Impact of renal function-based anti-tuberculosis drug dosage adjustment on efficacy and safety outcomes in pulmonary tuberculosis complicated with chronic kidney disease.

BACKGROUND: Dosages of anti-tuberculosis (TB) drugs are recommended to be adjusted according to renal function for patients complicated with chronic kidney disease (CKD). However, the efficacy and safety outcomes of such renal function-based dosage adjustments are not fully elucidated. METHODS: We retrospectively reviewed cases of pulmonary TB susceptible to first-line drugs that were treated at Jikei University Daisan Hospital between 2005 and 2014 with standard regimens based on dosage adjustments according to renal function recommended by international guidelines. Patients were divided into four groups, those with no, mild, moderate or severe CKD. In-hospital TB-related mortality, the rate of sputum culture conversion at 2 months, the frequency of adverse events (AEs), for which at least the temporal discontinuation of the suspect drug was required for patient improvement, and the rate of regimen change due to AEs were assessed. RESULTS: In the 241 enrolled patients (mean age, 64.1 years; 143 men), fourteen patients (5.8%) died due to TB during their hospitalization. The rate of sputum culture conversion at 2 months was 78.0%. The frequency of in-hospital TB-related death and the conversion rate in the groups did not vary significantly according to CKD severity including those in the non-CKD group (P = 0.310 and P = 0.864). Meanwhile, a total of 70 AEs were observed in 60 patients (24.9%) and the difference between the groups in the overall frequency of AEs was almost significant (P = 0.051). Moreover, for the 154 patients with CKD, severe CKD stage was a significant risk factor for regimen change (OR = 5.92, 95% CI = 1.08-32.5, P = 0.041), as were drug-induced hepatitis and cutaneous reaction (OR = 35.6, 95% CI = 8.70-145, P < 0.001; OR = 17.4, 95% CI = 3.16-95.5, P = 0.001; respectively). CONCLUSIONS: Adjusting the dosage of TB treatment for CKD patients according to the guidelines was efficient in terms of similar therapeutic outcome to that of the non-CKD group. However, AEs warrant attention to avoid regimen change in patients with severe CKD, even if the renal function-based dosage adjustment is performed.

Predictive factors for relapse of cryptogenic organizing pneumonia.

BACKGROUND: Relapse of cryptogenic organizing pneumonia (COP) may lead to poor long-term prognosis and necessitates multiple rounds of steroid treatment with potential adverse effects. The objective of this study is to identify predictive factors of COP relapse by comparing demographic and clinical variables between relapse and non-relapse groups. METHODS: During 2008-2013, 33 COP patients were treated, of which 23 (69.7%) and 10 patients (30.3%) were assigned to the non-relapse and relapse group, respectively. From medical records, we compared the following variables at initial episode: clinical characteristics, serum parameters, chest CT scan findings, and steroid treatment. RESULTS: Clinical characteristics, cumulative prednisone dose, and steroid treatment duration were similar between groups. In univariate analysis, alternatively, the proportion of patients with bilateral shadow pattern, traction bronchiectasis, and partial remission after steroid treatment was significantly higher in the relapse group. These differences were not significant by multivariate Cox regression analysis. CONCLUSIONS: We identified radiographic findings, such as bilateral shadow pattern, traction bronchiectasis, and partial remission, may have possibility of predictive factors for COP relapse. Larger-scale studies are required to confirm if any are independent predictors of COP relapse.

Paradoxical response with increased tumor necrosis factor-α levels to anti-tuberculosis treatment in a patient with disseminated tuberculosis.

