Ehsan Chitsaz

First-line anti-tuberculosis drug resistance patterns and trends at the national TB referral center in Iran—eight years of surveillance

OBJECTIVE Resistance to anti-tuberculosis (anti-TB) drugs is becoming a major and alarming threat in most regions worldwide. METHODS This was a descriptive cross-sectional study at a tertiary hospital in Iran, using patient medical records for 2000-2003. The findings were analyzed following the same framework as that used for previous reports from this center. RESULTS Among 1556 TB patients, drug susceptibility testing (DST) was performed for 548 culture-positive cases. Anti-TB drug resistance to both isoniazid and rifampin was identified in 10 (2.8%) of the new TB cases (multidrug-resistant TB; MDR-TB). Any resistance was detected in 228 (41.6%), showing an increasing trend in both new and retreatment cases. The data analysis revealed that drug-resistant TB had a statistically significant association with Afghan ethnicity, age>65 years, and the type of disease (retreatment vs. new TB case) (p<0.05). Also, assessment of the drug resistance trends showed a significant increase in resistance to any anti-TB agent, to isoniazid, and to streptomycin in new cases, and to all of the first-line anti-TB drugs in retreatment patients. CONCLUSIONS There has been an increasing trend in drug resistance in recent years, particularly in retreatment cases. Hence, revision of the national TB control program, reevaluation of the role of the World Health Organization category II (CAT II) regimen, as well as the conducting of a nationwide drug resistance survey, are recommended.

Incidence, clinical and epidemiological risk factors, and outcome of drug-induced hepatitis due to antituberculous agents in new tuberculosis cases.

Drug-induced hepatitis (DIH) is an important issue in tuberculosis (TB) treatment. We intend to assess the incidence, risk factors, and outcome of hepatitis due to anti-TB drugs. The study is carried out at the national TB referral center 2006-2008 including all documented new cases of TB. All patients received standard anti-TB treatment. If DIH occurred, all drugs were discontinued and reinitiated after liver function tests (LFT) normalization in a stepwise way. Of total 761 patients, 99 (13.0%) patients developed DIH during anti-TB treatment. There was no difference in sex, nationality, smoking, or opium use history between the hepatitis group and the control group (P > 0.05). DIH was significantly higher in patients older than 65 years (P = 0.019). The mean duration of DIH from the beginning of treatment was 17.53 ± 19.42 days (median = 12; 1-125 days). Also, the mean of the time elapsed from DIH till the (LFT) normalization was 10.26 ± 5.95 (median = 9; 0-32 days). Anorexia, nausea, vomiting, abdominal pain, jaundice, diarrhea, decreased level of consciousness, and fever were significantly higher in patients with DIH. In DIH group, 13 patients (13.4%) died, whereas in the control group, death occurred just in 21 cases (3.2%) (P < 0.001, 95% confidence interval = 2.26-9.70, odds ratio = 4.7). After adjusting with logistic regression, all the anticipated factors retained the statistical significance. Our study indicated that DIH most often occurs during the first 2 weeks of anti-TB treatment. DIH development is associated with old age, certain clinical manifestations, and higher death rates.

Nontuberculous Mycobacteria Among Patients Who are Suspected for Multidrug-Resistant Tuberculosis—Need for Earlier Identification of Nontuberculosis Mycobacteria

Background:In this study, we intended to find the prevalence of nontuberculosis mycobacteria (NTM) among patients who are referred as suspected multidrug-resistant tuberculosis (MDR-TB) cases to the only referral center in Iran. Methods:All patients referred to our center in 2002–2006 as MDR-TB with histories of treatment with standard and CAT II World Health Organization regimens were included in the study. Sputum smear and culture for acid-fast bacilli were performed for all patients 3 times. Sputum polymerase chain reaction was also performed for all patients. Mycobacterial identification was performed via polymerase chain reaction and routine identification tests for all culture-positive cases. Results:Of the 105 patients in the study, 12 (11.43%) were identified to have NTM infection. The identified mycobacteria were classified in order of prevalence as Chelonae (8 cases), Simiae (2 cases), Aloei (1 case), and Farcinogen (1 case). Based on radiologic findings, most of the cases demonstrated bilateral nodularity (83.3%) and also multifocal bronchiectasis (75%). Notably, cavitary lesions were present in 41.7% of the cases. Conclusion:Based on the findings of this study, it is essential that such cases be identified before commencing MDR-TB treatment.

