Faculty Bibliography

INTRODUCTION: Extensively Drug Resistant Tuberculosis (XDR-TB), is uncommon in developed countries with only 63 cases reported in the US between 1993-2011. Treatment is tailored to culture sensitivities with second line anti-tuberculosis (anti-TB) drugs. We report the first case in United States of compassionate use of bedaquiline for the treatment of pulmonary XDR-TB. CASE PRESENTATION: A 30 year-old man, former smoker, with diabetes, presented with fevers and hemoptysis one month after immigrating to New York from a high incidence country. His chest x-ray revealed bilateral cavitary upper lobe infiltrates (Figure 1). Sputum smears for acid-fast bacilli were positive as were cultures for Mycobacterium Tuberculosis. He was empirically started on first-line anti-TB drugs, and his regimen was modified as results from susceptibility testing became available eventually revealing XDR-TB. He was ultimately treated with pyrazinamide, ethionamide, paraminosalycilic acid, cycloserine, capreomycin, amoxicillin/clavulanic, meropenem and linezolid. As a result of multiple adverse effects from his XDR-TB treatment, especially linezolid induced demyelinating peripheral neuropathy, bedaquiline was obtained through a compassionate use program in order to maintain an effective treatment regimen for XDR-TB after the discontinuation of linezolid. He tolerated bedaquiline well experiencing only mild transaminitis and successfully completed his XDR-TB treatment. DISCUSSION: Three cases in the literature pertain to the compassionate use of bedaquiline. In each of these cases, bedaquiline was added in place of a fourth agent in a treatment regimen when there were no additional options remaining. QTC prolongation and increased risk of death have been noted in patients receiving bedaquiline. High incidences of nausea (35.3% vs. 25.7%) and hepatotoxicity (8.8% vs. 1.9%) have also been reported with bedaquiline when compared to placebo. CONCLUSIONS: Bedaquiline is a novel agent for the treatment of Pre-XDR or XDR Tuberculosis. In our patient bedaquiline was added to an effective XDR regimen to ameliorate the side effect profile in order to allow for the successful completion of therapy

BACKGROUND: One of the most controversial aspects of New York City's highly effective TB control program is the use of public health law and court-ordered detention to treat persistently recalcitrant patients with active TB. We now report on characteristics and outcomes of patients undergoing detention for completion of TB treatment due to nonadherence in New York City from 2002 through 2009. METHODS: A retrospective cohort study was designed to compare patients undergoing court-ordered detention (n = 79) and time-matched control subjects undergoing TB treatment in outpatient directly observed therapy (DOT) at Bellevue Hospital in New York City. RESULTS: From January 1, 2002, through December 31, 2009, 79 patients underwent court-ordered detention for TB treatment. Compared with patients completing treatment in DOT, univariate analysis found that detainees were younger; more likely to be of minority race/ethnicity; to have a history of substance abuse, tobacco use, homelessness, incarceration, HIV infection; and to be born in the United States. Multivariate analysis adjusting for other variables found smear positivity (OR = 3.93; 95% CI, 1.05-14.75; P = .04), mental illness (OR = 5.80; 95% CI, 1.18-28.51; P = .03), and substance abuse (OR = 9.25; 95% CI, 2.81-30.39; P < .01) to be the strongest independent predictors of likelihood of detention. Of those initially detained, 46 (58%) completed treatment during inpatient detention, 29(37%) completed treatment under outpatient court-ordered DOT, and four died during their hospitalization. CONCLUSIONS: The majority of patients undergoing court-ordered detention for TB treatment (95%) successfully completed therapy. Likelihood of detention was most strongly associated with factors expected to be associated with poor adherence, including mental illness and substance abuse.

Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug-drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline's utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and the development of other new drugs that are in the pipeline.