It has been reported that tuberculosis (TB) worsens after cessation of tumor necrosis factor-α inhibitors and starting anti-TB treatment. Little is known about the immunological pathogenesis of this paradoxical response (PR). We report the first case of a TB patient in whom PR occurred concurrently with elevation of circulating tumor necrosis factor-α (TNFα) levels. A 75-year-old woman, who had been treated with adalimumab for SAPHO syndrome, developed disseminated TB. Soon after administration of anti-TB treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol), and after discontinuation of adalimumab, a PR occurred. Serial testing of serum cytokine levels revealed a marked increase in TNFα, and a decline in interferon-γ levels. Despite intensive treatment with antibiotics, prednisolone, noradrenaline, and mechanical ventilation, acute respiratory distress syndrome developed and she died. Thus, overproduction of TNFα after cessation of TNFα inhibitors may partially account for the pathogenesis of a PR. This supports preventative or therapeutic reinitiation of TNFα inhibitors when PR occurs. Serial monitoring of circulating inflammatory cytokine levels could lead to earlier identification of a PR.

Effectiveness of hepatoprotective drugs for anti-tuberculosis drug-induced hepatotoxicity: a retrospective analysis.

BACKGROUND: The effectiveness of hepatoprotective drugs for DIH (drug induced hepatotoxicity) during tuberculosis treatment is not clear. We evaluated the effectiveness of hepatoprotective drugs by comparing the period until the normalization of hepatic enzymes between patients who were prescribed with the hepatoprotective drugs after DIH was occurred and patients who were not prescribed with the hepatoprotective drugs. METHODS: During 2006-2010, 389 patients with active tuberculosis were included in this study. DIH was defined as elevation of peak serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) of more than twice the upper limit of normal (ULN). We divided the patients into the severe (peak serum AST and/or ALT elevation of >5 times the ULN), moderate (peak serum AST and/or ALT elevation of >3 to ≤5 times the ULN), and mild DIH groups (peak serum AST and/or ALT elevation of >2 to ≤3 times the ULN). We compared the average period until the normalization of hepatic enzymes between patient subgroups with and without hepatoprotective drugs (ursodeoxycholic acid: UDCA, stronger neo-minophagen C: SNMC, and glycyrrhizin). RESULTS: In the severe group, there was no significant difference in the average period until the normalization between subgroups with and without hepatoprotective drugs (21.4 ± 10.8 vs 21.5 ± 11.1 days, P = 0.97). In the mild group, the period was longer in the subgroup with hepatoprotective drugs than that without hepatoprotective drugs (15.7 ± 6.2 vs 12.4 ± 7.9 days, P = 0.046). CONCLUSION: Regardless of the severity, hepatoprotective drugs did not shorten the period until the normalization of hepatic enzymes.

Thyroid metastasis from lung adenocarcinoma with EML4-ALK rearrangement.

Thyroid metastases from lung cancer are very rare. A woman aged 42 years with a tumour in the lower lobe of the right lung was diagnosed as having lung adenocarcinoma positive for echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase. Positron emission tomography demonstrated fluorodeoxyglucose accumulation in the lower lobe of the right lung, the right thyroid lobe and both adrenal glands. We performed fine-needle aspiration biopsy (FNAB) and used reverse transcriptase-PCR (RT-PCR) to diagnose the patient as having metastatic lung adenocarcinoma to the thyroid gland. We believe that FNAB combined with RT-PCR can be an effective method for diagnosing metastatic lung adenocarcinoma to the thyroid gland.

Medical thoracoscopy performed under local anesthesia is useful for diagnosing pleural metastasis of renal cell carcinoma.

A patient with a past history of renal cell carcinoma (RCC) presented to us with an exudative pleural effusion. Because pleural effusion cytology was inconclusive, we performed medical thoracoscopy under local anesthesia. Multiple white tumors measuring approximately 2 cm in diameter were observed on the parietal pleura. Metastatic carcinoma from RCC was diagnosed histologically. Although malignant effusions are rare in cases of RCC metastasis, clinicians should be aware of this possibility. When pleural effusion cytology is inconclusive in a patient with a past history of RCC, medical thoracoscopy can be useful for making the diagnosis of pleural metastasis.

[Mycobacterium xenopi lung infection in a patient with multiple lung cysts that responded well to chemotherapy: a case report].

