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Firoozeh F, Firoozeh A, Salmani A. An Update on the Prevalence of Nontuberculous Mycobacteria in Clinical Samples in Iran during 2000-2022: A Systematic Review and Meta-Analysis. mljgoums 2023; 17 (3) :22-31
URL: http://mlj.goums.ac.ir/article-1-1491-en.html
URL: http://mlj.goums.ac.ir/article-1-1491-en.html
1- Department of Microbiology, Islamic Azad University of Damghan, Damghan, Iran
2- Mashhad Uni Meed Sci , arez90fir89@yahoo.com
3- Gerash Uni Med Sci
2- Mashhad Uni Meed Sci , arez90fir89@yahoo.com
3- Gerash Uni Med Sci
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Figure 2- Forest plot of the meta-analysis of epidemiology of NTM in clinical samples from Iran
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Figure 3-Funnel plot of the meta-analysis of epidemiology of NTM in clinical samples from Iran
DISCUSSION
Since many studies do not consider infections caused by NTMs as a public health problem, there is not enough data about these microorganisms and their frequency distribution, at least in Middle Eastern and third-world countries. This has made developing infection control strategies challenging (21).
Our review showed that the prevalence of NTM in clinical samples varied from 0.1 to 72.7%. As mentioned in the results, the majority of NTM were isolated from respiratory and bronchoalveolar lavage samples. These findings emphasize the importance of identifying NTM from suspected pulmonary TB patients (22). In line with our findings, a study from Saudi Arabia reported that pulmonary (54.7%) and bronchial lavage/wash (22.1%) specimens were predominant (23). The difference in the prevalence of NTM in the studies reviewed in our survey might be due to the difference in the molecular techniques used in each study, the geographic region, types of clinical specimens, laboratory personnel skills, sanitation, and living conditions (4).
We showed that the combined prevalence of NTM isolated from clinical samples in Iran was 4.5% during 2000-2022. Because the manifestations of NTM and TB are similar and all NTM are acid-fast and cannot be segregated by phenotypic methods, NTM may be mistaken for TB. Moreover, diseases caused by NTM typically do not respond to anti-TB drugs (24). Furthermore, in some cases, patients with multi-drug resistant TB were in fact infected with NTM (25).
Reports should be interpreted with caution because it is often challenging to determine whether NTM are the real source of infection (1). In line with our results, the study from Saudi Arabia reported a prevalence rate of 1.4% for NTM (23). Studies by Pokam et al. (12) and Aliyu et al. (11) in Nigeria reported prevalence rates of 16.5% and 15%, respectively. However, higher prevalence rates were reported in studies from Canada (33%) and the Netherlands (25%) (26, 27). A systematic review and meta-analysis published by Nasiri et al. in 2015 reported a pooled prevalence rate of 10.2% in Iran, which is higher than the rate found in our study (11.2%). This could be related to the source of NTM because our study was focused on clinical samples, but the mentioned study was focused on suspected TB patients (18). In recent years, the reports of NTM have been rising, mainly because of the active search for NTM species, improvements in culture methods (28), and most importantly, the use of sensitive molecular techniques (22, 29).
Here, we detected a combined prevalence rate of 4.5% in clinical specimens, which is similar to the rate reported by Khaledi et al. in Iran in 2016 (2). Subgroup analysis in our review showed that the combined prevalence of M. simiae (35.8%), M. intracellulare (19%), and M. kansasii (13.4%) was highest among SGM, while M. fortuitum (24.6%), M. terrae (18.5%), and M. gastri (15.9%) were the most prevalent RGM. Evidence suggests that RGM species are among the most predominant NTM associated with nosocomial infections (40). As described by previous reports, tap water, dialysis water provided from tap water, drinking water, shower water, and piped water systems in clinical settings are the common sources of NTM-related nosocomial infections (30). In addition, RGM are relatively resistant to standard disinfectants such as chlorine, alkaline glutaraldehydes, and antimicrobial agents compared to M. tuberculosis; thus, their eradication is more difficult (31).
In line with our study, a previous review on the distribution of NTM species among environmental and clinical samples in the Middle East reported that 58.7% of isolates were SGM and 41.2% were RGM. This study also reported similar prevalence rates for SGM (56.4%) and RGM (44.6%) in Iran (21). Moreover, this study reported M. fortuitum (60.1%) as the most prevalent RGM isolated from clinical specimens in the Middle East (30). M. fortuitum was detected in 71.9%, 54.4%, 46.6%, and 48.9% of RGM isolates from Iran, Saudi Arabia, Turkey, and Pakistan, respectively (6). Other reports from Iran’s neighboring countries (Saudi Arabia and Kuwait) also found M. fortuitum as the predominant isolate (23, 32). The proportion of RGM in pulmonary diseases from Iran and other Asian countries is much higher than in European and North American countries (18, 22, 33). For example, studies from the Netherlands and the United States reported a prevalence rate of 3% and 5% for RGM, respectively (26, 34).
In our study, M. simiae was found as the most predominant SGM among NTM isolates. This finding is in agreement with the results of previous reviews from Iran (18, 22). On the contrary, in developed countries, M. avium complex has been described as the most common NTM species (35). It is noteworthy to mention that M. simiae is an endemic SGM in Iran. It is often not distinguishable from TB complex due to its similar clinical and radiologic manifestations as well as the lack of response to anti-TB drugs (36). Therefore, it is recommended to consider M. simiae in cases where anti-TB treatment does not respond (37). The spread of diseases caused by mycobacteria, especially respiratory diseases, and the possible inappropriate treatment imposes a lot of costs on both patients and health systems. Nevertheless, most laboratories do not have accurate diagnostic criteria for NTM owing to the lack of appropriate equipment and qualified experts (1). In recent studies, the increased use of molecular methods has increased the accuracy of NTM diagnosis (38). National TB reference laboratories necessitate standardizing existing protocols for the identification of NTM in Middle Eastern countries (21, 39). Thus, given the rising importance of NTM, quick and precise identification of NTM is of great importance for active management strategy against NTM Infections (21). The main limitation of the present study was that studies published in languages other than English and Persian have not been included in the analysis. Another limitation was that the protocol of this systematic review and meta-analysis was not registered in a standard platform like Cochrane or Prospero.
