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Non-tuberculous mycobacteria (NTM) have evolved as an emerging group of pathogens globally. Due to the pitfalls in identification, the majority of them are not familiar or remain ‘rare' to clinicians and microbiologists. In available literatures, a consolidated global data analysis is non-existent on rarely encountered NTM. A systematic review and meta-analysis have been carried out on 100 rare NTM species, which are possibly identified only by DNA sequencing methods, to establish their global epidemiology, emergence and clinical relevance. Articles published in English from 1956 to 2018 reporting rare NTM species were searched in MEDLINE, Scopus, Ovid and Embase. A total of 447 articles matched the selection criteria, and 1670 rare NTM cases were identified from 52 countries. The majority of the incidences were reported from North America (33.4%), followed by Europe (23.8%) and Asia (20.8%). Of 100 species, 43 were defined as emerging species, with 1351 (80.9%) new incidence cases globally. In total, 87 species caused clinically relevant pulmonary and extrapulmonary diseases. Interestingly, some NTM species showed significant geographic predominance, such as M. conceptionense to South Korea, M. shinjukuense to Japan; M. arupense and M. nonchromogenicum to the United States and M. riyadhense to Saudi Arabia. Rare NTM species mainly caused pulmonary infection (67.1%), while extrapulmonary infections generally comprised mycobacteremia and skin/soft tissue infections. In conclusion, the majority of rarely encountered NTM species are now well-established pathogens with valid clinical implications. The emergence of these rare pathogens warrants immediate local and international follow-ups. Their increasing clinical and pathological significance should not be disregarded.

Background: Non-tuberculous mycobacteria (NTM) causing pulmonary and extra-pulmonary diseases are increasing worldwide. A large paucity of data related to pediatric NTM diseases exists globally and particularly in Saudi Arabia. Methods: The first nationwide exploratory study on existence of NTM diseases among Saudi Arabian children (0–14 years old) has been carried out during 2016−2017. Suspected NTM isolates with clinical and demographical data were enrolled from regional reference laboratories. Species level identification of isolates was carried out by commercial line probe assays and gene sequencing. Results: In 12 months, 52 culture positive cases with 44(84.6%) confirmed disease incidences were identified. Demographically, Saudi nationals (86.5%) were dominated and 77.3% cases have different comorbid conditions. Lymphadenitis (40.4%) followed by 26.9% of pulmonary cases with 42.8% of confirmed clinical relevance were mainly reported. Species identification showed Mycobacterium simiae (31.8%), M. abscessus (23.1%) and nine other species including rarely encountering M. riyadhense. Ascites caused by M. monacense, pulmonary disease caused by M. riyadhense and M. monacense were rarest clinical events and reported for the first time globally in a pediatric cohort. Conclusions: Diverse NTM diseases even in immunocompetent children are an upcoming challenge in Saudi Arabia. Lack of awareness on NTM disease must be addressed with immediate development of management plans. Keywords: Pediatric non tuberculous mycobacterial disease, Saudi Arabia, NTM epidemiology, Mycobacterium simiae, M. riyadhense, M. abscessus, M. kubicae, M. monacense

Background: Despite exerted efforts to control and treat Mycobacterium tuberculosis (MTB) strains, Tuberculosis (TB) remains a public health menace. The emergence of complex drug-resistant profiles, such as multi-drug resistant and extensively drug-resistant MTB strains, emphasizes the need for early diagnosis of resistant cases, shorter treatment options, and effective medical interventions. Objective: Solutions for better clinical management of drug-resistant cases are either pathogencentered (novel chemotherapy agents) or host-directed approaches (modulating host immune response to prevent MTB invasion and pathogenesis). Results: Despite the overall potentiality of several chemotherapy agents, it is feared that their effectiveness could be challenged by sequential pathogen adaptation tactics. On the contrary, host-directed therapy options might offer a long-term conceivable solution. Conclusion: This review discusses the main suggestions proposed so far to resolve the clinical challenges associated with drug resistance, in the context of TB. These suggestions include novel drug delivery approaches that could optimize treatment outcome and increase patients’ compliance to the treatment.