An abnormal shadow was observed on the chest radiograph of a 39-year-old man during health examination. The chest CT scan showed a consolidation around the cysts in the left upper lobe. The patient was diagnosed with Mycobacterium xenopi lung infection based on the presence of acid-fast bacilli in the sputum culture several times, which were identified as Mycobacterium xenopi by DNA-DNA hybridization. Two weeks after the initation of chemotherapy with 4 drugs (isoniazid, rifampicin, ethambutol, and clarithromycin), the patient's sputum smear and culture test results were negative; additionally, the consolidation on the chest CT scan improved after 10 months of treatment. There have been several case reports on Mycobacterium xenopi lung infection in Japan. However, few have studied Mycobacterium xenopi lung infections associated with multiple lung cysts that responded well to chemotherapy are rare.

[Evaluation of tuberculosis treatment including levofloxacin (LVFX) in cases who could not continue standard regimen].

OBJECTIVE: The purpose of this study was to evaluate tuberculosis treatment including levofloxacin (LVFX) and to investigate the effectiveness of changing drug regimens at our hospital. SUBJECTS AND METHODS: A retrospective study was conducted on 331 patients with tuberculosis admitted to Tokyo National Hospital in 2005. Out of these 331 patients, LVFX was used in 48 (14.5%), 41 of which were initial-treatment cases. We studied why and how LVFX was used and compared bacteriological negative conversion rates between the initial-treatment cases in which the initial standard regimen was changed to regimens including LVFX, and those in which the initial standard regimen was either maintained throughout or modified with drugs other than LVFX. Sputum cultures were examined with Mycobacteria Growth Indicator Tube System (BACTEC MGIT 960). RESULTS: LVFX was used in 41 (13.6%) of 302 initial-treatment cases and in 7 (24.1%) of 29 retreatment cases. Out of the 269 initial-treatment cases starting with the standard regimen, LVFX was later used in 26 cases (9.7%). The reasons for using LVFX were adverse reaction to antituberculosis drugs in 23 cases (88.5%) and resistance to antituberculosis drugs in 3 cases (11.5%). We investigated the bacteriological conversion rate in 228 patients who could be followed up for more than five months. The conversion rates in 105 cases under the standard regimen including PZA (PZA+) were 92.4% in three months, 98.1% in four months, and 100% in five months. The rates in 56 cases under the standard regimen without PZA (PZA-) were 92.9 %, 98.2% and 100%,respectively. The rates of 22 cases under the initial regimen modified with LVFX (LVFX +) were 68.2 %, 95.5% and 100%, respectively. In 45 cases under the initial regimen modified with drugs other than LVFX (LVFX-), the rates were 80.0%, 97.8% and 100%, respectively. CONCLUSION: This study showed that LVFX was an effective drug in terms of the bacteriological conversion rate, without adverse reaction. LVFX is not approved as an antituberculosis drug in Japan, but it is often used in cases of MDR-TB or in situations in which the patients cannot continue treatment with the standard regimen. We hope that LVFX will be approved as an antituberculosis drug as soon as possible in Japan.

[Drug-induced hepatotoxicity caused by anti-tuberculosis drugs in tuberculosis patients complicated with chronic hepatitis].