Rationale: Cigarette smoke causes a field of injury and molecular changes in the airways even in histologically normal areas termed "field cancerization" which describes the site(s) of neoplasia and adjacent normal tissue with molecular abnormalities in common. MicroRNAs ( miRNAs) are small, non-coding RNAs that act as post-transcriptional regulators of gene expression by recognizing target sites in the 3' untranslated regions (3'UTRs) via incomplete base-pairing and induce mRNA degradation or translational repression. Deregulation of miRNAs has been linked to cancer initiation and progression, and miRNAs may act as tumor suppressor genes or oncogenes. We hypothesized that miRNA expression in the peripheral airways of smokers with lung cancer is distinct from that of smokers without lung cancer and therefore, miRNAs can be used as biomarkers for the early detection of lung cancer. Methods: We collected human peripheral airway epithelial cells by bronchoscopic brushing from the unaffected lung of thirteen smokers with lung adenocarcinoma and twelve control smokers. Total RNA was extracted from the peripheral airway epithelial cells by miRNAeasy and miRNA profiling was performed using the TaqMan Quantitative qRT-PCR miRNA Assay. Results: Comparison of miRNA levels in peripheral airway epithelial cells from smokers with or without lung cancer demonstrated 53 miRNAs that were significantly different (p<0.05) between the two groups. The majority of miRNAs were up-regulated (41 miRNAs) in lung cancer patients, including miR-21, miR-26a, miR-31, miR-34c, and miR-205. Down-regulated miRNAs included let-7b, let-7e, and miR-126. Several of the miRNAs with increased expression are of interest: miR-21 inhibits tumor suppressor protein PTEN, miR-26a suppresses PTEN and increases AKT phosphorylation and nuclear factor kappaB (NFkappaB) activation, miR-31 represses tumor suppressor genes LATS2 and PPP2R2A, miR-205 is associated with cancer relapses, and miR-34c, a p53 target induced by DNA damage, suggests the involvement of p53 pathway in field carcinogenesis. Down-regulated let-7b leads to higher expression of CYP2J2 and decreased miR-126 enhances adhesion, migration and invasion through increased Crk protein. Further gene expression and pathway analyses will corroborate the relationship between miRNAs and predicted pathways in real time. Conclusion: We discovered a profile of miRNAs in the contralateral lung of patients with lung cancer as biomarkers of field cancerization in smokers with lung adenocarcinoma. Further knowledge of field cancerization may lead to better understanding of tumorigenesis and development of biomarkers for early lung cancer detection

Rationale Cases of granulomatous reaction to pneumocystis have been reported in immuno-compromised patients, most commonly in HIV infected patients but also rarely in patients with hematologic disease. Because of the low incidence of G-PCP, there are only case reports and case series describing different presentations. It has been suggested that because of low organism burden and distribution of disease, bronchoscopy with lavage and biopsy has a low yield in non-HIV patients in diagnosing granulomatous pneumocystis pneumonia (G-PCP). We reviewed our cumulative experience in G-PCP, to characterize the disease and diagnostic approach among patients with different underlying diseases. Method We reviewed the medical records of patients whose pathology results were G-PCP in our tertiary urban hospitals between 1993 and 2012 including demographics, underlying disease, radiographic findings and diagnostic approach. Result We identified 38 G-PCP patients; 27 medical records were available for review. Sixteen patients were HIV-infected. The 11 non-HIV patients had lymphoma or rheumatoid arthritis. Nine of the 11 non-HIV patients had non-diagnostic bronchoscopies and required either CT guided core or open lung biopsy. By contrast, 13 of the 16 HIV patients had diagnostic bronchoscopies(p value=0.002). Among the 11 non-HIV patients, 4 had diffuse large B cell lymphoma that had been treated with multiple cycles of chemotherapy and were subsequently found to have solitary or multiple lung masses. Disease recurrence was suspected based on CT-PET scan findings. However, all pathology specimens showed non-necrotizing granulomatous inflammation with pneumocystis. None showed malignancy or acid fast bacilli. Of note, none of these patients had respiratory symptoms and pneumocystis pneumonia was not considered in the differential diagnosis prior to biopsy. All responded well to anti-pneumocystis therapy. Conclusion The presentation of granulomatous pneumocystis pneumonia in patients without HIV is often atypical. Specifically, the diagnosis should be considered in patients with treated large B cell lymphoma who present with a lung mass on chest imaging. Non-bronchoscopic biopsy is usually required for diagnosis

