Development of a population pharmacokinetic model of pyrazinamide to guide personalized therapy: impacts of geriatric and diabetes mellitus on clearance.

Objectives: This study was performed to develop a population pharmacokinetic model of pyrazinamide for Korean tuberculosis (TB) patients and to explore and identify the influence of demographic and clinical factors, especially geriatric diabetes mellitus (DM), on the pharmacokinetics (PK) of pyrazinamide (PZA). Methods: PZA concentrations at random post-dose points, demographic characteristics, and clinical information were collected in a multicenter prospective TB cohort study from 18 hospitals in Korea. Data obtained from 610 TB patients were divided into training and test datasets at a 4:1 ratio. A population PK model was developed using a nonlinear mixed-effects method. Results: A one-compartment model with allometric scaling for body size effect adequately described the PK of PZA. Geriatric patients with DM (age >70 years) were identified as a significant covariate, increasing the apparent clearance of PZA by 30% (geriatric patients with DM: 5.73 L/h; others: 4.50 L/h), thereby decreasing the area under the concentration-time curve from 0 to 24 h by a similar degree compared with other patients (geriatric patients with DM: 99.87 µg h/mL; others: 132.3 µg h/mL). Our model was externally evaluated using the test set and provided better predictive performance compared with the previously published model. Conclusion: The established population PK model sufficiently described the PK of PZA in Korean TB patients. Our model will be useful in therapeutic drug monitoring to provide dose optimization of PZA, particularly for geriatric patients with DM and TB.

Impact of birth season on second-to-fourth digit ratio, prostate volume, and prostate cancer.

PURPOSE: The second-to-fourth digit ratio (digit ratio), which is determined in utero, is associated with exposure to visible sunlight during early pregnancy and the season of birth. The digit ratio is also associated with benign prostatic hyperplasia (BPH) and prostate cancer. This suggests that BPH and prostate cancer may be related to the birth season. Therefore, this study aimed to determine whether prostate volume and prostate cancer were related to the birth season. MATERIALS AND METHODS: A total of 858 male patients with lower urinary tract symptoms were enrolled. The right digit ratio was measured, and the month of birth was surveyed. Serum prostate-specific antigen (PSA) levels were measured, and prostate volumes were measured by transrectal ultrasonography. Patients with suspected prostate cancer underwent prostate biopsy. RESULTS: The mean age, digit ratio, prostate volume, and serum PSA level of 858 patients were 61.6 years, 0.947, 36.2 mL, and 4.24 ng/mL, respectively. Age, serum PSA levels, prostate biopsy rates, and cancer detection rates did not differ significantly according to the birth season. However, compared with the summer birth group, the winter birth group had lower digit ratios (0.951±0.040 vs. 0.941±0.040; p=0.014), larger prostate volumes (33.4±14.9 mL vs. 38.2±20.7 mL; p=0.008), and more prostate cancer (5.3% vs. 11.3%; p=0.031). Multivariate analysis showed that birth season independently predicted prostate cancer. CONCLUSIONS: The relationships of birth season with prostate volume and prostate cancer may be due to differences in the amount of light exposure during early pregnancy.

Factors Preventing Nosocomial Outbreak Following a Single case of COVID-19 Diagnosed During Hospitalization: A Retrospective Review.

OBJECTIVE: Our hospital experienced a hospital shutdown and 2 week quarantine after a case of COVID-19 was diagnosed during hospitalization. We analyzed the reopening process following hospital closure and possible factors that prevented hospital spread. METHODS: We retrospectively reviewed the confirmed patient's medical records and results of epidemiological survey available from the infection control team of our hospital. RESULTS: A total of 117 hospital staff members were tested, 26 of whom were self-isolated. Of the 54 inpatients tested, 28 on the same floor, and 2 close contacts in the endoscopic room were quarantined in a single room. Finally, all quarantined hospital staff, inpatients and outpatients were tested for COVID-19 on the 14th day of close contact. The results were all negative, and the hospital work resumed completely. CONCLUSION: Although closing and isolating the hospital appeared to have played a useful role in preventing the spread of COVID-19 inside the hospital and to the local community, it is still debated whether or not the duration of hospital closure or quarantine was appropriate. The lessons from the 2-week hospital closure suggest that wearing a mask, hand hygiene and the ward environment are important factors in preventing nosocomial outbreaks of COVID-19.

