Gee Young Suh

Delamanid for Multidrug-Resistant Pulmonary Tuberculosis

BACKGROUND Delamanid (OPC-67683), a nitro-dihydro-imidazooxazole derivative, is a new antituberculosis medication that inhibits mycolic acid synthesis and has shown potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis. METHODS In this randomized, placebo-controlled, multinational clinical trial, we assigned 481 patients (nearly all of whom were negative for the human immunodeficiency virus) with pulmonary multidrug-resistant tuberculosis to receive delamanid, at a dose of 100 mg twice daily (161 patients) or 200 mg twice daily (160 patients), or placebo (160 patients) for 2 months in combination with a background drug regimen developed according to World Health Organization guidelines. Sputum cultures were assessed weekly with the use of both liquid broth and solid medium; sputum-culture conversion was defined as a series of five or more consecutive cultures that were negative for growth of M. tuberculosis. The primary efficacy end point was the proportion of patients with sputum-culture conversion in liquid broth medium at 2 months. RESULTS Among patients who received a background drug regimen plus 100 mg of delamanid twice daily, 45.4% had sputum-culture conversion in liquid broth at 2 months, as compared with 29.6% of patients who received a background drug regimen plus placebo (P=0.008). Likewise, as compared with the placebo group, the group that received the background drug regimen plus 200 mg of delamanid twice daily had a higher proportion of patients with sputum-culture conversion (41.9%, P=0.04). The findings were similar with assessment of sputum-culture conversion in solid medium. Most adverse events were mild to moderate in severity and were evenly distributed across groups. Although no clinical events due to QT prolongation on electrocardiography were observed, QT prolongation was reported significantly more frequently in the groups that received delamanid. CONCLUSIONS Delamanid was associated with an increase in sputum-culture conversion at 2 months among patients with multidrug-resistant tuberculosis. This finding suggests that delamanid could enhance treatment options for multidrug-resistant tuberculosis. (Funded by Otsuka Pharmaceutical Development and Commercialization; ClinicalTrials.gov number, NCT00685360.).

Treatment Outcomes for HIV-Uninfected Patients with Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis

BACKGROUND Multidrug-resistant (MDR) tuberculosis (TB) is more difficult to treat than is drug-susceptible TB. To elucidate the optimal therapy for MDR TB, we assessed the treatment outcomes and prognostic factors for patients with MDR TB. METHODS This study included patients who received an individualized treatment regimen for MDR TB at Samsung Medical Center, a tertiary referral hospital in Seoul, Korea, from January 1995 through December 2004. To identify the prognostic factors related to favorable treatment outcomes, univariate comparison and multiple logistic regression were performed. RESULTS Of 155 patients, 18 (12%) had newly diagnosed MDR TB, 81 (52%) had previously received treatment with first-line drugs, and 56 (36%) had received treatment with second-line drugs. The isolated strains were resistant to a median of 5 drugs. Twenty-seven patients (17%) had extensively drug-resistant (XDR) TB at the start of treatment. Outcome assessment revealed that 102 patients (66%) were cured or completed therapy. The treatment success rates did not differ significantly between patients with non-XDR MDR TB and those with XDR TB (66% vs. 67%). Surgical resection was performed more frequently for patients with XDR TB than for those with non-XDR MDR TB (48% vs. 17%). Combined surgical resection, body mass index >/=18.5 (calculated as the weight in kilograms divided by the square of the height in meters), use of >4 effective drugs, and a negative sputum smear result were independent predictors of a favorable outcome. CONCLUSIONS Early aggressive treatment comprising at least 4 effective drugs and surgical resection, when indicated, may improve the outcome for patients with MDR TB or XDR TB.