Despite the efficacy of antibiotics to protect humankind against many deadly pathogens, such as Mycobacterium tuberculosis, nothing can prevent the emergence of drug-resistant strains. Several mechanisms facilitate drug resistance in M. tuberculosis including compensatory evolution, epistasis, clonal interference, cell wall integrity, efflux pumps, and target mimicry. In this study, we present recent findings relevant to these mechanisms, which can enable the discovery of new drug targets and subsequent development of novel drugs for treatment of drug-resistant M. tuberculosis.

Objectives Mycobacterium tuberculosis DNA has been detected in multiple organs in people without active tuberculosis or a history of tuberculosis. Molecular testing for metabolic activity has suggested that M tuberculosis DNA represents viable bacilli. Whether transplanted organs with M tuberculosis DNA can result in tuberculosis in recipients has not been assessed. Methods Biopsies obtained at the time of living donor liver transplantation were tested for the presence of M tuberculosis DNA using in situ PCR. The cohort of recipients was longitudinally followed for the development of tuberculosis. Results Living donor liver transplantation was performed for 270 patients. Mean age was 33 years (median: 41 years, range: 1-80 years). Recipients were followed for a mean of 68 months (median: 72 months, range: 1-138 months) after transplantation. Mycobacterium tuberculosis DNA was detected in 25 of 155 donated livers (16%) with liver biopsies available for testing. None of the recipients of these livers received tuberculosis chemoprophylaxis and only one (4%) developed tuberculosis 15 months after transplantation. Among the entire cohort of 270 patients, post-transplant tuberculosis was diagnosed in four patients (1.48%) at an incidence rate of 2.61 cases per 1000 transplant-years. No factors associated with developing tuberculosis were identified, including positive M tuberculosis DNA in transplanted livers. Conclusions Mycobacterium tuberculosis DNA in living donor transplanted livers did not result in tuberculosis despite post-transplant immunosuppression.

We explored in detail the nationwide existence of Mycobacterium riyadhense in Saudi Arabia. In 18 months, 12 new cases of M. riyadhense infection were observed, predominantly among Saudi nationals, as a cause of pulmonary disease. M. riyadhense may be emerging as a more common pathogen in Saudi Arabia.

We describe the clinical and genetic characteristics of multi-drug resistant tuberculosis (MDR-TB) in a family cluster in the western region of Kingdom of Saudi Arabia diagnosed between 2012 and 2016. All cases had risk factors for tuberculosis acquisition and they were not household contacts of the index case. Genetic analysis detected both MDR-TB and pre-extensively drug-resistant tuberculosis (pre-XDR TB) strains in the index case and confirmed tuberculosis transmission between two cases. Lack of early diagnosis of MDR-TB by molecular testing and lack of extended contact tracing contributed to the transmission of MDR-TB among this family cluster over four years. Keywords: Multidrug resistant tuberculosis, Family cluster

Despite low infectious potential of extrapulmonary tuberculosis (EPTB), it poses significant clinical challenges in terms of diagnosis and treatment monitoring. Understanding the main demographical risk factors for disease characteristics of EPTB plays a crucial role in speeding up diagnosis process and improving overall clinical experience. The aim of this study was to investigate the main demographical and clinical risk factors for EPTB among adults and adolescents for the first time in Saudi Arabia. A cross-sectional multicenter study was carried out on a collection of 902 extrapulmonary Mycobacterium tuberculosis complex (MTBC) isolates with demographical and clinical data. All isolates were subjected to spoligotyping and 24-loci based MIRU-VNTR typing. The association between two potential variables was assessed using odd ratios (OR) calculations. Independent risk factors for EPTB and diseases characteristics of EPTB were identified using multivariate regression model analyses. Gender was found to be significantly associated with lymph node, gastrointestinal, central nervous system and urogenital TB. Lymph node TB showed statistical association to age group below 25 years, non-Saudis and South East Asian ethnicity. While gastrointestinal TB demonstrated an association with patients above 60 years old, and Saudis. Multivariate analysis showed that gender is an independent risk factor to urogenital TB (p 0.03) and lymph node TB (p 0.005). On the other hands, South Asian (p 0.01) and South East Asian (p 0.03) ethnicities were both identified as independent risk factors significantly associated with EPTB. MTBC lineages, site of infections, gender, HIV and smear positivity showed no significant association. Nationwide qualitative-studies are highly warranted in the future to further understand the main demographic risk factors for disease characteristics of EPTB.