CONCLUSION
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INTRODUCTION
Nontuberculosis mycobacteria (NTM) are described as mycobacterial pathogens other than
Mycobacterium tuberculosis (MOTT) and Mycobacterium leprae strains. They are a heterogeneous group of bacteria that cause a fundamental but frequently unvalued global burden of disease (1, 2). These ubiquitous bacteria have a high prevalence in the environment. There is ample evidence that these microorganisms originate from the environment. In the 1980s, NTM was identified as a human pathogen (3, 4). Although most NTM are saprophytes, one-third of them are related to human diseases (5). Generally, most NTM are aerobic, immotile bacteria with a firm and dense cell wall (6). The thickness of NTM cell wall functions as a natural protective shield against disinfectants and antibiotics (7). Therefore, NTM grow in most environments around humans. The increasing rate of infections caused by NTMs may be related to the presence of NTMs in domestic and animal products, medical devices, drinking water systems, water tanks, and shower streams (8).
Infections caused by NTM are relatively uncommon and often reported in immunocompromised persons (9). Certain features of NTM are similar to M. tuberculosis that make NTM difficult to differentiate (10). Nevertheless, NTM usually do not respond to common tuberculosis (TB) drug regimens, causing misdiagnosis and poor treatment, especially in low-resource settings (11). Current evidence advises that diseases resulting from NTM are much more prevalent globally than previously believed, and possibly rising in frequency worldwide (12). A report from Canada showed that the incidence of NTM was 150,000 cases per year (13).
In 1959, Ernest Runyon classified NTM based on growth rates, colony morphology, and pigmentation (14). Accordingly, NTM were categorized into four groups: rapid growers (groups I to III) and slow growers (group IV) (15, 16). Slowly growing species (SGM) typically require more than 7 days before colonies become visible on solid media, while rapidly growing species (RGM) form colonies on selective media within 2–5 days (17). These organisms cause four distinct clinical diseases, including progressive pulmonary disease, superficial lymphadenitis, disseminated diseases of the skin, and soft tissue infections (17).
The subject of NTM is particularly troubling in developing countries owing to limited published information and unsuitable identification. Meta-analysis studies on the prevalence of NTM have been previously conducted in Iran. Given that the last meta-analysis on this subject dates back to 2016 (18), this study aimed to investigate the prevalence of NTM in clinical samples during 2000-2022.
MATERIALS AND METHODS
This systematic review and meta-analysis was conducted by reviewing published studies on the prevalence of NTM among clinical samples in Iran. The study was carried out according to Preferred Reporting Items for Meta-Analyses and Systematic Reviews (PRISMA) protocol. The search was performed only for original cross-sectional studies in Persian and English that have been published between January 2000 and 2022 in international electronic databases, such as Scopus, PubMed, Web of Science, Google Scholar, and Scientific Information Database, IranMedex, Magiran, and IranDoc. The search process was according to the combination of Medical Subject Headings (MeSH) text words such as “non-tuberculosis mycobacteria”, “NTM”, “MOTT”, “atypical mycobacterium”, “RGM”, “SGM”, and “Iran”.
As an example among the different databases, the search strategy strings in PubMed are summarized as follows; Non-tuberculosis Mycobacteria (MeSH Terms) OR atypical mycobacterium (MeSH Terms) OR NTM (Title/Abstract), MOTT (MeSH Terms)) AND (rapid-growing mycobacterium (MeSH Terms) OR RGM (Title/Abstract)), AND (slow-growing
Mycobacterium (MeSH Terms), OR SGM (Title/Abstract)). All searches were performed in Persian databases with Persian equivalent words with the same strategy. In addition, the reference section of the original and review studies was screened to find further articles for inclusion in the present systematic review and meta-analysis. All of these searches have completed by two researchers individually.
Duplicates were initially identified and eliminated after entering all the recognized studies into a self-created database. After that, the articles were assessed by two reviewers (AF and AS) by screening titles, abstracts, topics, and finally full texts. At each level, the reviewers independently screened the articles and finally merged their conclusions. Discrepancies were resolved by discussion before finalizing the records for the next level. In case of disagreements, a third assessor was assigned to make a decision. Finally, the studies were assessed for eligibility before the final selection.
We included studies that met the following eligible inclusion criteria: (1) original data, (2) studies on the prevalence of NTM, and (3) studies with accepted standard methods including growth in Lowenstein-Jensen media containing p-nitrobenzoate or thiophene-carboxylic acid hydrazide, growth rate, pigment production, growth at 42 °C and 44 °C, tellurite reduction, arylsulfatase activity, tween hydrolysis, nitrate reduction, catalase, urease, tolerance to the NaCl 5%, and molecular methods such as PCR-RFLP (PRA hsp65), sequencing of hsp, PCR and sequencing of 16s rRNA, multiplex allele-specific PCR (MAS-PCR), Line Probe Assay (LPA), PCR and sequencing rpoB gene, sequencing erm gen, multilocus sequence analysis of 16S rRNA, rpoB, and ITS genes. Reviews, case reports, and conference abstracts were excluded. , studies not performed according to the accepted standard methods.
The studies’ quality was assessed using the criteria specified in Critical Appraisal Skills Programmed checklists (www.casp-UK) (19). This assessment is based on answers to 10 questions designed for each study. If any query data was available, the answer was ‘yes’. In case of doubt or lack of appropriate answer, the answer was ‘no’ or ‘cannot tell’. Based on the number of questions answered "yes", the studies were classified into three categories: good (score of 8-10), moderate (score of 6-8), and poor (score of <6) (20). Finally, weakly scored studies were not enrolled in the study.
In this review, two researchers independently extracted the data including the first author, study’s time, publication time, geographic location, NTM, methods, and mean age of patients. Meta-analysis was conducted for determining the prevalence of NTM at 95% confidence interval (CI) by comprehensive meta-analysis (V2.0, Biostat, Englewood, NJ, USA).