Clinical characteristics and treatment outcomes of chronic necrotizing pulmonary aspergillosis: a review of 43 cases

OBJECTIVES Chronic necrotizing pulmonary aspergillosis (CNPA) is uncommon, and the optimal therapeutic regimen has not been established. In a retrospective cohort study, we investigated the clinical characteristics and treatment outcomes of patients with CNPA. METHODS We reviewed the medical records of all patients who had been diagnosed with CNPA at our institution over the last 10 years. RESULTS Forty-three patients were identified. Their median age was 60 years (interquartile range (IQR) 45-65 years), and 34 (79%) of the patients were men. The most common underlying lung disease was pulmonary tuberculosis (n=40, 93%). After CNPA was diagnosed, all patients were treated with antifungal drugs, including oral itraconazole (n=39, 91%) or intravenous amphotericin B (n=4, 9%). Seventeen (40%) patients discontinued therapy early (<3 months), 14 patients due to death and three to loss of follow-up. Twenty-six (60%) patients received oral itraconazole at a daily dose of 200-400mg for more than 3 months. The median treatment duration was 6 months (IQR 6-12 months). In these 26 patients, clinical improvement was observed in 15 (58%) and radiological improvement was observed in 11 (42%). Ten (38%) patients showed no improvement. Twenty-two (51%) patients died, including 18 (42%) CNPA-related deaths, during a median follow-up of 15 months (IQR 2.5-32 months). The median survival time was 62 months. CONCLUSIONS CNPA is difficult to treat and often has a poor outcome. Further studies with more patients are needed to identify the optimal therapy for patients with CNPA.

Association of body temperature and antipyretic treatments with mortality of critically ill patients with and without sepsis: multi-centered prospective observational study

IntroductionFever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness.MethodsWe designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring > 48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality.ResultsWe recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P = 0.028, acetaminophen: 2.05, P = 0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P = 0.15, acetaminophen: 0.58, P = 0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU 36.5°C to 37.4°C), MAXICU ≥ 39.5°C increased risk of 28-day mortality in septic patients (adjusted odds ratio 8.14, P = 0.01), but not in non-septic patients (adjusted odds ratio 0.47, P = 0.11).ConclusionsIn non-septic patients, high fever (≥ 39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis.Trial registrationClinicalTrials.gov: NCT00940654

Repeated derecruitments accentuate lung injury during mechanical ventilation.

OBJECTIVES The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. DESIGN Prospective, randomized, experimental animal study. SETTING University laboratory. SUBJECTS Specific pathogen-free pigs (Choong-Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. INTERVENTIONS After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. MEASUREMENTS AND MAIN RESULTS After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. CONCLUSIONS Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.Objectives:The aim of our study was to assess whether repeated derecruitments induced by the repetitive withdrawal of high positive end-expiratory pressure could induce lung injury in a swine model. Design:Prospective, randomized, experimental animal study. Setting:University laboratory. Subjects:Specific pathogen-free pigs (Choong–Ang Laboratory Animals, Seoul, Korea) weighing around 30 kg. Interventions:After lung injury was induced by repeated saline lavage, pigs were ventilated in pressure-limited mode with the highest possible positive end-expiratory pressure with a tidal volume of 8 mL/kg and maximum inspiratory pressure of 30 cm H2O. With this initial ventilator setting, the control group (n = 5) received ventilation without derecruitments for 4 hours, and in the derecruitment group (n = 5), derecruitments were repeatedly induced by intentional disconnection of the ventilatory circuit for 30 seconds every 5 minutes for 4 hours. Measurements and Main Results:After the initial increase in positive end-expiratory pressure, the PaO2 increased to greater than 450 mm Hg in both groups. The PaO2 remained at greater than 450 mm Hg in the control group persistently, but in the derecruitment group, PaO2 significantly decreased to 427.7 mm Hg (adjusted p = 0.03) after 2 hours and remained significant for the rest of the study. PaCO2, oxygenation index, and alveolar-arterial oxygen gradient also significantly increased after 2 hours compared with the control group. However, the variables of respiratory mechanics except for minute volume at 2-hour point showed no difference between the two groups for the duration of the study. Histologically, significant bronchiolar injury was observed in the dependent portion of the derecruitment group compared with the controls (p = 0.03), but not in the nondependent area of the lung. Conclusions:Repeated derecruitments exacerbated lung injury, particularly at the bronchiolar level in the dependent portion. Strategies to minimize this type of injury should be incorporated when designing optimal ventilator strategies in acute respiratory distress syndrome patients.