Larger Testicular Volume Is Independently Associated with Favorable Indices of Lung Function.

BACKGROUND: Men with chronic obstructive pulmonary disease, have reduced endogenous testosterone levels, but the relationship between pulmonary function and endogenous testosterone levels, is inconsistent. Testicular volume is a known indicator of endogenous testosterone levels, male fertility, and male potency. In the present study, the authors investigated the relationship, between testicular volume and lung function. METHODS: One hundred and eighty-one South Korean men age 40-70, hospitalized for urological surgery, were retrospectively enrolled, irrespective of the presence of respiratory disease. Study subjects underwent pulmonary function testing, prior to procedures, and testicular volumes were measured by orchidometry. Testosterone levels of patients in blood samples collected between 7 AM and 11 AM, were measured by a direct chemiluminescent immunoassay. RESULTS: The 181 study subjects were divided into two groups, by testicular volume (≥35 mL vs. <35 mL), the larger testes group, had better lung functions (forced vital capacity [FVC]: 3.87±0.65 L vs. 3.66±0.65 L, p=0.037; forced expiratory volume in 1 second [FEV1]: 2.92±0.57 L vs. 2.65±0.61 L, p=0.002; FVC % predicted: 98.2±15.2% vs. 93.8±13.1%, p=0.040; FEV1 % predicted: 105.4±19.5% vs. 95.9±21.2%, p=0.002). In addition, the proportion of patients with a FEV1/FVC of <70%, was lower in the larger testes group. Univariate analysis conducted using linear regression models, revealed that testicular volume was correlated with FVC (r=0.162, p=0.029), FEV1 (r=0.218, p=0.003), FEV1/FVC (r=0.149, p=0.046), and FEV1 % predicted (r=0.178, p=0.017), and multivariate analysis using linear regression models, revealed that testicular volume was a significant predictive factor for FEV1 % predicted (ß=0.159, p=0.041). CONCLUSION: Larger testicular volume was independently associated, with favorable indices of lung function. These results suggest that androgens, may contribute to better lung function.

The Need for a Well-Organized, Video-Assisted Asthma Education Program at Korean Primary Care Clinics.

BACKGROUND: The purpose of this study was to assess the effect of our new video-assisted asthma education program on patients' knowledge regarding asthma and asthma control. METHODS: Adult asthmatics who were diagnosed by primary care physicians and followed for at least 1 year were educated via smart devices and pamphlets. The education sessions were carried out three times at 2-week intervals. Each education period lasted at most 5 minutes. The effectiveness was then evaluated using questionnaires and an asthma control test (ACT). RESULTS: The study enrolled 144 patients (mean age, 56.7±16.7 years). Half of the patients had not been taught how to use their inhalers. After participating in the education program, the participants' understanding of asthma improved significantly across all six items of a questionnaire assessing their general knowledge of asthma. The proportion of patients who made errors while manipulating their inhalers was reduced to less than 10%. The ACT score increased from 16.6±4.6 to 20.0±3.9 (p<0.001). The number of asthmatics whose ACT score was at least 20 increased from 45 (33.3%) to 93 (65.3%) (p<0.001). The magnitude of improvement in the ACT score did not differ between patients who received an education session at least three times within 1 year and those who had not. The majority of patients agreed to the need for an education program (95.8%) and showed a willingness to pay an additional cost for the education (81.9%). CONCLUSION: This study indicated that our newly developed education program would become an effective component of asthma management in primary care clinics.

Qualitative and quantitative results of interferon-γ release assays for monitoring the response to anti-tuberculosis treatment.

BACKGROUND/AIMS: The usefulness of interferon-γ release assays (IGRAs) in monitoring to responses to anti-tuberculosis (TB) treatment is controversial. We compared the results of two IGRAs before and after anti-TB treatment in same patients with active TB. METHODS: From a retrospective review, we selected patients with active TB who underwent repeated QuantiFERON-TB Gold (QFN-Gold, Cellestis Limited) and T-SPOT.TB (Oxford Immunotec) assays before and after anti-TB treatment with first-line drugs. Both tests were performed prior to the start of anti-TB treatment or within 1 week after the start of anti-TB treatment and after completion of treatment. RESULTS: A total of 33 active TB patients were included in the study. On the QFN-Gold test, at baseline, 23 cases (70%) were early secreted antigenic target 6-kDa protein 6 (ESAT-6) or culture filtrate protein 10 (CFP-10) positive. On the T-SPOT. TB test, at baseline, 31 cases (94%) were ESAT-6 or CFP-10 positive. Most of patients remained both test-positive after anti-TB treatment. Although changes in interferon-γ release responses over time were highly variable in both tests, there was a mean decline of 27 and 24 spot-forming counts for ESAT-6 and CFP-10, respectively on the T-SPOT.TB test (p < 0.05 for all). CONCLUSIONS: Although limited by the small number of patients and a short-term follow-up, there was significant decline in the quantitative result of the T-SPOT. TB test with treatment. However, both commercial IGRAs may not provide evidence regarding the cure of disease in Korea, a country where the prevalence of TB is within the intermediate range.