OBJECTIVES: To investigate retrospectively the incidence of drug-induced hepatitis (DIH) caused by antituberculosis drugs including isoniazid (INH), rifampicin (RFP), with and without pyrazinamide (PZA), and to evaluate risk factors for DIH in tuberculosis patients complicated with chronic hepatitis (CH). MATERIALS: One hundred and seven tuberculosis patients with CH (M/F= 96/11, mean age +/- SE, 60.8 +/- 1.4 yr) admitted to our hospital during 1998-2006, whose laboratory data had been followed before and at least 2 months after starting antituberculosis chemotherapy, were enrolled in this study. Of these, 58 were being treated with anti-tuberculosis chemotherapy consisting of INH, RFP and PZA (HRZ group) and the remaining 49 with INH and RFP (HR group). For a case-control study, patients admitted to the hospital during the same period and without CH were selected to each CH patient (n=107) of the same gender, the same treatment regimens, and the same age. Clinical diagnosis of CH was based on laboratory data and in some cases pathological findings; etiology of CH was C-CH (CH caused by hepatitis C virus) in 68 patients, B-CH (CH caused by hepatitis B virus) in 23, and alcoholic CH in 16. METHODS: DIH was defined by elevation of serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) at 1 or 2 months after starting anti-tuberculosis chemotherapy. For patients with serum levels of AST or ALT already abnormally high before starting chemotherapy, an increase of > 1.5 times from the initial serum level was defined to indicate DIH, whereas for patients with AST and ALT within the normal range, and increase of > 3X the normal upper limit was defined to indicate DIH. The incidence of DIH was calculated separately in the groups HRZ and HR for patients with and patients without CH (control). In the HRZ group, the severity of DIH was defined by the maximum serum levels of AST and ALT, and their mean values were compared between CH patients and the control. Risk factors for DIH were examined by comparing patients with and without CH. The clinical course after development of DIH was also followed. [Results] The incidence of DIH in the HRZ group was 13/ 58 (22.4%) for CH patients and 10/36 (27.8%), 2/13 (15.4%) and 1/9 (11.1%) for C-CH, B-CH and alcoholic hepatitis patients, respectively, which was significantly (p < 0.05) higher than that in the control [4/58 (6.9%)]. Confining to the C-CH patients, the incidence of DIH was 10/36 (27.8%) compared with the control 2/36 (5.6%) (p < 0.05). In contrast, the incidence of DIH in the HR group was not significantly different between CH patients and the control, [2/49 (4.1%) vs 2/49 (4.1%)], respectively. The severity of DIH in the HRZ group estimated by the maximum level of serum AST and ALT was not significantly different in CH patients and the control (176.6 +/- 28.1 vs. 311.0 +/- 154.5 IU/L for AST and 187.8 +/- 19.1 vs. 277.8 +/- 72.4 IU/L for ALT). Of the 13 CH patients suffering from DIH caused by antituberculosis chemotherapy containing INH, RFP and PZA, 3 were continued treatment without altering the regimen, and 9 were continued treatment after changing the regimen to INH and RFP, omitting PZA. The one remaining patient was re-treated using INH, RFP and ethambutol (EB), but this again resulted in development of DIH, and he was ultimately treated with INH, EB and levofloxacin, with a successful outcome. Thus, at least 12 out of the 13 CH patients who developed DIH in the HRZ group could be treated by an anti-tuberculosis chemotherapy regimen containing INH and RFP excluding PZA. In C-CH patients who were treated with INH, RFP and PZA, the incidence of DIH was significantly higher when the daily alcohol intake was >20 g [8/18 (44.4%)] compared with those <20 g [0/10 (0%)] (p < 0.05), indicating that alcohol is a risk factor for DIH in C-CH patients treated with INH, RFP and PZA. CONCLUSIONS: In CH patients, anti-tuberculosis chemotherapy containing INH and RFP without PZA can be used safely. The inclusion of PZA in the regimen does substantially increase the incidence of DIH but nonetheless it can be used with caution, especially bearing in mind that daily alcohol intake of >20 g is a significant risk factor for C-CH patients.

[Features of bronchial tuberculosis--an analysis of 103 cases].