Random effect model was used and tested with Cochran’s Q test and I2 to determine the possibility of heterogeneity between studies. Egger weighted regression test was applied for the statistical assessment of publication bias, and p-values less than 0.05 were considered statistically significant. In addition, funnel plot was used to evaluate publication bias in the studies.
RESULTS
As shown in figure 1, 1,078 articles were retrieved through database searches. After excluding 452 duplicate articles, 626 studies were assessed, 201 of which were removed because of title or abstract irrelevance. Next, 425 full texts were evaluated for content and method. Finally, 26 eligible studies were systematically reviewed and analyzed.
The characteristics of the included studies are summarized in table 1. The mean age of patients positive for NTM was between 11 and 80 years. Geographic locations included Tehran, Kashan, Khuzestan, Tabriz, Yazd, Golestan, Kermanshah, Mashhad, and Hormozgan (Table 1).
All included studies used conventional methods for the detection of mycobacteria. These methods were growth in Lowenstein-Jensen media containing p-nitrobenzoate or thiophene-carboxylic acid hydrazide, growth rate, pigment production, growth at 42 °C and 44 °C, tellurite reduction, arylsulfatase activity, tween hydrolysis, nitrate reduction, catalase, urease, and tolerance to the NaCl 5%. The majority of NTM were isolated from respiratory and bronchoalveolar lavage samples.
Our review showed that the prevalence of NTMs in positive mycobacterial cultures varied from 0.1 to 72.7%. As shown in table 2 and figure 2, the combined prevalence of NTM in clinical samples was 4.5% (95% Cl: 3.1-6.5, Q = 1562.7, Z = 15.2, I2 =98.4, and p=0.00).
According to funnel plot, publication bias was visually found among the included studies (Figure 3). Egger’s weighted regression test results also suggested the presence of bias in the studies (p=0.6). Therefore, there is a possibility of publication bias due to the existence of small studies included in this review.
As reported in table 2, the most common SGM among NTM species were Mycobacterium simiae [35.8% (95% CI 16.4-44.4)], Mycobacterium intracellulare [19% (95% CI 8.7-28.3)], and Mycobacterium kansasii [13.4% (95% CI 7.3-24.3)], while Mycobacterium fortuitum [24.6% (95% CI 12.9-46.7)], Mycobacterium terrae [18.5 % (95% CI 11.5-29.2)], and Mycobacterium gastri [15.9%(95% CI6.0-41.2)] were the most prevalent RGM among NTM species.
Table 1-Characteristics of the studies included in the review
Nontuberculosis mycobacteria (NTM) are described as mycobacterial pathogens other than
Mycobacterium tuberculosis (MOTT) and Mycobacterium leprae strains. They are a heterogeneous group of bacteria that cause a fundamental but frequently unvalued global burden of disease (1, 2). These ubiquitous bacteria have a high prevalence in the environment. There is ample evidence that these microorganisms originate from the environment. In the 1980s, NTM was identified as a human pathogen (3, 4). Although most NTM are saprophytes, one-third of them are related to human diseases (5). Generally, most NTM are aerobic, immotile bacteria with a firm and dense cell wall (6). The thickness of NTM cell wall functions as a natural protective shield against disinfectants and antibiotics (7). Therefore, NTM grow in most environments around humans. The increasing rate of infections caused by NTMs may be related to the presence of NTMs in domestic and animal products, medical devices, drinking water systems, water tanks, and shower streams (8).
Infections caused by NTM are relatively uncommon and often reported in immunocompromised persons (9). Certain features of NTM are similar to M. tuberculosis that make NTM difficult to differentiate (10). Nevertheless, NTM usually do not respond to common tuberculosis (TB) drug regimens, causing misdiagnosis and poor treatment, especially in low-resource settings (11). Current evidence advises that diseases resulting from NTM are much more prevalent globally than previously believed, and possibly rising in frequency worldwide (12). A report from Canada showed that the incidence of NTM was 150,000 cases per year (13).
In 1959, Ernest Runyon classified NTM based on growth rates, colony morphology, and pigmentation (14). Accordingly, NTM were categorized into four groups: rapid growers (groups I to III) and slow growers (group IV) (15, 16). Slowly growing species (SGM) typically require more than 7 days before colonies become visible on solid media, while rapidly growing species (RGM) form colonies on selective media within 2–5 days (17). These organisms cause four distinct clinical diseases, including progressive pulmonary disease, superficial lymphadenitis, disseminated diseases of the skin, and soft tissue infections (17).
The subject of NTM is particularly troubling in developing countries owing to limited published information and unsuitable identification. Meta-analysis studies on the prevalence of NTM have been previously conducted in Iran. Given that the last meta-analysis on this subject dates back to 2016 (18), this study aimed to investigate the prevalence of NTM in clinical samples during 2000-2022.
MATERIALS AND METHODS
This systematic review and meta-analysis was conducted by reviewing published studies on the prevalence of NTM among clinical samples in Iran. The study was carried out according to Preferred Reporting Items for Meta-Analyses and Systematic Reviews (PRISMA) protocol. The search was performed only for original cross-sectional studies in Persian and English that have been published between January 2000 and 2022 in international electronic databases, such as Scopus, PubMed, Web of Science, Google Scholar, and Scientific Information Database, IranMedex, Magiran, and IranDoc. The search process was according to the combination of Medical Subject Headings (MeSH) text words such as “non-tuberculosis mycobacteria”, “NTM”, “MOTT”, “atypical mycobacterium”, “RGM”, “SGM”, and “Iran”.
As an example among the different databases, the search strategy strings in PubMed are summarized as follows; Non-tuberculosis Mycobacteria (MeSH Terms) OR atypical mycobacterium (MeSH Terms) OR NTM (Title/Abstract), MOTT (MeSH Terms)) AND (rapid-growing mycobacterium (MeSH Terms) OR RGM (Title/Abstract)), AND (slow-growing
Mycobacterium (MeSH Terms), OR SGM (Title/Abstract)). All searches were performed in Persian databases with Persian equivalent words with the same strategy. In addition, the reference section of the original and review studies was screened to find further articles for inclusion in the present systematic review and meta-analysis. All of these searches have completed by two researchers individually.
