobials. A possible insight into this phenomenon is the recent discovery of an inducible macrolide resistance (erm) gene in Mycobacterium fortuitum and Mycobacterium abscessus. This gene can produce in-vivo resistance without resulting in a 'resistant' MIC for macrolides.
The NTM pose an increasing problem for clinicians and are associated with significant obstacles that thwart successful treatment of NTM disease. Continued progress in the areas of disease pathogenesis and therapy will improve the outlook for these patients.
Current Opinion in Infectious Diseases 04/2010; 23(2):185-90. · 4.93 Impact Factor
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ABSTRACT: We studied the factors that control IL-17 production in human Mycobacterium tuberculosis infection. CD4(+) cells from healthy tuberculin reactors produced IL-17 in response to autologous M. tuberculosis-stimulated monocytes, and most IL-17(+) cells were Ag experienced, CD4(+)CD62L(-). IL-17 production by CD4(+) cells was inhibited by anti-IL-23, but not by Abs to IL-1, IL-6, or TGF-beta. Anti-NKG2D reduced IL-17 production and the frequency of CD4(+)CD62(-) IL-17(+) cells, suggesting that NKG2D stimulates IL-17 production. CD4(+)NKG2D(+) cells did not produce IL-17. Monocytes and alveolar macrophages from healthy donors produced IL-23 in response to M. tuberculosis. Addition of CD4(+) cells markedly enhanced IL-23 production by M. tuberculosis-stimulated monocytes, and this was inhibited by anti-NKG2D and by Abs to UL-16 binding protein (ULB)1, a ligand for NKG2D on APCs. We conclude that binding of NKG2D to UL-16 binding protein (ULB)1 contributes to IL-23-dependent IL-17 production by CD4(+) cells in human M. tuberculosis infection.
The Journal of Immunology 09/2009; 183(3):1940-5. · 5.79 Impact Factor
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David E Griffith
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ABSTRACT: Nontuberculous mycobacterial disease, especially pulmonary disease, is increasingly encountered by clinicians. Therapy of the most common nontuberculous mycobacterial pathogen, Mycobacterium avium complex, improved with the introduction of macrolide-containing regimens, but treatment for this and most other nontuberculous mycobacterial pathogens remains difficult.
Treatment trials with macrolide-containing regimens for Mycobacterium avium complex lung disease have yielded generally favorable outcomes. Studies consistently show that in-vitro susceptibility to macrolides remains the only in-vitro susceptibility for Mycobacterium avium complex that correlates with in-vivo response. Patients who have macrolide-resistant Mycobacterium avium complex isolates are much harder to treat and have higher mortality than patients with macrolide-susceptible isolates. Studies also consistently show that patients who fail therapy, even those who remain macrolide susceptible in vitro, are more difficult to treat than patients without previous therapy.
There have been no significant treatment advances for Mycobacterium avium complex lung disease, and nontuberculous mycobacterial disease in general, since the advent of the newer macrolides. It has become clear that the best opportunity for treatment success is the first treatment effort. It is also clear that protection against the emergence of macrolide-resistant Mycobacterium avium complex isolates is critically important. For further progress in the treatment of these pathogens, new and more active drugs must be developed.
Current Opinion in Infectious Diseases 05/2007; 20(2):198-203. · 4.93 Impact Factor
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David E Griffith,
Timothy Aksamit,
Barbara A Brown-Elliott,
Antonino Catanzaro,
Charles Daley,
Fred Gordin,
Steven M Holland,
Robert Horsburgh,
Gwen Huitt,
Michael F Iademarco,
Michael Iseman,
Kenneth Olivier,
Stephen Ruoss,
C Fordham von Reyn,
Richard J Wallace,
Kevin Winthrop
American Journal of Respiratory and Critical Care Medicine 03/2007; 175(4):367-416. · 11.08 Impact Factor
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Ankita Garg,
Peter F Barnes,
Angel Porgador,
Sugata Roy,
Shiping Wu,
Jagpreet S Nanda, David E Griffith,
William M Girard,
Nenoo Rawal,
Sreerama Shetty,
Ramakrishna Vankayalapati
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ABSTRACT: We previously showed that human NK cells used the NKp46 receptor to lyse Mycobacterium tuberculosis H37Ra-infected monocytes. To identify ligands on H37Ra-infected human mononuclear phagocytes, we used anti-NKp46 to immunoprecipitate NKp46 from NK cells bound to its ligand(s) on H37Ra-infected monocytes. Mass spectrometry analysis identified a 57-kDa molecule, vimentin, as a putative ligand for NKp46. Vimentin expression was significantly up-regulated on the surface of infected monocytes, compared with uninfected cells, and this was confirmed by fluorescence microscopy. Anti-vimentin antiserum inhibited NK cell lysis of infected monocytes, whereas antiserum to actin, another filamentous protein, did not. CHO-K1 cells transfected with a vimentin construct were lysed much more efficiently by NK cells than cells transfected with a control plasmid. This lysis was inhibited by mAb-mediated masking of NKp46 (on NK cells) or vimentin (on infected monocytes). ELISA and Far Western blotting showed that recombinant vimentin bound to a NKp46 fusion protein. These results indicate that vimentin is involved in binding of NKp46 to M. tuberculosis H37Ra-infected mononuclear phagocytes.