OBJECTIVES: The aim of this study is to clarify the features of bronchial tuberculosis. MATERIALS AND METHODS: We analyzed the clinicopathological data from 103 out of 4467 (2.3%) cases of culture positive tuberculosis admitted to the National Hospital Organization Tokyo National Hospital in the period from 1993 to 2004 in which bronchial tuberculosis was confirmed by bronchofiberscopy. RESULTS: There were 62 women and 41 men, and 53 cases were less than 50 years old. The most common symptom, namely cough was observed in 70 cases, while 79 cases showed III1 to III2 on roentgenographic examination, and 81 cases were smear-positive for acid-fast bacilli in the sputum. Regarding the bronchofiberscopic findings, ulcers were detected in 60 cases, and the major site of bronchial tuberculosis was in the left main bronchus (35 cases). The number of the cases in which the time span from the onset of symptoms to diagnosis took over 3 months was 29, and 26 of them were "doctor's delay" cases which had a history of medical consultation resulting in diagnosis and treatment of other diseases, such as bronchial asthma (7 cases). There were 41 cases in which the second bronchofiberscopic findings have been reviewed, and regardless of the length of the span from the onset to diagnosis, the first bronchofiberscopy mostly revealed ulcer within 1 month after the start of treatment for tuberculosis, and 3 months after the start of treatment, many patients developed fibrous scars. Between 1999 to 2004, the first bronchofiberscopies were usually performed within 2 weeks to 1 month after the start of the treatment in contrast to the cases admitted between 1993 to 1998 in which bronchofribroscopy was mainly performed before the start of the treatment. However, there were no differences in the findings due to the timing of bronchofiberscopy. CONCLUSION: The clinical characteristics of bronchial tuberculosis have not changed, and the delay of diagnosis of bronchial tuberculosis due to doctor's delay also continues to be an important issue today. In patients showing positive sputum smear for mycobacteria, the timing of bronchofiberscopy, although required upon medical examination, is considered to be more appropriately performed from 2 weeks to 1 month after the start of treatment from the view point of nosocomial tuberculosis infection control strategy.

[Bone and joint tuberculosis concurrent with tuberculosis of other organs].

OBJECTIVES: To study the characteristics of bone or joint tuberculosis (TB) accompanied by TB in other organs (especially the lung), and to study patients' and doctors' delay in detecting bone or joint TB. SUBJECTS AND METHODS: A retrospective study was conducted on 33 patients with bone or joint TB concurrent with TB of other organs, especially the lung, who were admitted to our hospital between 1981 and 2005. The patients were divided into the following three groups according to the organ of concurrent TB : (1) miliary TB group (N = 10), (2) pulmonary TB group (N = 19), and (3) other TB site group (N = 4). The relationship between bone/joint TB and TB of other organs was studied by comparing the three groups with respect to the time of appearance of musculo-skeletal symptoms or signs such as swelling and pain and that of symptoms or signs originating from other organs, such as cough, sputum, miliary pattern on chest radiograph and superficial lymph node swelling. RESULTS: The mean age (SD) of patients was 50.5 (18.9) yr, and the male to female ratio was 23 : 10. Among 33 patients, bone TB (including 18 spinal TB) was detected in 24 patients, joint TB in 14, and abscess in 3 (concurrent lesions in some patients). The mean intervals from onset of symptoms to consultation (patients' delay), from consultation to diagnosis (doctors' delay) and from symptom onset to diagnosis (total delay) were 5.5 (13.9), 3.4 (5.2) and 8.9 (13.9) months, respectively. (1) Bone/joint TB concurrent with miliary TB (N = 10) In 8 patients with mean age of 61.0 (17.4) yr, musculo-skeletal symptoms/signs preceded respiratory symptoms or appearance of miliary pattern on chest radiograph by 7.8 (7.2) (range; 1-24) months. The patients', doctors' and total delays were 0.4 (0.5), 7.3 (7.8), and 7.7 (7.6) months, respectively. In most cases, bone/joint TB was diagnosed after the onset of miliary pattern on chest radiograph. In one patient with simultaneous onset of musculo-skeletal and respiratory symptoms/signs (age 21 yr), the interval of total delay was 1 month, and in one patient with musculoskeletal symptoms which appeared six months later than respiratory symptoms (age 28 yr), the interval of total delay was 2 months. (2) Bone/joint TB concurrent with active pulmonary TB (N = 19). In this group, the mean age was 52.2 (17.1) yr, and males were predominant (M/F = 15/4). Active pulmonary TB was diagnosed by positive sputum culture in 13 patients, by positive sputum smear or PCR results in 4 patients, and by the clinical course in 2 patients. Ten patients (53%) had a previous TB history. Cavitary lesion was observed in 15 patients, and the upper lobes were predominantly involved on chest radiograph in 19 patients, indicating that the pulmonary TB was probably post-primary (reactivation) in all patients. In 9 patients with mean age of 49.7 (15.7) yr, musculo-skeletal symptoms/signs preceded respiratory symptoms by 14.1 (14.0) (range; 4-48) months. The patients', doctors' and total delays were 13.3 (17.8), 3.8 (6.6), and 17.1 (16.1) months, respectively. On the other hand, in 10 patients with mean age of 54.5 (18.7) yr, musculo-skeletal symptoms/signs and respiratory symptoms/signs appeared simultaneously, and the total delay was 2.7 (1.9) months. Twelve of 19 patients (63%) had complications such as diabetes mellitus, steroid use, and liver diseases. In cases with miliary or pulmonary tuberculosis, the total delay in diagnosis (Y) correlates positively with the time lag from onset of musculo-skeletal symptoms to respiratory symptoms/signs (X), and the regression line (Y = 0.94X + 2.3, r = 0.98, p < 0.001) was almost linear (Y = X), indicating that the diagnosis of bone/joint TB was made just after the diagnosis of miliary or pulmonary TB. (3) Bone/joint TB concurrent with TB of other sites (N = 4) In 2 female cases (21 and 28 yrs) with cervical lymph node TB, musculo-skeletal symptoms/signs and cervical lymph node swelling appeared simultaneously. In a 54-yr male patient, musculo-skeletal symptoms/signs appeared 5 years after appearance of testicular enlargement, and testicular TB was diagnosed by biopsy simultaneously. In a 33 year-old male patient, musculo-skeletal symptoms/signs appeared 7 months after the drainage of pleural and pericardial effusions (TB was not diagnosed initially), and then the diagnosis of bone/joint, pleural, and pericardial tuberculosis was made for the first time. CONCLUSIONS: In middle-aged or elderly patients with active bone/joint TB, miliary TB is sometimes caused by bacillemia originating from the infected bone/joint lesions. In cases with bone/joint TB and concurrent pulmonary TB, bone/joint TB and pulmonary TB are probably reactivated independently as a result of decreased systemic immunocompetence.