Duplicates were initially identified and eliminated after entering all the recognized studies into a self-created database. After that, the articles were assessed by two reviewers (AF and AS) by screening titles, abstracts, topics, and finally full texts. At each level, the reviewers independently screened the articles and finally merged their conclusions. Discrepancies were resolved by discussion before finalizing the records for the next level. In case of disagreements, a third assessor was assigned to make a decision. Finally, the studies were assessed for eligibility before the final selection.
We included studies that met the following eligible inclusion criteria: (1) original data, (2) studies on the prevalence of NTM, and (3) studies with accepted standard methods including growth in Lowenstein-Jensen media containing p-nitrobenzoate or thiophene-carboxylic acid hydrazide, growth rate, pigment production, growth at 42 °C and 44 °C, tellurite reduction, arylsulfatase activity, tween hydrolysis, nitrate reduction, catalase, urease, tolerance to the NaCl 5%, and molecular methods such as PCR-RFLP (PRA hsp65), sequencing of hsp, PCR and sequencing of 16s rRNA, multiplex allele-specific PCR (MAS-PCR), Line Probe Assay (LPA), PCR and sequencing rpoB gene, sequencing erm gen, multilocus sequence analysis of 16S rRNA, rpoB, and ITS genes. Reviews, case reports, and conference abstracts were excluded. , studies not performed according to the accepted standard methods.
The studies’ quality was assessed using the criteria specified in Critical Appraisal Skills Programmed checklists (www.casp-UK) (19). This assessment is based on answers to 10 questions designed for each study. If any query data was available, the answer was ‘yes’. In case of doubt or lack of appropriate answer, the answer was ‘no’ or ‘cannot tell’. Based on the number of questions answered "yes", the studies were classified into three categories: good (score of 8-10), moderate (score of 6-8), and poor (score of <6) (20). Finally, weakly scored studies were not enrolled in the study.
In this review, two researchers independently extracted the data including the first author, study’s time, publication time, geographic location, NTM, methods, and mean age of patients. Meta-analysis was conducted for determining the prevalence of NTM at 95% confidence interval (CI) by comprehensive meta-analysis (V2.0, Biostat, Englewood, NJ, USA).
Random effect model was used and tested with Cochran’s Q test and I2 to determine the possibility of heterogeneity between studies. Egger weighted regression test was applied for the statistical assessment of publication bias, and p-values less than 0.05 were considered statistically significant. In addition, funnel plot was used to evaluate publication bias in the studies.
RESULTS
As shown in figure 1, 1,078 articles were retrieved through database searches. After excluding 452 duplicate articles, 626 studies were assessed, 201 of which were removed because of title or abstract irrelevance. Next, 425 full texts were evaluated for content and method. Finally, 26 eligible studies were systematically reviewed and analyzed.
The characteristics of the included studies are summarized in table 1. The mean age of patients positive for NTM was between 11 and 80 years. Geographic locations included Tehran, Kashan, Khuzestan, Tabriz, Yazd, Golestan, Kermanshah, Mashhad, and Hormozgan (Table 1).
All included studies used conventional methods for the detection of mycobacteria. These methods were growth in Lowenstein-Jensen media containing p-nitrobenzoate or thiophene-carboxylic acid hydrazide, growth rate, pigment production, growth at 42 °C and 44 °C, tellurite reduction, arylsulfatase activity, tween hydrolysis, nitrate reduction, catalase, urease, and tolerance to the NaCl 5%. The majority of NTM were isolated from respiratory and bronchoalveolar lavage samples.
Our review showed that the prevalence of NTMs in positive mycobacterial cultures varied from 0.1 to 72.7%. As shown in table 2 and figure 2, the combined prevalence of NTM in clinical samples was 4.5% (95% Cl: 3.1-6.5, Q = 1562.7, Z = 15.2, I2 =98.4, and p=0.00).
According to funnel plot, publication bias was visually found among the included studies (Figure 3). Egger’s weighted regression test results also suggested the presence of bias in the studies (p=0.6). Therefore, there is a possibility of publication bias due to the existence of small studies included in this review.
As reported in table 2, the most common SGM among NTM species were Mycobacterium simiae [35.8% (95% CI 16.4-44.4)], Mycobacterium intracellulare [19% (95% CI 8.7-28.3)], and Mycobacterium kansasii [13.4% (95% CI 7.3-24.3)], while Mycobacterium fortuitum [24.6% (95% CI 12.9-46.7)], Mycobacterium terrae [18.5 % (95% CI 11.5-29.2)], and Mycobacterium gastri [15.9%(95% CI6.0-41.2)] were the most prevalent RGM among NTM species.