The Journal of Immunology 12/2006; 177(9):6192-8. · 5.79 Impact Factor
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David E Griffith,
Barbara A Brown-Elliott,
Brett Langsjoen,
Yansheng Zhang,
Xi Pan,
William Girard,
Kenwyn Nelson,
James Caccitolo,
Julio Alvarez,
Sara Shepherd,
Rebecca Wilson,
Edward A Graviss,
Richard J Wallace
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ABSTRACT: The clinical features and outcome of macrolide-resistant Mycobacterium avium complex (MAC) lung disease are not known.
Characterize patients, treatment, and isolates in macrolide-resistant MAC lung disease.
Retrospective chart review, susceptibility testing, molecular fingerprinting, and DNA sequence analyses of resistant MAC isolates.
We identified 51 patients over a 15-yr period with clarithromycin-resistant MAC (minimum inhibitory concentration (MIC)>or=32 microg/ml) lung disease at a single referral center. Twenty-four (47%) patients had nodular disease with bronchiectasis and 27 (53%) had upper lobe cavitary disease. Most patients (77%) had M. intracellulare. Sequencing of the 23S r-RNA gene showed 49 of 51 isolates (96%) with the expected mutation in adenine 2058 or 2059. Risk factors for resistance included macrolide monotherapy or combination with a quinolone only (39/51 or 76%). Macrolide resistance developed in 12 of 303 (4.0%) patients started on the American Thoracic Society-recommended two companion drugs, with no risk difference in clarithromycin versus azithromycin and daily versus intermittent therapy. Sputum conversion with macrolide-resistant MAC occurred in 11 of 14 (79%) patients who received more than 6 mo of injectable aminoglycoside therapy and lung resection, compared with 2 of 37 (5%) who did not. The 1-yr mortality in patients who remained culture positive was 34% (13/38) compared with 0% (0/13) of patients who became culture negative (converted).
Macrolide resistance rarely occurs in patients also receiving ethambutol and a rifamycin. Macrolide-resistant MAC lung disease requires aggressive drug and surgical therapy for cure.
American Journal of Respiratory and Critical Care Medicine 10/2006; 174(8):928-34. · 11.08 Impact Factor
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ABSTRACT: Mycobacterium avium complex pulmonary disease (MAC-PD) is associated with substantial morbidity, and standard daily multidrug therapy is difficult to tolerate. Objectives: To characterize response to a three-times-weekly (TIW) regimen of clarithromycin, ethambutol, and rifampin.
A 1-yr prospective noncomparative trial of TIW treatment was conducted during 2000-2003 in 17 U.S. cities. Participants were 91 HIV-negative adults, diagnosed with moderate to severe MAC-PD, who originally participated in a trial of an inhaled IFN-gamma treatment. Improvement in sputum culture, high-resolution computed tomography (HRCT), and symptoms were assessed.
Treatment response rates (and median response times) were 44% (2 mo or longer) for culture, 60% (5.5-11.5 mo) for HRCT, and 53% (8.5 mo) for symptoms. Having noncavitary, compared with cavitary, disease increased culture response by 4.0 times (95% confidence interval [CI], 1.7-9.2) and HRCT response by 4.9 times (95% CI, 1.9-13.0). Culture response was 1.5 times (95% CI, 1.1-2.2) higher for older subjects and 2.2 times (95% CI, 1.0-4.7) higher for previously untreated subjects. Being smear-negative increased culture response by 2.3 times (95% CI, 1.1-5.2) but decreased HRCT response by 4.4 times (95% CI, 1.7-11.5). Increasing ethambutol use by 5 mo increased culture response by 1.5 times (95% CI, 1.0-2.1) but decreased symptom response. Not having chronic obstructive pulmonary disease, bronchiectasis, or poor lung function increased symptom response by 1.9 to 3.9 times.