[Coexisting lung cancer and active pulmonary mycobacteriosis].

We reviewed 72 patients with coexisting lung cancer and pulmonary mycobacteriosis, and discuss the features and transition of these coexistent cases. There were 56 pulmonary tuberculosis (PTB) cases and 16 non-tuberculous mycobacteriosis (PNTM) cases, 62 men and 10 women, with a mean age of 69 years. In 43 cases, both diseases were concurrently detected, lung cancer was first detected in 19 cases, and mycobacteriosis was first detected in 10 cases. The frequency of lung cancer in cases with active pulmonary mycobacteriosis was 1.2%. Pulmonary mycobacteriosis was characterized by Type II (40 cases) and Spread 2 (42 cases) on chest X-rays; the most frequent histologic type of lung cancer was squamous cell carcinoma (32 cases) and most were stage III-IV cases (57 cases). After PTB treatment, the negative conversion rate of sputum cultures in both the concurrently detected group and the group in which lung cancer was initially detected was 56% within one month and 94% within 2 months. For the treatment of lung cancer, 33 cases received supportive care, 13 patients underwent resection and 17 received chemotherapy or chemoradiotherapy. In PNTM cases, both lung cancer and pulmonary mycobacteriosis showed a slight state compared to those in PTB cases, and in the group in which lung cancer was initially detected, both diseases were more advanced or severe than those in the concurrently detected group or in the group in which mycobacteriosis was initially detected. The rate of coexisting lung cancer and pulmonary mycobacteriosis was unchanged at 1-2%, and the incidence of stage IV lung cancer cases has increased recently. Coexisting lung cancer and pulmonary mycobacteriosis is an important condition in respiratory disease in Japan. Physicians should be aware of the possibility of PTB coexisting with lung cancer.