Inactive Hepatitis B Surface Antigen Carrier State and Hepatotoxicity During Antituberculosis Chemotherapy

STUDY OBJECTIVES To determine whether inactive hepatitis B surface antigen (HBsAg) carriers are at a higher risk of drug-induced hepatotoxicity than control subjects during antituberculosis treatment with standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide. DESIGN Retrospective case-control study. SETTING Tertiary university medical center. PATIENTS One hundred ten inactive HBsAg carriers with newly diagnosed active tuberculosis who had been treated with isoniazid, rifampin, ethambutol, and/or pyrazinamide were included in the study population. Inactive HBsAg carriers were defined as follows: (1) positive for HbsAg; (2) negative for hepatitis B e antigen (HBeAg), positive for antibody to HBeAg; (3) < 10(5) copies per mL of serum hepatitis B virus DNA; and (4) normal pretreatment aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels. Ninety-seven HBsAg-negative patients who received standard antituberculosis medication were selected as control subjects. RESULTS The baseline characteristics of the 110 inactive HBsAg carriers were similar to those of the 97 noncarriers. A total of 85% of persons in both groups had received an initial treatment regimen that included pyrazinamide. Thirty-eight inactive HBsAg carriers (35%) and 19 control subjects (20%) exhibited elevated liver enzyme levels during antituberculosis treatment (p = 0.016). Drug-induced hepatotoxicity, which was defined as a liver transaminase level of >/= 120 IU/L, occurred more frequently in HBsAg carriers (9 of 110 carriers; 8%) than in control subjects (4 of 97 control subjects; 4%), although this was not a statistically significant discrepancy (p = 0.230). More importantly, HBsAg carriers (n = 9; 8%) who received antituberculosis therapy evidenced a higher proportion of moderate-to-severe drug-induced hepatotoxicity when compared with the control subjects (n = 2; 2%; p = 0.05). Isoniazid and rifampin were reintroduced as therapy after AST/ALT levels returned to baseline values in 10 patients (6 HBsAg carriers and 4 control subjects) among the 13 patients exhibiting drug-induced hepatotoxicity, and these retrials proved to be successful in 7 patients (5 HBsAg carriers and 2 control subjects). CONCLUSIONS Tuberculosis treatment in HBsAg-positive and HBeAg-negative inactive carriers could be pursued in the usual manner, using standard short-course regimens of isoniazid, rifampin, ethambutol, and/or pyrazinamide, with the condition that monthly liver function tests are performed.

Clinical characteristics of health care-associated pneumonia in a Korean teaching hospital.

BACKGROUND Health care-associated pneumonia (HCAP) has been proposed as a new category of respiratory infection. ATS/IDSA guidelines state that all patients with HCAP should receive empirical therapy directed at multidrug-resistant pathogens. However, recent data from other countries have reported a different picture of HCAP. METHODS We conducted a retrospective observational study of patients with HCAP and CAP who were hospitalized through the emergency department in January-December 2008 at Samsung Medical Center, Seoul, Korea, and compared clinical characteristics, severity, distribution of pathogen, and outcomes. RESULTS In total, 345 patients hospitalized with pneumonia were eligible, 182 (52.8%) with HCAP and 163 (47.2%) with CAP. Patients with HCAP had greater comorbidity and higher Pneumonia Severity Index (PSI) score (P < 0.001). Although Streptococcus pneumoniae was the most frequently isolated pathogen in HCAP and CAP patients, the occurrence of potentially drug-resistant pathogens (29.3% vs. 13.0%; P = 0.044) and inappropriate initial antimicrobial treatment (24.6% vs. 8.7%; P = 0.032) were significantly higher in HCAP patients. Patients with HCAP had a longer duration of hospital stay (13 [8-18] vs. 8 [6-12] days; P < 0.001), and higher in-hospital mortality (19.2% vs. 7.4%; P = 0.001). In a multiple logistic regression analysis, however, in-hospital mortality was independently associated with higher PSI class (OR 2.82, 95% CI 1.19-6.70) and ICU admission (OR 15.37, 95% CI 3.58-66.05). CONCLUSIONS Severity of illness, rather than type of pneumonia, was the main predicting factor for in-hospital mortality among patients with pneumonia hospitalized through the emergency department.