Acute Respiratory Distress Syndrome as the Initial Clinical Manifestation of an Antisynthetase Syndrome.

Antisynthetase syndrome has been recognized as an important cause of autoimmune inflammatory myopathy in a subset of patients with polymyositis and dermatomyositis. It is associated with serum antibody to aminoacyl-transfer RNA synthetases and is characterized by a constellation of manifestations, including fever, myositis, interstitial lung disease, mechanic's hand-like cutaneous involvement, Raynaud phenomenon, and polyarthritis. Lung disease is the presenting feature in 50% of the cases. We report a case of a 60-year-old female with acute respiratory distress syndrome (ARDS), which later proved to be an unexpected and initial manifestation of anti-Jo-1 antibody-positive antisynthetase syndrome. The present case showed resolution of ARDS after treatment with high-dose corticosteroids. Given that steroids are not greatly beneficial in the treatment of ARDS, it is likely that the improvement of the respiratory symptoms in this patient also resulted from the prompt suppression of the inflammatory systemic response by corticosteroids.

Spontaneous Pneumomediastinum: An Unusual Pulmonary Complication in Anorexia Nervosa.

Spontaneous pneumomediastinum (PM) is an uncommon condition in which free air enters the mediastinum. This usually occurs either through esophageal tears after vigorous vomiting, or after alveolar rupture subsequent to a rapid increase in intra-alveolar pressure. Spontaneous PM is a rare entity in anorexia nervosa (AN) and self-induced vomiting is often the cause of PM in patients with AN. We experienced a case of spontaneous PM in an anorexic adolescent, in whom vomiting was not the cause of PM.

Recurrent Pseudomonas aeruginosa Infection in Chronic Lung Diseases: Relapse or Reinfection?

BACKGROUND: Pseudomonas aeruginosa infection is particularly associated with progressive and ultimately chronic recurrent respiratory infections in chronic obstructive pulmonary disease, bronchiectasis, chronic destroyed lung disease, and cystic fibrosis. Its treatment is also very complex because of drug resistance and recurrence. METHODS: Forty eight cultures from 18 patients with recurrent P. aeruginosa pneumonia from 1998 to 2002 were included in this study. Two or more pairs of sputum cultures were performed during 2 or more different periods of recurrences. The comparison of strains was made according to the phenotypic patterns of antibiotic resistance and chromosomal fingerprinting by pulsed field gel electrophoresis (PFGE) using the genomic DNA of P. aeruginosa from the sputum culture. RESULTS: Phenotypic patterns of antibiotic resistance of P. aeruginosa were not correlated with their prior antibiotic exposition. Fifteen of 18 patients (83.3%) had recurrent P. aeruginosa pneumonia caused by the strains with same PFGE pattern. CONCLUSION: These data suggest that the most of the recurrent P. aeruginosa infections in chronic lung disease occurred due to the relapse of prior infections. Further investigations should be performed for assessing the molecular mechanisms of the persistent colonization and for determining how to eradicate clonal persistence of P. aeruginosa.

Effect of inhaled tiotropium on spirometric parameters in patients with tuberculous destroyed lung.