Table 1-Characteristics of the studies included in the review
| First author (reference) | Time of study | Date of publication | Location | Sample size | NTM Number (%) | Identification methods | Mean age of patient (years) | |
| Derakhshani Nejad(40) | 2003-11 | 2014 | Tehran | 8322 | 124 | Conventional tests, PCR-RFLP |
57 ±18.9 | |
| Heidari(41) | 2007-8 | 2009 | Tehran | 371 | 43 | Conventional tests, PCR-RFLP |
14-80 | |
| Nasiri(42) | 2010-12 | 2014 | Tehran | 6426 | 9 | Conventional tests, sequencing |
11-80 | |
| Javid(43) | 2007- 8 | 2009 | Golestan | 104 | 17 | Conventional tests, sequencing |
14 ≤65 | |
| Shafipour(44) | 2010-11 | 2013 | Golestan | 336 | 16 | Conventional tests | 44 ±23.3 | |
| Moghtaderi(45) | 2000-10 | 2011 | Tabriz | 235 | 15 | Conventional tests | - | |
| Heidar Nejad(46) | 2001 | 2001 | Tabriz | 165 | 10 | Conventional tests | 44.01±18.23 | |
| Naserpour Farivar(47) |
2002- 4 | 2006 | Sistan- Baluchestan | 210 | 59 | Conventional tests | 20 ≤60 | |
| Naderi(48) | 2003- 4 | 2006 | Sistan- Blochestan |
150 | 20 | Conventional tests | - | |
| Namaei (49) | 2002 | 2003 | R.Khorasan | 1700 | 8 | Conventional tests | - | |
| Hashemi-Shahraki (50) | 2008-12 | 2014 | Khuzestan | 2313 | 92 | Conventional tests, sequencing |
- | |
| Hashemi- Shahraki(51) |
2009-12 | 2013 | khuzestan | 190 | 23 | Conventional tests, sequencing |
48.3-57.1 | |
| Khosravi(52) | 2007-8 | 2009 | Khuzestan | 150 | 8 | Conventional tests PCR-RFLP |
24-36 | |
| Yazdi(53) | 2009-10 | 2012 | Yazd | 32 | 1 | Conventional tests | ||
| Zilaee(54) | 2012-15 | 2016 | Kashan | 106 | 4 | PRA hsp65 | - | |
| Nour-Neamatollahie(55) | 2011-13 | 2017 | Tehran | 10,377 | 59 | PCR-RFLP (PRA hsp65 | 50.9 ± 7.6 | |
| Nasiri(56) | 2014-16 | 2018 | Tehran | 410 | 56 | PCR-RFLP (PRA hsp65) | 50.9 ± 7.6 | |
| Nasiri(57) | 2016-17 | 2018 | Tehran | 230 | 12 | hsp 65- PRA, sequencing of 16S rRNA, rpoB, and ITS genes |
51.4 | |
| Irandoost(58) | 2014-16 | 2018 | Tehran | 6800 | 64 | PRA and sequencing of hsp65 | - | |
| Aghajani(59) | 2011-19 | 2019 | Tehran | 15829 | 591 | hsp65- PRA, sequencing 16S rRNA, rpoB |
50.7 ±18.4 | |
| Mortazavi(60) | 2015-17 | 2019 | Tehran | 478 | 53 | hsp65-PRA, sequencing 16S rRNA, rpoB |
43.4 ±15.7 | |
| Davari(61) | 2013-15 | 2018 | Tehran | 520 | 61 | Multilocus sequence analysis of 16S rRNA, 2rpoB, and ITS genes |
49.6 ± 16.6 | |
| Karami-Zarandi(62) | 2017-19 | 2019 | Tehran | 5061 | 60 | LPA, PCR and sequencing 16s rRNA |
58.3±18.3 | |
| Khosravi(63) | 2016-18 | 2018 | Khuzestan Kermanshah Hormozgan |
55 | 40 | PCR and sequencing rpoB gene, sequencing erm gene | 47.4 ±19.9 | |
| Ayoubi(64) | 2011- 18 | 2021 | Tehran | 15771 | 658 | (RFLP)-PCR of a hsp65 fragment, Nested-PCR | - | |
| Shafipour(65) | 2016-18 | 2021 | Gorgan | 2994 | 12 | Conventional tests, PCR(16S rRNA gene) | 59.9 ± 16.9 |
| Subgroups | Number of studies | Heterogeneity test | Egger’s test | Random model | |||||||
| Prevalence (95% CI) | Z | p | Q | p | I | t | p | ||||
| Combined NTM | 26 | 4.5(3.1-6.5) | 15.2 | 0.00 | 1562.7 | 0.00 | 98.4 | 0.5 | 0.6 | ||
| Slowly growing mycobacteria | |||||||||||
| M. simiae | 25 | 35.8(16.4-44.4) | 2.5 | 0.01 | 102.3 | 0.00 | 93.1 | 3.1 | 0.01 | ||
| M. kansasii | 22 | 13.4(7.3-24.3) | 5.1 | 0.00 | 64.1 | 0.00 | 87.5 | 0.6 | 0.5 | ||
| M. gordonae | 13 | 6.6(0.6-17.5) | 3.6 | 0.00 | 31.5 | 0.00 | 90.4 | 1.4 | 0.27 | ||
| M. intracellulare | 13 | 19(8.7-28.3) | 17.4 | 0.00 | 2.7 | 0.4 | 0.00 | 2.2 | 0.15 | ||
| M. avium complex | 12 | 10.3(1.6-18.1) | 14.8 | 0.00 | 1.7 | 0.45 | 0.00 | 0.65 | 0.63 | ||
| M. szulgai | 23 | 9.1 (3.2-28.1) | 2.1 | 0.00 | 1.1 | 0.00 | 0.00 | 0.00 | 0.03 | ||
| Rapid growing mycobacteria | |||||||||||
| M. fortuitum | 24 | 24.6(12.9-46.7) | 2.2 | 0.02 | 152.3 | 0.00 | 94 | 2.1 | 0.06 | ||
| M. abscessus | 12 | 10.6(4.3-11.8) | 9.1 | 0.00 | 2.1 | 0.00 | 0.00 | 1 | 0.31 | ||
| M. chelonae | 11 | 6.8(3.8-11.7) | 10.7 | 0.00 | 2.2 | 0.31 | 12.4 | 1 | 0.01 | ||
| M.thermoresistibile | 10 | 2.95(1.4-8.1) | 7.2 | 0.00 | 0.76 | 0.00 | 0.00 | 0.00 | 0.00 | ||
| M. terrae | 19 | 18.5 (11.5-29.2) | 8.1 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | 0.00 | ||
| M. gastri | 23 | 15.9 (6.0-41.2) | 6.4 | 0.00 | 1.4 | 0.00 | 0.00 | 0.00 | 0.00 | ||
Figure 2- Forest plot of the meta-analysis of epidemiology of NTM in clinical samples from Iran
Figure 3-Funnel plot of the meta-analysis of epidemiology of NTM in clinical samples from Iran
DISCUSSION
Since many studies do not consider infections caused by NTMs as a public health problem, there is not enough data about these microorganisms and their frequency distribution, at least in Middle Eastern and third-world countries. This has made developing infection control strategies challenging (21).