Performance of QuantiFERON-TB Gold test compared to tuberculin skin test in detecting latent tuberculosis infection in HIV- positive individuals in Iran.

BACKGROUND: There is limited data about the performance of QuantiFERON-TB Gold (QFT-G) test in detecting latent tuberculosis infection (LTBI) in our region. We intended to determine the performance of QFT-G compared to conventional tuberculin skin test (TST) in detecting LTBI in HIV-positive individuals in Iran. METHODS: This study was conducted in a HIV clinic in Tehran, Iran in April 2007. A total of 50 consecutive HIV-positive patients, not currently affected with active tuberculosis (TB), were recruited; 43 (86%) were male. The mean age was 38 ± 7.2 years (21–53). All had history of Bacillus Calmette Guerin (BCG) vaccination. A TST with purified protein derivative (PPD) and whole-blood interferon-gamma release assay (IGRA) in reaction to ESAT-6 and CFP-10 antigens was performed and measured by enzyme-linked immuno-sorbent assay (ELISA). The agreement between TST and QFT-G results were analyzed using Kappa test. RESULTS: A total of 36 (72%) patients had negative and 14 (28%) revealed positive TST. For QFT-G, 20 (40%) tested positive, 19 (38%) tested negative, and the results in 11 cases (22%) were indeterminate. A total of 14 (28%) patients had a CD4 count of <200. Of the 14, TST + group, 12 had QFT-G +, only one case TST+/QFT-G-, and QFT-G was indeterminate in one TST positive case. Of the 36 patients with negative TST tests, 8 (22%) had positive GFT-G and 10 (28%) yielded indeterminate results. There was no association between a positive TST and receiving highly active anti-retroviral therapy (HAART) or absolute CD4 counts. Similarly, the association between QFT-G results and receiving HAART or CD4 counts was not significant (P = 0.06). Although TST results were not significantly different in patients with CD4 < 200 vs. CD4 >200 (P = 0.295), association between QFT-G results and CD4 cutoff of 200 reached statistical significance (P = 0.027). Agreement Kappa coefficient between TST and QFT-G was 0.54 (Kappa = 0.54, 95% CI = 38.4-69.6,P < 0.001). CONCLUSION: Detecting LTBI in HIV-positive individuals showed moderate agreement between QFT-G and LTBI in our study. Interestingly, our findings revealed that nontuberculous mycobacteria and prior BCG vaccination have minimal influence on TST results in HIV patients in Iran.

Treatment outcome, mortality and their predictors among HIV-associated tuberculosis patients

The risk of death is significantly higher in HIV-infected patients with tuberculosis (TB). This study aims to evaluate the impact of demographic, clinical and laboratory characteristics on the treatment outcome and mortality of TB/HIV co-infected patients in a tertiary TB centre in Iran. In total, 111 patients were recruited from 2004 to 2007. Mycobacteriological studies and demographic, clinical, and laboratory data from all patients were analysed and predictors of unsuccessful outcomes as well as mortality were determined. The mean age for all 111 TB-HIV patients was 38 ± 9 years (range 22–70) and 107 (96.3%) were men; 104 (93.7%) had a history of drug abuse and 96 (86.4%) had a history of imprisonment. The method of HIV transmission was intravenous drug use in 88 (79.3%). Twenty-three (20.7%) had a history of Category 1 (CAT I) TB treatment and six (5.4%) Category 2 (CAT II) treatment. Combination antiretroviral therapy (cART) was given to 48 (43.2%). No significant associations were found between treatment outcomes or mortality and gender, smoking, drug and alcohol abuse, imprisonment, method of transmission, history of CAT I and CAT II treatments, CD4 counts or adverse effects (P > 0.05). Administration of cART led to significantly better outcomes (P < 0.001). Lower serum albumin levels and low body weight were significantly associated with mortality.

Impact of extensively drug-resistant tuberculosis on treatment outcome of multidrug-resistant tuberculosis patients with standardized regimen: report from Iran.