BACKGROUND: In Korea, patients with destroyed lung due to tuberculosis (TB) account for a significant portion of those affected by chronic pulmonary function impairment. The objective of our research was to evaluate the efficacy of inhaled tiotropium bromide in TB destroyed lung. METHODS: We compared the effectiveness of inhaled tiotropium bromide for 2 months between pre- and post-treatment pulmonary function tests performed on 29 patients with destroyed lung due to TB. RESULTS: The mean age of the total number of patients was 63±9 years, where 15 patients were male. The pre-treatment mean forced expiratory volume in 1 second (FEV1) was 1.02±0.31 L (44.1±16.0% predicted). The pre-treatment mean forced vital capacity (FVC) was 1.70±0.54 L (52.2±15.8% predicted). Overall, the change in FEV1% predicted over baseline with tiotropium was 19.5±19.1% (p<0.001). Twenty patients (72%) got better than a 10% increase in FEV1 over baseline with tiotropium, but one patient showed more than a 10% decrease in FEV1. Overall, the change in FVC% predicted over baseline with tiotropium was 18.5±19.9% (p<0.001). Seventeen patients (59%) experienced greater than a 10% increase in FVC over baseline with tiotropium; 12 (41%) patients had stable lung function. CONCLUSION: The inhaled tiotropium bromide therapy may lead to improve lung functions in patients with TB destroyed lung. However, the long-term effectiveness of this treatment still needs to be further assessed.

Second to fourth digit ratio: a predictor of adult lung function.

Sex and sex hormones play a major role in lung physiology. It has been proposed that the ratio of the second to fourth digits (digit ratio) is correlated with fetal sex hormones. We therefore hypothesized that digit ratio might help predict lung function. We investigated the relationship between digit ratio and pulmonary function test (PFT) findings. A total of 245 South Korean patients (162 male, 83 female) aged from 34 to 90 years who were hospitalized for urological surgery were prospectively enrolled. Before administering the PFTs, the lengths of the second and fourth digits of the right hand were measured by a single investigator using a digital Vernier caliper. In males (n = 162), univariate and multivariate analysis using linear regression models showed that digit ratio was a significant predictive factor of forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) (FVC: r = 0.156, P = 0.047; FEV1: r = 0.160, P = 0.042). In male ever-smokers (n = 69), lung functions (FVC and FEV1) were correlated with smoking exposure rather than digit ratio. In female never-smokers (n = 83), lung functions (FEV1 and FEV1/FVC ratio) were positively correlated with digit ratio on univariate analysis (FEV1: r = 0.242, P = 0.027; FEV1/FVC ratio: r = 0.245, P = 0.026). Patients with lower digit ratios tend to have decreased lung function. These results suggest that digit ratio is a predictor of airway function.

Inverted Tako-Tsubo cardiomyopathy associated with bronchoalveolar lavage.

Tako-Tsubo cardiomyopathy (TTC), also known as transient left ventricular (LV) ballooning syndrome or stress-induced cardiomyopathy, is characterised by transient LV dysfunction in the absence of significant angiographic coronary stenoses, frequently provoked by an episode of emotional or physical stress. In TTC, typically transient akinesis or dyskinesis of the LV apical segments with normal or hypercontractile basal wall motions is observed. Recently, several cases of atypical or inverted transient TTC sparing the LV apex have been reported. We report a case of inverted TTC showing akinesis of the basal and mid-ventricular segments of the LV with apical hyperkinesia triggered by bronchoscopy with bronchoalveolar lavage.

Evaluation of therapeutic response of tuberculoma using F-18 FDG positron emission tomography.

BACKGROUND: Monitoring the response to antituberculosis (anti-TB) treatment can be difficult in patients with tuberculoma. We have retrospectively assessed the ability of F-18 fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) to evaluate the response to anti-TB treatment in patients with tuberculoma. METHODS: Two patients with tuberculoma underwent repeat PET scans during anti-TB treatment. Changes in maximal standard uptake value (SUV) of the tuberculoma on PET images were analyzed between 2 scans. Initial PET scans were performed before the start of anti-TB treatment (T0), and later scans were performed after completion of treatment (T1). RESULTS: In a 57-year-old female patient with clinical TB, maximal SUV of tuberculoma on PET scan decreased from 2.6 (at T0) to an undetectable value (at T1) at an interval of 187 days. In a 60-year-old woman with biopsy-proven TB, maximal SUV of tuberculoma on PET scan decreased from 4.8 (at T0) to 1.1 (at T1) at an interval of 192 days. CONCLUSION: PET scans may be useful for monitoring responses to anti-TB treatment in patients with tuberculoma.

Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis.