TIW therapy was less effective for MAC-PD patients with cavitary disease and a history of chronic obstructive pulmonary disease, bronchiectasis, or previous treatment for MAC-PD. Further research is needed to study the long-term outcomes of TIW treatment.
American Journal of Respiratory and Critical Care Medicine 07/2006; 173(11):1283-9. · 11.08 Impact Factor
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ABSTRACT: We studied the role of NK cell-activating receptors and their ligands in the lysis of mononuclear phagocytes infected with the intracellular pathogen Mycobacterium tuberculosis. Expression of the activating receptors NKp30, NKp46, and NKG2D were enhanced on NK cells by exposure to M. tuberculosis-infected monocytes, whereas expression of DNAX accessory molecule-1 and 2B4 was not. Anti-NKG2D and anti-NKp46 inhibited NK cell lysis of M. tuberculosis-infected monocytes, but Abs to NKp30, DNAX accessory molecule-1, and 2B4 had no effect. Infection of monocytes up-regulated expression of the NKG2D ligand, UL-16 binding protein (ULBP)1, but not expression of ULBP2, ULBP3, or MHC class I-related chain A or chain B. Up-regulation of ULBP1 on infected monocytes was dependent on TLR2, and anti-ULBP1 abrogated NK cell lysis of infected monocytes. The dominant roles of NKp46, NKG2D, and ULBP1 were confirmed for NK cell lysis of M. tuberculosis-infected alveolar macrophages. We conclude that NKp46 and NKG2D are the principal receptors involved in lysis of M. tuberculosis-infected mononuclear phagocytes, and that ULBP1 on infected cells is the major ligand for NKG2D. Furthermore, TLR2 contributes to up-regulation of ULBP1 expression.
The Journal of Immunology 11/2005; 175(7):4611-7. · 5.79 Impact Factor
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ABSTRACT: Ethambutol (EMB) is an important component of multidrug treatment regimens for Mycobacterium avium complex lung disease. Ocular toxicity is the most important potential EMB toxicity, especially in the elderly population with M. avium complex lung disease. Two hundred twenty-nine patients with M. avium complex lung disease, 55% women and 53% with nodular/bronchiectatic disease, received a mean of 16.1 +/- 10.8 months of multidrug therapy that included EMB. Fifty patients (22%) were known to have preexisting ocular disease. While on EMB, 97 (42%) patients consulted an opthalmologist and 24 (10%) stopped EMB at least temporarily. Eight of 139 patients (6%) on daily therapy were diagnosed with EMB ocular toxicity, whereas 0 of 90 patients on intermittent therapy had EMB ocular toxicity (p = 0.05). All patients with EMB ocular toxicity developed symptoms between outpatient clinic appointments; none were diagnosed with routine visual acuity and color vision testing. All patients with EMB ocular disease returned to baseline ocular status after discontinuation of EMB. Intermittent EBM administration was associated with less ocular toxicity than daily EMB administration in this patient population.
American Journal of Respiratory and Critical Care Medicine 08/2005; 172(2):250-3. · 11.08 Impact Factor
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ABSTRACT: We initiated a prospective trial of an intermittent clarithromycin-containing regimen for the treatment of patients with Mycobacterium kansasii lung disease. Eighteen patients (10 men and 8 women) with M. kansasii lung disease received a regimen consisting of 500-1000 mg of clarithromycin, 25 mg/kg ethambutol, and 600 mg of rifampin 3 times per week. The primary treatment end point was a 12-month period during which sputum cultures were sterile while the patient was receiving therapy. Four male patients were lost to follow-up, but all of the remaining patients successfully completed therapy without significant drug-related adverse events. The mean time (+/- standard deviation [SD]) to sputum conversion was 1.0+/-0.9 months, and the mean duration (+/-SD) of therapy was 13.4+/-0.9 months. No patient who successfully completed therapy had relapsed after a mean (+/-SD) of 46+/-8.0 months. Clarithromycin- and rifampin-containing regimens offer the possibility of effective short-course and intermittent treatment of M. kansasii lung disease.