The limited experience in treating patients with extensively drug-resistant tuberculosis (XDR-TB) shows a therapeutic success rate under 50-60% and there are no publications regarding the outcome of these patients treated with standardized regimens. All multidrug-resistant tuberculosis (MDR-TB) patients hospitalized at the Masih Daneshvari Hospital in Tehran, Iran, during 2004-2007 were recruited. Drug susceptibility testing to 14 drugs (including eight second-line drugs) was performed and a standardized regimen with ofloxacin, cycloserine, prothionamide, and amikacin was administered for all patients. Outcome of the patients was studied, comparing between the MDR-TB non-XDR-TB and the XDR-TB. Fifty-one patients were included, 12 with XDR-TB criteria. Of 51, 48 were HIV negative and HIV status was unknown in three cases. All 12 were HIV negative. XDR-TB infection was significantly associated only with age (p = 0.039). The success rates for the total 51 MDR-TB, the 39 MDR-TB non-XDR-TB, and the 12 XDR-TB patients were 76.5% (39 patients), 87.2% (34 patients), and 41.7% (5 patients), respectively. Resistance to ofloxacin, ciprofloxacin, and amikacin were found to be significantly associated with unsuccessful outcome. In this setting, a standardized second-line drugs regimen produces high treatment success rates in MDR-TB patients unless XDR-TB is present.

Drug abuse profile - patient delay, diagnosis delay and drug resistance pattern - among addict patients with tuberculosis.

Socioeconomic problems limit the access of drug users to health-care services. This descriptive cross-sectional study was carried out by making use of the medical records of new case tuberculosis (TB) patients hospitalized at Masih Daneshvari Hospital, the national referral centre in Iran, from 2003 to 2006. Demographic and personal characteristics of the patients and type of disease were collected and categorized. Of the 944 patients with confirmed TB, 143 (15.1%) were drug users, among whom 140 (97.9%) were men with just three women drug users. The mean age of the drug users group was 43.04 ± 13.81 years. The type of drug used was opium in 100 cases (69.9%), heroin in 29 (20.3%), opium and heroin together in four (2.8%) and all three, opium, heroin and crack, in two (1.4%). For 238 high-risk patients, an HIV test was performed and HIV infection was confirmed in 33 cases. Patient delay was longer in drug users (P = 0.000) against other patients, whereas diagnosis delay was shorter (P = 0.007). Drug susceptibility tests were performed for 515 patients with positive cultures. One hundred and thirty-three (14.1%) were found to have ‘any resistance’ to anti-TB drugs, and 10 (1.1%) individuals had multidrug-resistant TB. Twenty-six (19.5%) of the individuals who showed resistance to first-line agents were drug users. There was no significant relation between drug resistance and drug use (P = 0.4). In conclusion, it seems that active case finding for TB and HIV in addict cases must be contained in harm reduction packages. Moreover, the manifestations of the disease should be considered seriously regardless of attributing them to drug use.

Revised Category II regimen as an alternative strategy for retreatment of Category I regimen failure and irregular treatment cases.