BACKGROUND: Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a relatively common and highly morbid clinical event. However, clinical data on AE in non-IPF interstitial pneumonia are sparse. This study was performed to find the frequency, clinical features, and outcome of AE in non-IPF interstitial pneumonia. METHODS: Retrospective analysis of 10 patients who satisfied the modified Akira criteria for AE during follow-up of 74 patients with surgical lung biopsy-confirmed idiopathic nonspecific interstitial pneumonia (I-NSIP) and 93 patients with biopsy-confirmed interstitial pneumonia associated with collagen vascular disease (CVD-IP). RESULTS: AE occurred in six patients with I-NSIP (1-year frequency, 4.2%) and in four patients with CVD-IP (rheumatoid arthritis [RA], n = 3; scleroderma, n = 1), with 1-year frequency of 3.3%. Median age was 58 years (range, 47 to 75); six patients were female. AE occurred in two patients immediately after surgical biopsy. Median duration of acute symptom before hospital admission was 10 days (range, 1 to 30). Median ratio of Pao(2) to the fraction of inspired oxygen (Fio(2)) was 172 (range, 107 to 273), and Pao(2)/Fio(2) ratio was < 200 in six patients. Surgical lung biopsy performed at the time of AE in two patients revealed diffuse alveolar damage superimposed on nonspecific interstitial pneumonia pattern. Four patients with I-NSIP survived to discharge and were followed up for 24 months (range, 6 to 121). CONCLUSION: AE occurred in the patients with I-NSIP with apparently better prognosis. In patients with CVD-IP, AE occurred mostly with RA-usual interstitial pneumonia in our small series with poor outcome.

Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular disease-related subtypes.

BACKGROUND: To investigate whether the better prognosis of interstitial pneumonias associated with collagen vascular disease (CVD) compared with idiopathic interstitial pneumonia (IIP) is due to higher frequency of the nonspecific interstitial pneumonia (NSIP) pattern in CVD, we compared the outcomes of patients from these two groups with the same histopathologic pattern. SUBJECTS: The clinical features and survival of 362 patients (269 with IIP and 93 with CVD) diagnosed using surgical lung biopsy were analyzed. RESULTS: The mean survival of the CVD group (131.0 mo) was longer than that of the IIP group (80.5 mo) (p<0.0001). The patients with usual interstitial pneumonia pattern among the CVD group (n=36) was younger, female, and predominantly nonsmoking compared with the IIP group (n=203). Although baseline lung functions were not significantly different, the CVD group survived longer (mean, 177.0 mo) than the IIP group (mean, 66.9 +/- 6.5 mo; p=0.001). By multivariate analysis, younger age, better pulmonary function, and the presence of a CVD were independent prognostic factors. In NSIP pattern, no significant differences in survival, clinical features, or lung function were found between the two groups. CONCLUSION: Our data suggest that the better prognosis of patients in the CVD group is not solely due to the predominance of the NSIP pattern. The prognosis of patients with the usual interstitial pneumonia pattern in CVD is better than in those with idiopathic pulmonary fibrosis, despite the same pathologic pattern. In contrast, in those with an NSIP pattern, the prognosis is similar in both groups.

Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis.

OBJECTIVES: Although linezolid has good in vitro activity against Mycobacterium tuberculosis, its long-term use in the treatment of multidrug-resistant tuberculosis (MDR-TB) may be limited by its cost and serious adverse reactions. We therefore evaluated the efficacy and tolerability of a reduced dose of linezolid, in combination with other anti-TB drugs, in patients with intractable or extensive MDR-TB. METHODS: MDR-TB patients unresponsive to at least three cycles of treatment were treated with daily-half doses of linezolid (600 mg once per day) plus at least four companion drugs. RESULTS: As of March 2006, eight patients, all HIV-negative, had been treated with linezolid for 3-18 months. Cultures became negative in all patients in an average of 82 days. Four patients developed peripheral neuropathy, two developed optic neuropathy and one developed anaemia. Although optic neuropathy resolved after cessation of linezolid therapy, peripheral neuropathy continued. One patient completed 18 months of linezolid therapy. Two patients, who have taken linezolid for 15-17 months, are still on treatment and remain in culture conversion. Three patients stopped linezolid after 7-9 months, two because of side effects and one for economic reasons, but remain on treatment with other second-line drugs with culture conversion. Two patients died from severe respiratory failure, but both previously had shown culture conversion. CONCLUSIONS: Although daily-half doses of linezolid were effective in patients with intractable or extensive MDR-TB, this dosage regimen did not reduce long-term use-related side effects, such as peripheral and optic neuropathy.