Our review showed that the prevalence of NTM in clinical samples varied from 0.1 to 72.7%. As mentioned in the results, the majority of NTM were isolated from respiratory and bronchoalveolar lavage samples. These findings emphasize the importance of identifying NTM from suspected pulmonary TB patients (22). In line with our findings, a study from Saudi Arabia reported that pulmonary (54.7%) and bronchial lavage/wash (22.1%) specimens were predominant (23). The difference in the prevalence of NTM in the studies reviewed in our survey might be due to the difference in the molecular techniques used in each study, the geographic region, types of clinical specimens, laboratory personnel skills, sanitation, and living conditions (4).
We showed that the combined prevalence of NTM isolated from clinical samples in Iran was 4.5% during 2000-2022. Because the manifestations of NTM and TB are similar and all NTM are acid-fast and cannot be segregated by phenotypic methods, NTM may be mistaken for TB. Moreover, diseases caused by NTM typically do not respond to anti-TB drugs (24). Furthermore, in some cases, patients with multi-drug resistant TB were in fact infected with NTM (25).
Reports should be interpreted with caution because it is often challenging to determine whether NTM are the real source of infection (1). In line with our results, the study from Saudi Arabia reported a prevalence rate of 1.4% for NTM (23). Studies by Pokam et al. (12) and Aliyu et al. (11) in Nigeria reported prevalence rates of 16.5% and 15%, respectively. However, higher prevalence rates were reported in studies from Canada (33%) and the Netherlands (25%) (26, 27). A systematic review and meta-analysis published by Nasiri et al. in 2015 reported a pooled prevalence rate of 10.2% in Iran, which is higher than the rate found in our study (11.2%). This could be related to the source of NTM because our study was focused on clinical samples, but the mentioned study was focused on suspected TB patients (18). In recent years, the reports of NTM have been rising, mainly because of the active search for NTM species, improvements in culture methods (28), and most importantly, the use of sensitive molecular techniques (22, 29).
Here, we detected a combined prevalence rate of 4.5% in clinical specimens, which is similar to the rate reported by Khaledi et al. in Iran in 2016 (2). Subgroup analysis in our review showed that the combined prevalence of M. simiae (35.8%), M. intracellulare (19%), and M. kansasii (13.4%) was highest among SGM, while M. fortuitum (24.6%), M. terrae (18.5%), and M. gastri (15.9%) were the most prevalent RGM. Evidence suggests that RGM species are among the most predominant NTM associated with nosocomial infections (40). As described by previous reports, tap water, dialysis water provided from tap water, drinking water, shower water, and piped water systems in clinical settings are the common sources of NTM-related nosocomial infections (30). In addition, RGM are relatively resistant to standard disinfectants such as chlorine, alkaline glutaraldehydes, and antimicrobial agents compared to M. tuberculosis; thus, their eradication is more difficult (31).
In line with our study, a previous review on the distribution of NTM species among environmental and clinical samples in the Middle East reported that 58.7% of isolates were SGM and 41.2% were RGM. This study also reported similar prevalence rates for SGM (56.4%) and RGM (44.6%) in Iran (21). Moreover, this study reported M. fortuitum (60.1%) as the most prevalent RGM isolated from clinical specimens in the Middle East (30). M. fortuitum was detected in 71.9%, 54.4%, 46.6%, and 48.9% of RGM isolates from Iran, Saudi Arabia, Turkey, and Pakistan, respectively (6). Other reports from Iran’s neighboring countries (Saudi Arabia and Kuwait) also found M. fortuitum as the predominant isolate (23, 32). The proportion of RGM in pulmonary diseases from Iran and other Asian countries is much higher than in European and North American countries (18, 22, 33). For example, studies from the Netherlands and the United States reported a prevalence rate of 3% and 5% for RGM, respectively (26, 34).
In our study, M. simiae was found as the most predominant SGM among NTM isolates. This finding is in agreement with the results of previous reviews from Iran (18, 22). On the contrary, in developed countries, M. avium complex has been described as the most common NTM species (35). It is noteworthy to mention that M. simiae is an endemic SGM in Iran. It is often not distinguishable from TB complex due to its similar clinical and radiologic manifestations as well as the lack of response to anti-TB drugs (36). Therefore, it is recommended to consider M. simiae in cases where anti-TB treatment does not respond (37). The spread of diseases caused by mycobacteria, especially respiratory diseases, and the possible inappropriate treatment imposes a lot of costs on both patients and health systems. Nevertheless, most laboratories do not have accurate diagnostic criteria for NTM owing to the lack of appropriate equipment and qualified experts (1). In recent studies, the increased use of molecular methods has increased the accuracy of NTM diagnosis (38). National TB reference laboratories necessitate standardizing existing protocols for the identification of NTM in Middle Eastern countries (21, 39). Thus, given the rising importance of NTM, quick and precise identification of NTM is of great importance for active management strategy against NTM Infections (21). The main limitation of the present study was that studies published in languages other than English and Persian have not been included in the analysis. Another limitation was that the protocol of this systematic review and meta-analysis was not registered in a standard platform like Cochrane or Prospero.
CONCLUSION
In summary, our findings indicate a relatively high combined prevalence of NTM in clinical samples in Iran. Some of these species such as M. simiae can have clinical and radiologic manifestations similar to those of TB and are resistant to anti-TB drugs. Therefore, standardizing the use of molecular methods for the detection of NTM seems necessary.
ACKNOWLEDGMENTS
None.
DECLARATIONS
FUNDING
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethics approvals and consent to participate
Not applicable.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest regarding the publication of this article.
FUNDING
The authors received no financial support for the research, authorship, and/or publication of this article.
Ethics approvals and consent to participate
Not applicable.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest regarding the publication of this article.