RATIONALE: The diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been previously described. However, there is a lack of evidence comparing types of sedation used during this procedure. Many publications suggest use of general anesthesia during the procedure. We make two comparisons to describe the effect of choosing general anesthesia versus conscious sedation. First, we compared EBUS-TBNA while using general anesthesia versus conscious sedation to evaluate if the choice of sedation affects the diagnostic sensitivity and specificity. Next, we compared the amount of medication used for conscious sedation during EBUS-TBNA versus Wang transbronchial needle aspiration (TBNA). METHODS: A retrospective review was done of patients undergoing EBUS-TBNA and Wang TBNA at our institution over a 22-month period from January 2009 to October 2010. The pathologic tissue diagnosis and a reference standard for all sampled lymph nodes were recorded. The reference standard included mediastinoscopy, thoracic surgery, or a complete clinical follow-up pertaining to the diagnosis of the sampled lymph nodes. The choice of general anesthesia versus conscious sedation and the amount given under conscious sedation was recorded. RESULTS: A total of 116 bronchoscopies were performed. Documentation of data, follow-up, and reference standard was available for 37 patients that underwent EBUS-TBNA with general anesthesia and 22 patients that underwent EBUS-TBNA with conscious sedation. The diagnostic sensitivity and specificity of EBUS-TBNA under general anesthesia was 76.2% and 100% respectively. The diagnostic sensitivity and specificity of EBUS-TBNA under conscious sedation was 71% and 100% respectively. Next, the amount of conscious sedation given for EBUS-TBNA and Wang TBNA were compared for each procedure. The average amount of midazolam given was 12.1mg in EBUS-TBNA versus 7.4mg in Wang TBNA (P<0.001), fentanyl was 252.1mcg in EBUS-TBNA versus 178.9mcg in Wang TBNA (P=0.002), and lidocaine 1% was 29.6ml in EBUS-TBNA versus 25.5ml in Wang TBNA (P=0.09). No major adverse events were recorded during conscious sedation for EBUS-TBNA and Wang TBNA groups. CONCLUSION: First, the diagnostic performance of EBUS-TBNA is not affected by the choice of sedation at our institution. This is supported by the similar sensitivity and specificity observed with anesthesia and conscious sedation during EBUS-TBNA procedures. Second, when conscious sedation was used for the EBUS-TBNA, more midazolam and fentanyl were given compared to conventional TBNA. We conclude that the choice of sedation does not affect diagnostic performance of EBUS-TBNA. Conscious sedation can be used to obtain the same diagnostic result of EBUS-TBNA, though a significant increase in medication is required

Rationale: The use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become a common diagnostic procedure for the diagnosis of mediastinal and hilar lymphadenopathy. In recent years, we have implemented the use of EBUS-TBNA at our multi-centered university institution. The aim of the present study was to compare our initial sensitivity and specificity of EBUS-TBNA to Wang transbronchial needle aspiration (TBNA) in the diagnosis of malignancy and sarcoidosis. Methods: This retrospective study reviewed all patients who had undergone EBUS-TBNA and Wang TBNA in a heterogeneous population at our institution over a twenty-two month period from January 2009 to October 2010. A total of 116 consecutive patients with suspected malignancies or sarcoidosis were investigated with either EBUS-TBNA or Wang TBNA. This data includes patients from the beginning of a new EBUS-TBNA program. Excluded from this study were those without a final diagnosis, a diagnosis of infection, or a diagnosis of interstitial lung disease. The pathologic tissue diagnosis was defined by the cytologic evidence of tumor or non-necrotizing granulomatous inflammation without evidence of infection. All procedure samples were compared to a reference standard or a definitive diagnosis was obtained either by invasive testing such as mediastinoscopy, thoracic surgery, or a complete clinical follow-up pertaining to the sampled lymph nodes. Results: A total of 70 patients underwent EBUS-TBNA, 41 patients underwent TBNA, and 5 patients underwent both procedures. The sensitivity and specificity of EBUS-TBNA for malignancy was 75% (18/24) and 100% (3/3) respectively. The sensitivity of conventional TBNA for malignancy was 66.6% (18/27) and the specificity could not be calculated due to the lack of true negatives identified in this group. The sensitivity and specificity of EBUS-TBNA for sarcoidosis was 65.2% (15/23) and 100% (6/6) respectively. The sensitivity of conventional TBNA for sarcoidosis was 35.7% (5/14) and the specificity could not be calculated due to the lack of true negatives identified in this group. Conclusion: In our institution, real-time ultrasound imaging with EBUS-TBNA improved our sensitivity in both the diagnosis of malignancies and sarcoidosis when compared with Wang TBNA. These results are similar to previously published data