Currently, the Category (CAT) II regimen is recommended for patients who have failed the CAT I regimen. We have determined before that prevalence of multidrug-resistant tuberculosis (MDR TB) is relatively high among these patients. On the other hand, the retreatment success rate with CAT II in CAT I treatment failures and defaults is nearly 50%. Therefore, we tried to find another strategy with a higher success rate. From January 2004 to November 2007, 105 patients with pulmonary TB, who failed a prior CAT I regimen or with more than one course of irregular anti-TB treatment, were included in this study, whereas five cases with nontuberculous mycobacteria were excluded. Drug susceptibility testing (DST), for first line anti-TB drugs, and polymerase chain reaction were performed. By the time of availability of DST that took 3 to 4 months, a pilot protocol consisted of isoniazid, rifampin, ethambutol, ofloxacin, cycloserine, and amikacin was started. Then therapeutic regimen was adjusted based on four categories of DST pattern: sensitive, non-MDR pattern, MDR pattern, and culture-negative. Sensitive patients received the standard CAT I regimen, non-MDR patients an individualized regimen based on DST, MDR patients a standard second-line regimen, and culture-negatives a standard CAT I plus a 6-month injectable agent. Treatment outcomes were categorized and analyzed. Forty-eight patients with prior CAT I treatment failure and 52 with more than one irregular treatment courses were included in the analysis. Six percent of subjects had confirmed HIV infection. Seventy-two percent of subjects were assigned to a good outcome and 28% were assigned to a poor outcome group. Seventeen percent were culture-negative. Regarding DST pattern, 13% isolated strains were completely sensitive to first-line drugs. 53% strains were MDR, 10% monodrug-resistant, and 7% polydrug-resistant. There was no significant association between DST pattern and outcome (P = 0.13). The irregular regimen was associated with MDR TB as twice as CAT I regimen failure (69.2% versus 35.4%, P = 0.004). Patients with MDR TB significantly experienced more side effects than non-MDR-TBs (47% versus 27%, P = 0.102). Of 100 patients, 72% were cured, 5% abandoned treatment, 12% died, 6% were classified as treatment failures, 1% relapsed, and 5% were transferred out. Of 53 patients with MDR TB, 33 subjects were cured and seven died. All together, successful outcome was achieved in 62.2%, 76%, and 76% of MDR TB, non-MDR TB, and completely sensitive cases, respectively. A retreatment strategy based on DST and replacing the Category II regimen with an intermediate regimen called revised CAT II may improve clinical outcomes among Category I treatment failures and defaults who found to have active, infectious MDR TB. This strategy significantly reduces delays to MDR TB diagnosis and to the initiation of MDR TB therapy. Success rate of this strategy is 62.2% and 72% in MDR TB and overall CAT I failure cases and defaulters, respectively.

Standardised second-line treatment of multidrug-resistant tuberculosis during pregnancy.

We describe the efficacy and outcome of standardised second-line anti-tuberculosis (TB) medications during pregnancy. Treatment outcomes of five pregnant women with documented multidrug-resistant TB (MDR-TB) referred to the National Research Institute of Tuberculosis and Lung Diseases from 2003 to 2009 were analysed in two categories, maternal and neonatal. Patients became pregnant during treatment for MDR-TB without any changes in their anti-tuberculosis regimen. None of them had any adverse effects during pregnancy and delivery. No adverse effects were observed in mothers or neonates. The treatment of MDR-TB during pregnancy with a standardised second-line regimen in this study population was safe, with an acceptable rate of treatment success.We describe the efficacy and outcome of standardised second-line anti-tuberculosis (TB) medications during pregnancy. Treatment outcomes of five pregnant women with documented multidrug-resistant TB (MDR-TB) referred to the National Research Institute of Tuberculosis and Lung Diseases from 2003 to 2009 were analysed in two categories, maternal and neonatal. Patients became pregnant during treatment for MDR-TB without any changes in their anti-tuberculosis regimen. None of them had any adverse effects during pregnancy and delivery. No adverse effects were observed in mothers or neonates. The treatment of MDR-TB during pregnancy with a standardised second-line regimen in this study population was safe, with an acceptable rate of treatment success.

Coexisting venous thromboembolism in patients with tuberculosis12

Tuberculosis (TB) is one of the most devastating curable infectious diseases. [1] TB persists as a major cause of morbidity and mortality worldwide. Respiratory infections can increase the risk of venous thromboembolism (VTE). [2] Specifically, evidence exists about the hypercoagulability state in tuberculosis. [3,4] Hypercoagulability in tuberculosis patients may be due to the increase in plasma fibrinogen and factorVIII, and reactive thrombocytosis. [3]On theother hand, stasis might occur due to local compression of veins by the enlarged reactive lymph nodes or immobility caused by severe respiratory compromise, and there is some evidence regarding endothelial dysfunction in tuberculosis patients. [3–5] Endothelial injury may be a result of bodily reactions to Kochs Bacillus, or the use of Rifampin. [6] Being able to affect all the three components of the Virchows triad, TB could be a significant risk factor for VTE. However, few studies have addressed this potential relationship. Accordingly, this study was conducted to determine the relative frequency of VTE among TB patients in a regional referral hospital in Iran.