Research Article: Systematic Review |
Subject:
Others
Received: 2022/03/2 | Accepted: 2022/06/6 | Published: 2023/05/21 | ePublished: 2023/05/21
Received: 2022/03/2 | Accepted: 2022/06/6 | Published: 2023/05/21 | ePublished: 2023/05/21
References
1. Raju RM, Raju SM, Zhao Y, Rubin EJ. Leveraging advances in tuberculosis diagnosis and treatment to address nontuberculous mycobacterial disease. Emerging infectious diseases. 2016; 22(3): 365. [View at Publisher] [DOI:10.3201/eid2203.151643] [PubMed] [Google Scholar]
2. Khaledi A, Bahador A, Esmaeili D, Ghazvini K. Prevalence of Nontuberculous Mycobacteria (NTM) in Iranian clinical specimens: systematic review and meta-analysis. Journal of Medical Bacteriology. 2016;5(3-4):29-40. [View at Publisher] [Google Scholar]
3. Falkinham 3rd J. Epidemiology of infection by nontuberculous mycobacteria. Clinical microbiology reviews. 1996;9(2):177-215. [DOI:10.1128/CMR.9.2.177] [PubMed] [Google Scholar]
4. Khaledi A, Bahador A, Esmaeili D, Tafazoli A, Ghazvini K, Mansury D. Prevalence of nontuberculous mycobacteria isolated from environmental samples in Iran: A meta-analysis. Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences. 2016;21. [DOI:10.4103/1735-1995.187306] [PubMed] [Google Scholar]
5. Hagiwara E, Komatsu S, Nishihira R, Shinohara T, Baba T, Ogura T. Clinical characteristics and prevalence of pneumothorax in patients with pulmonary Mycobacterium avium complex disease. Journal of Infection and Chemotherapy. 2013; 19(4): 588-92. [View at Publisher] [DOI:10.1007/s10156-012-0518-0] [PubMed] [Google Scholar]
6. Hett EC, Rubin EJ. Bacterial growth and cell division: a mycobacterial perspective. Microbiology and Molecular Biology Reviews. 2008;72(1):126-56. [View at Publisher] [DOI:10.1128/MMBR.00028-07] [PubMed] [Google Scholar]
7. van Ingen J, Boeree MJ, van Soolingen D, Mouton JW. Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria. Drug Resistance Updates. 2012; 15(3): 149-61. [View at Publisher] [DOI:10.1016/j.drup.2012.04.001] [PubMed] [Google Scholar]
8. Faria S, Joao I, Jordao L. General overview on nontuberculous mycobacteria, biofilms, and human infection. Journal of pathogens. 2015;2015:809014. [View at Publisher] [DOI:10.1155/2015/809014] [PubMed] [Google Scholar]
9. Gopinath K, Singh S. Non-tuberculous mycobacteria in TB-endemic countries: are we neglecting the danger? PLoS neglected tropical diseases. 2010;4(4):e615. [View at Publisher] [DOI:10.1371/journal.pntd.0000615] [PubMed] [Google Scholar]
10. Muyoyeta M, Schaap J, De Haas P, Mwanza W, Muvwimi M, Godfrey-Faussett P, et al. Comparison of four culture systems for Mycobacterium tuberculosis in the Zambian National Reference Laboratory. The international journal of tuberculosis and lung disease. 2009;13(4):460-5. [View at Publisher] [PubMed] [Google Scholar]
11. Aliyu G, El-Kamary SS, Abimiku Al, Brown C, Tracy K, Hungerford L, et al. Prevalence of non-tuberculous mycobacterial infections among tuberculosis suspects in Nigeria. PloS one. 2013;8(5):e63170. [View at Publisher] [DOI:10.1371/journal.pone.0063170] [PubMed] [Google Scholar]
12. Pokam BT, Asuquo AE. Acid-fast bacilli other than mycobacteria in tuberculosis patients receiving directly observed therapy short course in cross river state, Nigeria. Tuberculosis research and treatment. 2012;2012:301056. [View at Publisher] [DOI:10.1155/2012/301056] [PubMed] [Google Scholar]
13. Ernst P, Fitzgerald JM, Spier S. Canadian asthma consensus conference summary of recommendations. Canadian Respiratory Journal. 1996; 3(2): 89-101. [View at Publisher] [DOI:10.1155/1996/314657] [Google Scholar]
14. RUNYON EH. Anonymous mycobacteria in pulmonary disease. Med Clin North Am. 1959;43(1):273-90. [DOI:10.1016/S0025-7125(16)34193-1] [PubMed] [Google Scholar]
15. Jarzembowski JA, Young MB. Nontuberculous mycobacterial infections. Archives of pathology & laboratory medicine. 2008;132(8):1333-41. [View at Publisher] [DOI:10.5858/2008-132-1333-NMI] [PubMed] [Google Scholar]
16. Porvaznik I, Solovič I, Mokrý J. Non-tuberculous mycobacteria: classification, diagnostics, and therapy. Respiratory treatment and prevention. 2017; 944: 19-25. [View at Publisher] [DOI:10.1007/5584_2016_45] [PubMed] [Google Scholar]
17. Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot tub lung: presenting features and clinical course of 21 patients. Respiratory medicine. 2006;100(4):610-5. [View at Publisher] [DOI:10.1016/j.rmed.2005.08.005] [PubMed] [Google Scholar]
18. Nasiri MJ, Dabiri H, Darban-Sarokhalil D, Hashemi Shahraki A. Prevalence of non-tuberculosis mycobacterial infections among tuberculosis suspects in Iran: systematic review and meta-analysis. PloS one. 2015;10(6):e0129073. [DOI:10.1371/journal.pone.0129073] [PubMed] [Google Scholar]
19. Programme CAS. 10 questions to help you make sense of qualitative research. Public Health Resource Unit England; 2006.
