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.

Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma.

Asthma is a global health problem affecting around 300 million individuals of all ages, ethnic groups and countries. It is estimated that around 250,000 people die prematurely each year as a result of asthma. Concepts of asthma severity and control are important in evaluating patients and their response to treatment, as well as for public health, registries, and research (clinical trials, epidemiologic, genetic, and mechanistic studies), but the terminology applied is not standardized, and terms are often used interchangeably. A common international approach is favored to define severe asthma, uncontrolled asthma, and when the 2 coincide, although adaptation may be required in accordance with local conditions. A World Health Organization meeting was convened April 5-6, 2009, to propose a uniform definition of severe asthma. An article was written by a group of experts and reviewed by the Global Alliance against Chronic Respiratory Diseases review group. Severe asthma is defined by the level of current clinical control and risks as "Uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity (including impaired lung function or reduced lung growth in children)." Severe asthma includes 3 groups, each carrying different public health messages and challenges: (1) untreated severe asthma, (2) difficult-to-treat severe asthma, and (3) treatment-resistant severe asthma. The last group includes asthma for which control is not achieved despite the highest level of recommended treatment and asthma for which control can be maintained only with the highest level of recommended treatment.

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.

Representative drug susceptibility patterns for guiding design of re-treatment regimens for multidrug-resistant tuberculosis in Iran.

BACKGROUND AND OBJECTIVE: The prevalence of multidrug-resistant tuberculosis (MDR-TB) has increased substantially in the past 20 years, however, there are no data specific to Iran. This study investigated patients suspected to have MDR-TB, attending the TB referral hospital in Iran. METHODS: All patients suspected of having MDR-TB on hospital admission in the period 2003-2005 were included in this study. Sputum from all patients was tested for smear and culture, and drug sensitivity testing was performed using the proportion method. Patients were categorized into three groups based on their history of medical treatment. Group I consisted of patients with CAT I regimen failure; Group II consisted of patients with a history of CAT II regimen failure and Group III comprised patients with a history of more than two courses of irregular CAT I anti-TB regimen. RESULTS: There were 105 patients recruited; 32 in Group I, 53 in Group II and 20 in Group III. There were no significant differences between the three groups in their resistance to first-line anti-TB drugs. Fifty-five patients were diagnosed with MDR-TB. The prevalence of MDR-TB was 56% (18 cases) in group I, 49% (26 cases) in group II and 55% (11 cases) in group III. No significant difference in the pattern of drug resistance was observed between the three groups. CONCLUSION: The prevalence of MDR-TB was high in this study. The lack of response of MDR-TB patients to CAT II treatment indicates that antibiotic sensitivity testing is essential in patients with CAT I treatment failure.

Trends of drug resistant Mycobacterium tuberculosis in a tertiary tuberculosis center in Iran.

OBJECTIVE: To determine the drug resistance pattern to first line antituberculous drugs in National Research Institute of Tuberculosis and Lung Disease and to compare resistant rates with previous studies. METHODS: An anterograde cross-sectional study was performed. The study includes all adults with documented pulmonary tuberculosis (TB) that were hospitalized in National Research Institute of Tuberculosis and Lung Disease in Tehran, from June 2003 to September 2004. Demographic characteristic, TB categories, and drug susceptibility test results were recorded. Two previous studies regarding drug susceptibility in Iran were selected as historical controls. RESULTS: One hundred and ninety-six new cases and 68 previously treated patients were enrolled in the study. The strains of 61% of new patients and 21% of previously treated patients were fully sensitive to all drugs. The most common resistance was streptomycin (27%) followed by isoniazid (23%) in new cases. Multiple drug resistant strains were noted in 2.6% (95% CI 0.8% to 5.8%) of new cases versus 56% (95% CI 43% to 68%) in previously treated group. The frequency of primary drug resistance to isoniazid was 9.8%-15% or streptomycin 9.8%-13% in the previous studies (p<0.00001). CONCLUSION: While these rates may not reflect the true prevalence of drug resistance on a national scale, it does partially demonstrate some defects in the existing tuberculosis control program. The significant increase of isoniazid and streptomycin resistance in the last few years would present a serious challenge to effective management of TB.

Extensively drug-resistant tuberculosis treatment outcome in Iran: a case series of seven patients.

BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB) has recently been identified as a major threat to global health. XDR-TB poses a risk of higher failure rates and death during TB treatment. We report herein the outcomes of XDR-TB in patients treated with the standardized regimen in Iran. PATIENTS AND METHODS: Between 2002 and 2006, seven patients were diagnosed with XDR-TB. All patients were treated with the standardized second-line regimen containing cycloserine, prothionamide, amikacin, and ofloxacin. First-line drugs, such as ethambutol and pyrazinamide, were added to the regimen if drug susceptibility testing showed sensitivity to these drugs. RESULTS: Four (57.1%) patients were male. All seven patients were HIV-negative. The patient age range was 22-79 years. Of the seven cases, the final outcome was 'cure' in two (28.6%), 'relapse' in one, 'treatment failure' in one, and 'death' in two; the outcome for one patient was unknown. CONCLUSION: Our study shows a poor prognosis in patients with XDR-TB. This indicates the necessity of detecting XDR-TB cases earlier, as well as the need to gain access to more second-line agents. This is particularly important in resource-limited settings in order to administer individualized regimens.

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.

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.

Is standardized treatment appropriate for non-XDR multiple drug resistant tuberculosis cases? A clinical descriptive study.

The clinical relevance of second-line drug susceptibility test (DST) results with respect to treatment outcome is unknown in non-XDR MDR patients. This study was carried out in the sole national referral centre for TB in Iran between 2002 and 2006. Multidrug-resistant tuberculosis (MDR-TB) patients who had DST to second-line drugs were included. For all MDR-TB patients the standard second-line regimen was initiated. Outcome of treatment based on DST to second-line drugs was analysed. 53 patients were included. DST for second-line drugs was available for 40 patients. Seven patients returned to Afghanistan during treatment. Among the remainder, 13 (30.4%) cases were Iranian. Mean age was 40.8 + 19.7 y. The relatively small sample size imposes some limitations on this study. However, in this study, there was no difference in resistance to second-line drugs by nationality. No significant correlation was seen between resistance to second-line drugs and outcome of treatment. In conclusion, the treatment outcome according to WHO definitions was appropriate in the study population by the use of standardized treatment regimens. Follow-up studies on a long-term basis are however needed in order to detect possible relapses.

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.

Inherited disorders of the IL-12-IFN-gamma axis in patients with disseminated BCG infection.

Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.

Primary immune deficiencies presenting in adults: seven years of experience from Iran.

Primary immunodeficiencies (PIDs) are not solely diseases of childhood. We describe the clinical presentation and outcome for 55 adult patients with previously unrecognized PIDs. This series provides unique data regarding PIDs presenting in adulthood, and serves as a timely reminder that physicians must consider the diagnosis of PIDs in their adult patients. Using the experience gained from these patients, we outline key "warning signs" suggestive of an underlying PID. Only through increased physician awareness will patients with PIDs receive timely diagnosis and optimal management.

Arylamine N-acetyltransferase 2 slow acetylator polymorphisms in unrelated Iranian individuals.

OBJECTIVE: To determine the frequency of mutations at the polymorphic gene coding for arylamine N-acetyltransferase 2 (NAT2, EC 2.3.1.5) and NAT2 genotypes associated with slow acetylation in healthy Iranian individuals. METHODS: The polymorphisms in the NAT2 gene from 88 unrelated healthy subjects (48 men/40 women) from the general Tehran population were discriminated using polymerase chain reaction (PCR) with allele-specific primers (341 C > T) and PCR-restriction fragment length polymorphism analysis (481 C > T, 590 G > A, and 857 G > A). RESULTS: Frequencies of the studied polymorphisms showed the most common alleles to be NAT2*4 (0.43) and NAT2*5, 481 C > T (0.32), followed by NAT2*6 (0.19) and NAT2*7 (0.06), previously referred to as WT, M1, M2, and M3, respectively. The most prevalent genotypes were NAT2*4/*5 [(31.8%; 95% confidence interval (CI): 29-34%] and *4/*4 (18.2%; 95% CI: 16-21%). When grouped according to the expected phenotypical effects, the resulting genotypes revealed the significant prevalence of the subjects with slow (32.9%) and intermediate (48.9%) acetylation status compared with wild-type rapid (18.2%) acetylators (P < 0.01). CONCLUSIONS: The overall allele pattern and acetylator status distribution in Iranians displayed the considerable prevalence of "slow acetylators" over "rapid acetylators," similar to those of Caucasians except for a minor difference observed in the frequency of the NAT2*7 allele. Nucleic acid testing for common NAT2 mutations might be a potentially useful tool for an accurate phenotype interpretation and identification of Iranian individuals at risk.