Clinical Infectious Diseases 12/2003; 37(9):1178-82. · 9.15 Impact Factor
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ABSTRACT: Prior reports have suggested that CD14 mediates uptake of Mycobacterium tuberculosis into porcine alveolar macrophages and human fetal microglia, but the contribution of CD14 to cell entry in human macrophages has not been studied. To address this question, we used flow cytometry to quantify uptake by human monocytes and alveolar macrophages of M. tuberculosis expressing green fluorescent protein. Neutralizing anti-CD14 antibodies did not affect bacillary uptake and the efficiency of bacillary entry was similar in THP-1 cells expressing low and high levels of CD14. However, most internalized bacteria were found in CD14+ but not in CD14- monocytes because M. tuberculosis infection upregulated CD14 expression. We conclude that: (1) CD14 does not mediate cellular entry by M. tuberculosis; (2) M. tuberculosis infection upregulates CD14 expression on mononuclear phagocytes, and this may facilitate the pathogen's capacity to modulate the immune response.
FEMS Immunology & Medical Microbiology 06/2003; 36(1-2):63-9. · 2.44 Impact Factor
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ABSTRACT: This section discusses the methods of laboratory diagnosis of nontuberculous mycobacteria (NTM) using conventional biochemical and nutritional requirements, acid-fast smear microscopy, high performance liquid chromatography (HPLC), antibiotic susceptibility testing, and newer genetic methods such as molecular probes, polymerase chain reaction restriction fragment length polymorphism analysis (PRA), and 16S rDNA sequence analysis. This article discusses how laboratory results are applied by clinicians, and some of the difficulties and controversies regarding the diagnosis of NTM disease after the laboratory work is complete.
Clinics in Laboratory Medicine 01/2003; 22(4):911-25, vi. · 1.97 Impact Factor
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ABSTRACT: The rapidly growing mycobacteria (RGM) differ from slow-growing mycobacteria such as Mycobacterium tuberculosis by virtue of their more rapid growth in culture media and their in vitro resistance to standard antituberculosis drugs. The RGM can produce numerous infections including chronic lung disease. The most common causes of pulmonary disease are Mycobacterium abscessus and Mycobacterium fortuitum. This article reviews the management of patients with lung disease caused by RGM.
Clinics in Chest Medicine 10/2002; 23(3):623-32, vii. · 3.28 Impact Factor
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David E Griffith
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ABSTRACT: Mycobacterium kansasii presents clinically in a manner most resembling tuberculosis. Diagnosis is usually not difficult; however, the significance of M kansasii isolates from some patients may be hard to determine. Usually, the presence of even one respiratory culture positive for M kansasii is sufficient to make a diagnosis, though few patients can have single respiratory culture positive for M kansasii without evidence of active disease. If not started on medication, these patients must be followed closely. Effective treatment can usually be accomplished with a rifampin-based regimen, or a rifabutin-based regimen for HIV-seropositive patients receiving antiretroviral therapy. Short course and intermittent regimens for treating M kansaii disease show promise but are not yet recommended for routine use.
Clinics in Chest Medicine 10/2002; 23(3):613-21, vi. · 3.28 Impact Factor
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ABSTRACT: The genomic DNA patterns (genotypes) of 55 episodes of late positive sputum isolates, collected after >or=4 consecutive months of negative sputum cultures, in prospective macrolide treatment trials of Mycobacterium avium complex (MAC) lung disease were assessed by pulsed-field gel electrophoresis (PFGE). Having >or=2 cultures positive for MAC after completion of therapy was documented 23 times; of 20 episodes studied by PFGE, 17 (85%) represented new genotypes (i.e., new infections), and 87% occurred in patients with nodular bronchiectasis. With >or=2 positive cultures after therapy was stopped prematurely, 6 (86%) of 7 episodes were relapses. Single positive cultures after completion of therapy occurred 16 times; only 1 (6%) was predictive of a subsequent relapse. No late isolates were macrolide resistant. Thus, relapses of MAC lung disease with these macrolide regimens are unusual, and most infections after completing therapy resulted from new strains in patients with nodular bronchiectasis.
The Journal of Infectious Diseases 07/2002; 186(2):266-73. · 6.41 Impact Factor
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ABSTRACT: Assessing the impact of the diagnosis if NTM lung disease on the patient and choosing appropriate therapy are separate considerations. Health care professionals have progressed from an era when patients had unrecognized, progressive, and untreated NTM disease to an era when NTM disease is diagnosed frequently but therapy is either unnecessary or possibly worse than the disease. Perhaps the 1990 ATS statement was correct. The problem is not diagnosing patients with NTM lung disease, the problem is deciding what to do with them after they are diagnosed.
Infectious Disease Clinics of North America 04/2002; 16(1):235-49. · 3.03 Impact Factor