Early intervention can improve clinical outcome of acute interstitial pneumonia

Study objectives: To report on our experience with acute interstitial pneumonia (AIP) in which patients underwent early diagnostic procedures and received mechanical ventilation with a “lung-protective” strategy and early institution of immunosuppressive therapy. Design: A retrospective chart review. Setting: A tertiary referral hospital. Participants: Ten patients with AIP who presented with idiopathic ARDS and showed diffuse alveolar damage on surgical lung biopsy specimens from July 1995 to March 2004. Measurements and results: The median age of patients was 65.5 years (age range, 38 to 73 years). Patients presented with a median duration of severe dyspnea of 9.5 days (range, 2 to 34 days) at the hospital visit. All patients required mechanical ventilation beginning at median time of hospital day 1 (range, hospital day 0 to 5), which continued for a median duration of 9.5 days (range, 4 to 98 days). Patients received ventilation in the pressure assist-control mode with a median tidal volume of 6.97 mL/kg (range, 6.05 to 8.86 mL/kg) and median positive end-expiratory pressure of 11 cm H2O (range, 8 to 16 cm H2O). An aggressive diagnostic workup for respiratory infection, including BAL at a median time of hospital day 2 (range, hospital day 1 to 5) was performed. High-dose steroid pulse therapy was initiated on median hospital day 3.5 (range, hospital day 1 to 8), while surgical lung biopsy was performed on median hospital day 4 (range, hospital day 2 to 7). Eight patients (80%) survived to hospital discharge. Conclusion: Earlier intervention, such as an aggressive diagnostic approach, mechanical ventilation with lung-protective strategy, and the early institution of immunosuppressive may improve clinical outcome in patients with AIP.

Six-month Therapy with Aerosolized Interferon-γ for Refractory Multidrug-Resistant Pulmonary Tuberculosis

The aim of this study was to investigate the adjuvant effects of interferon-gamma (IFN-γ) inhalation therapy for six months in the treatment of refractory multidrug-resistant pulmonary tuberculosis (MDR-TB). Aerosolized IFN-γ was given to six MDR-TB patients with persistent positive smears and cultures despite long-term medical treatment. The patients received aerosolized two million international units of IFN-γ three times a week for 6 months while they continued on identical antituberculous chemotherapy. Before IFN-γ inhalation therapy, the patients received a median of 6.5 (range, 4 to 7) antituberculous drugs for median duration of 29 months (range,7 to 76). After IFN-γ inhalation therapy, sputum smears remained persistently positive in all patients throughout the study period. Sputum cultures were transiently negative at the 4th month in two patients, but became positive again at the end of 6 months of IFN-γ therapy. Five patients had radiological improvement including three patients who showed a decrease in the size of the cavitary lesions. Resectional surgery could be performed in one patient in whom substantial clinical and radiological improvement was noted after IFN-γ inhalation therapy. These results suggest that IFN-γ inhalation therapy may be effective for some cases of refractory MDR-TB who are otherwise not responding to conventional therapy.

Occult nodal metastasis in patients with non-small cell lung cancer at clinical stage IA by PET/CT

Background and objective:  The introduction of 18F‐FDG PET/CT has enhanced the diagnostic accuracy of nodal staging for non‐small cell lung cancer (NSCLC). We analysed risk factors for occult nodal metastasis in patients with clinical stage IA NSCLC as determined by 18F‐FDG PET/CT.