Epidemiology of multidrug-resistant, extensively drug resistant, and totally drug resistant tuberculosis in Middle East countries.

The 2015 represent the deadline for the global tuberculosis (TB) targets set through the Millennium Development Goals (MDG). From 2016 and onward, new goals were set to end the global TB epidemic via implementing new campaign entitled "the End TB Strategy". The major hurdle to end TB epidemic in several parts of the world is the emergence and spread of drug resistant Mycobacterium tuberculosis (MTB) strains. The better understanding of the actual global burden of drug resistant tuberculosis would feed into better implementing the End TB Strategy. In this article we summarize the current knowledge on the patterns of drug resistance tuberculosis cases in the Middle East countries. These countries are served by the Eastern Mediterranean Regional Office (EMRO), one out of six regional offices of World Health Organization. Middle East countries are characterized by geographic vicinity and population's interaction. However, they are dissimilar in several aspects such as economy and health infrastructures. Regarding economy, countries in this region are ranging from wealthy to very poor. Prevalence of tuberculosis and patterns drug resistance tuberculosis cases are also following variable trends within countries of this region. In almost all Middle East countries, there is under-reporting of drug-resistance tuberculosis cases. There are shortages in the infrastructures and facilities for detecting the pattern of drug-resistance tuberculosis. For instance, sixout of 14 countries have neither in-country capacity nor a linkage with a partner laboratory for second-line drug susceptibility testing and only 4 countries have registered site performing Xpert MTB/RIF.

Overview of drug-resistant tuberculosis worldwide.

Even in the 21st century, we are losing the battle against eradication of tuberculosis (TB). In 2015, 9.6 million people were estimated to have fallen ill with TB, of which 1.5 million people died. This is the real situation despite the well-structured treatment programs and availability of effective treatment options since the 1950s. The high mortality rate has been associated with other risk factors, such as the HIV epidemic, underlying diseases, and decline of socioeconomic standards. Furthermore, the problem of drug resistance that was recognized in the early days of the chemotherapeutic era raises serious concerns. Although resistance to a single agent is the most common type, resistance to multiple agents is less frequent but of greater concern. The World Health Organization estimated approximately 5% of all new TB cases involved multidrug-resistant (MDR)-TB. The estimation for MDR-TB is 3.3% for new cases, and 20.5% for previously treated cases. Failure to identify and appropriately treat MDR-TB patients has led to more dangerous forms of resistant TB. Based on World Health Organization reports, 5% of global TB cases are now considered to be extensively drug resistant (XDR), defined as MDR with additional resistance to both fluoroquinolones and at least one second-line injectable drug. XDR-TB had been reported by 105 countries by 2015. An estimated 9.7% of people with MDR-TB have XDR-TB. More recently, another dangerous form of TB bacillus was identified, which was named totally drug resistant (TDR-TB) or extremely drug resistant TB. These strains were resistant to all first- and second-line anti-TB drugs. Collectively, it is accepted that 2% of MDR-TB strains turn to be TDR-TB. This number, however, may not reflect the real situation, as many laboratories in endemic TB countries do not have proper facilities and updated protocols to detect the XDR or TDR-TB strains. Nevertheless, existing data emphasize the need for additional control measures, such as new diagnostic methods, better drugs, and more effective vaccines to prevent the spread of these strains around the world.

Modification of Acute Physiology and Chronic Health Evaluation II score through recalibration of risk prediction model in critical care patients of a respiratory disease referral center.

BACKGROUND: Several models have been developed to measure the severity of illness in intensive care unit (ICU) patients, It is suggested that the models should be customized depending on the characteristics of different population of patients. This study is aimed to assess and modify the performance of Acute Physiology and Chronic Health Evaluation II (APACHE-II) model in a respiratory diseases referral center. MATERIALS AND METHODS: A total of 730 patients, admitted to an intensive care unit during one year, were divided into two sets (71% training and 29% test). Our modified APACHE-II model was developed and calibrated on training set. Then, the integrity of the customized model was checked and compared to the original APACHE-II, on the test set. Logistic regression was used to develop ROC analysis, F-measure and kappa coefficient and were employed to calibrate the model. RESULTS: Both Original and Our modified APACHE-II scores performed acceptable discriminative power (AUC = 0.908: 95%CI 0.861-0.854; and AUC = 0.856: 95%CI 0.789-0.923, respectively); the difference was not significant (P = 0.132). Our modified APACHE-II showed improved accuracy (87.9% vs. 84.1%) and sensitivity (56.4% vs. 16.3%) compared to the original model. F-measure and Kappa also gave the impression of improvement for our modified APACHE-II system. CONCLUSION: The results demonstrated that a modified APACHE-II system in a local ICU of respiratory disease could have similar discrimination and comparable calibration to the original model.

Interferon-gamma receptor-1 gene promoter polymorphisms and susceptibility to leprosy in children of a single family.

The autosomal recessive disorder, because of a single mutation in interferon-γ receptor-1(IFNGR1) at position -56, was found to be associated with susceptibility to leprosy in children of the same family. The existence of such heterozygous carriers might explain the crucial role of IFNGR1 in the host defense against intracellular pathogens such as Mycobacterium leprae. The single nucleotide polymorphisms (SNPs) in major candidate genes, i.e., natural resistance-associated macrophage protein 1 (NRAMP1), vitamin D receptor (VDR), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-12-receptor 1 (IL-12R1), were not found to be associated with this disease.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Use of PCR and culture for detection of Mycobacterium tuberculosis in specimens from patients with normal and slow responses to chemotherapy.

In order to examine the utility of PCR as a tool for monitoring the response to short-course chemotherapy, clinical data from 162 tuberculosis patients with drug-susceptible cultures and variables associated with a slow response to antibiotic treatment were retrospectively evaluated. Initial samples were positive by smear in 106 patients and by PCR in 156 patients. A rapid response to therapy was found in 132 patients who had both smear and culture-negative results after 2 months of treatment. After 6 months of therapy, 5 other patients in this group were considered clinically cured but 20 patients had positive cultures. For these 20 patients with a slow response to therapy, treatment was continued for an additional 2-4 months and 15 patients were subsequently cured. However, of all the cured patients 7 had PCR-positive samples at the end of treatment. When these cases were correlated with therapeutic outcome, it was found that 3 of the PCR-positive but none of the PCR-negative patients had a clinical relapse during subsequent follow-up. We conclude that culture and PCR tests are highly informative when used to control the rate of response to therapy. A post-treatment positive result on PCR may be associated with a poor clinical outcome or may predict the likelihood of clinical relapse. Culture and PCR tests, as opposed to smear results, may be the key parameters for individually guiding the duration of treatment in TB patients with a poor response to standard therapy.