20. Hosseini M, Shakerimoghaddam A, Ghazalibina M, Khaledi A. Aspergillus coinfection among patients with pulmonary tuberculosis in Asia and Africa countries; a systematic review and meta-analysis of cross-sectional studies. Microbial pathogenesis. 2020;141:104018. [View at Publisher] [DOI:10.1016/j.micpath.2020.104018] [PubMed] [Google Scholar]
21. Velayati AA, Rahideh S, Nezhad ZD, Farnia P, Mirsaeidi M. Nontuberculous mycobacteria in Middle East: Current situation and future challenges. International journal of mycobacteriology. 2015;4(1):7-17. [View at Publisher] [DOI:10.1016/j.ijmyco.2014.12.005] [PubMed] [Google Scholar]
22. Velayati AA, Farnia P, Mozafari M, Mirsaeidi M. Nontuberculous mycobacteria isolation from clinical and environmental samples in Iran: twenty years of surveillance. BioMed research international. 2015;2015:254285. [View at Publisher] [DOI:10.1155/2015/254285] [PubMed] [Google Scholar]
23. Varghese B, Memish Z, Abuljadayel N, Al-Hakeem R, Alrabiah F, Al-Hajoj SA. Emergence of clinically relevant non-tuberculous mycobacterial infections in Saudi Arabia. PLoS neglected tropical diseases. 2013; 7(5): e2234. [View at Publisher] [DOI:10.1371/journal.pntd.0002234] [PubMed] [Google Scholar]
24. Maiga M, Siddiqui S, Diallo S, Diarra B, Traoré B, Shea YR, et al. Failure to recognize nontuberculous mycobacteria leads to misdiagnosis of chronic pulmonary tuberculosis. PloS one. 2012;7(5):e36902. [View at Publisher] [DOI:10.1371/journal.pone.0036902] [PubMed] [Google Scholar]
25. Shahraki AH, Heidarieh P, Bostanabad SZ, Khosravi AD, Hashemzadeh M, Khandan S, et al. "Multidrug-resistant tuberculosis" may be nontuberculous mycobacteria. European journal of internal medicine. 2015;26(4):279-84. [View at Publisher] [DOI:10.1016/j.ejim.2015.03.001] [PubMed] [Google Scholar]
26. Van Ingen J, Bendien SA, De Lange WC, Hoefsloot W, Dekhuijzen PR, Boeree MJ, et al. Clinical relevance of non-tuberculous mycobacteria isolated in the Nijmegen-Arnhem region, The Netherlands. Thorax. 2009;64(6):502-6. [DOI:10.1136/thx.2008.110957] [PubMed] [Google Scholar]
27. Marras TK, Daley CL. Epidemiology of human pulmonary infection with nontuberculous mycobacteria. Clinics in chest medicine. 2002;23(3):553-68. [DOI:10.1016/S0272-5231(02)00019-9] [PubMed] [Google Scholar]
28. Chu H, Zhao L, Xiao H, Zhang Z, Zhang J, Gui T, et al. Prevalence of nontuberculous mycobacteria in patients with bronchiectasis: a meta-analysis. Archives of medical science: AMS. 2014;10(4):661. [View at Publisher] [DOI:10.5114/aoms.2014.44857] [PubMed] [Google Scholar]
29. Hernández-Garduño E. Comment on "Nontuberculous Mycobacteria Isolation from Clinical and Environmental Samples in Iran: Twenty Years of Surveillance". BioMed research international. 2015;2015:327068. [View at Publisher] [DOI:10.1155/2015/327068] [PubMed] [Google Scholar]
30. De Groote MA, Huitt G. Infections due to rapidly growing mycobacteria. Clin Infect Dis. 2006; 42(12): 1756-63. [View at Publisher] [DOI:10.1086/504381] [PubMed]
31. Carson LA, Petersen NJ, Favero MS, Aguero SM. Growth characteristics of atypical mycobacteria in water and their comparative resistance to disinfectants. Applied and Environmental Microbiology. 1978;36(6):839-46. [View at Publisher] [DOI:10.1128/aem.36.6.839-846.1978] [PubMed] [Google Scholar]
32. Mokaddas E, Ahmad S. Species spectrum of nontuberculous mycobacteria isolated from clinical specimens in Kuwait. Current microbiology. 2008; 56(5): 413-7. [View at Publisher] [DOI:10.1007/s00284-008-9102-3] [PubMed] [Google Scholar]
33. Simons S, Van Ingen J, Hsueh P-R, Van Hung N, Dekhuijzen PR, Boeree MJ, et al. Nontuberculous mycobacteria in respiratory tract infections, eastern Asia. Emerging infectious diseases. 2011;17(3):343. [DOI:10.3201/eid170310060] [PubMed] [Google Scholar]
34. O'Brien RJ, Geiter LJ, Snider Jr DE. The epidemiology of nontuberculous mycobacterial diseases in the United States: results from a national survey. American Review of Respiratory Disease. 1987;135(5):1007-14. [DOI] [PubMed] [Google Scholar]
35. Cowman S, Burns K, Benson S, Wilson R, Loebinger M. The antimicrobial susceptibility of non-tuberculous mycobacteria. Journal of Infection. 2016;72(3):324-31. [View at Publisher] [DOI:10.1016/j.jinf.2015.12.007] [PubMed] [Google Scholar]
36. Baghaei P, Tabarsi P, Farnia P, Marjani M, Sheikholeslami FM, Chitsaz M, et al. Pulmonary disease caused by Mycobacterium simiae in Iran's national referral center for tuberculosis. The Journal of Infection in Developing Countries. 2012;6(01):23-8. [View at Publisher] [DOI:10.3855/jidc.1297] [PubMed] [Google Scholar]
37. Tabarsi P, Baghaei P, Farnia P, Mansouri N, Chitsaz E, Sheikholeslam F, et al. Nontuberculous mycobacteria among patients who are suspected for multidrug-resistant tuberculosis-need for earlier identification of nontuberculosis mycobacteria. The American journal of the medical sciences. 2009;337(3):182-4. [View at Publisher] [DOI:10.1097/MAJ.0b013e318185d32f] [PubMed] [Google Scholar]
38. Dvorska L, Bartos M, Martin G, Erler W, Pavlik I. Strategies for differentiation, identification and typing of medically important species of mycobacteria by molecular methods. VETERINARNI MEDICINA-PRAHA-. 2001;46(11/12):309-28. [View at Publisher] [DOI:10.17221/7890-VETMED] [Google Scholar]
39. Bahador A, Esmaeili D, Khaledi A, Ghorbanzadeh R. An in vitro assessment of the antibacterial properties of nanosilver Iranian MTA against Porphyromonas gingivalis. Journal of Chemical and Pharmaceutical Research. 2013;5(10):65-71. [View at Publisher] [Google Scholar]
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