Introduction: Screening for Latent Tuberculosis Infections (LTBI) constitutes a key step in health surveillance programs especially among adults of high-risk groups. To our knowledge, this is the first systematic and meta-analysis review that aims to critically assess and compare the agreement of QuantiFERON-TB Gold In-Tube (QFT-GIT) and Tuberculin Skin Testing (TST) among adults of high-risk groups in Saudi Arabia and compare results with other sites of the Middle East. Methodology: Kappa estimates were meta-analyzed using random effect model and several subgroup analyzes were performed to explain overall heterogeneity. Funnel plot, Begg’s and Egger’s tests were employed to assess overall publication bias. Results: 18 studies were meta-analyzed, comprising 5070 adults of high-risk groups. Pooled kappa estimates from Saudi Arabia (κ = 0.29, 95% CI: 0.16, 0.41) showed lower rate of agreement compared to other sites of the Middle East (κ = 0.33, 95% CI: 0.25, 0.41). However, a significant level of heterogeneity (I2 = 96.7%, p > 0.001) were identified across collected evidence. Begg’s and Egger’s tests confirmed absence of significant publication bias in this review (p = 0.49 and p = 0.16, respectively). Conclusion: This work revealed fair to poor agreement between TST and QFT-GIT, indicating that these two tests are not interchangeable in such settings. Substantial evidence is still needed before considering the sole use of QFT-GIT as an alternative to TST in these populations. Moreover, there is an urgent need for longitudinal studies in Saudi Arabia and the Middle East to accurately assess precision of LTBI diagnosis.

Nationality stratified by site of infection. Table shows the distribution of pulmonary and extrapulmonary cases among 39 nationalities included in the study. (PDF 194 kb)

Nationality of the patient and distribution of lineages. The figure shows the distribution of major MTBC lineages among top 11 nationalities. (PDF 277 kb)

Statistical association of major MTBC lineages and extrapulmonary site of infections. (PDF 112 kb)

Saudi Arabia is the third-largest Arab country with a moderate annual burden of tuberculosis. However, tuberculosis (TB) is among several infectious diseases that have not been brought under control, despite the government’s considerable efforts. This is clearly evidenced by the ongoing transmission of several imported and indigenous clades of Mycobacterium tuberculosis. In addition, the country faces the threat from rising proportions of extrapulmonary TB, non-tuberculous mycobacterial infections, and drug resistance. Furthermore, the country falls behind the global targets set by World Health Organization for the success rate of TB treatment. The country needs more population-based research studies, centralized and easily accessible clinical data registries, and centralized research and diagnostic facilities. This review focused on the trends of mycobacterial infections and on future proposals to improve TB control measures in Saudi Arabia.

In Saudi Arabia, there were no nationwide screening studies conducted so far to determine the aminoglycoside and fluoroquinolone resistance among multidrug-resistant tuberculosis (MDR-TB) isolates. Therefore, as the first attempt in the country, a retrospective analysis has been conducted on a nationwide collection of 2,956 M. tuberculosis clinical isolates screened with phenotypic drug susceptibility testing to define MDR-TB. Enrolled MDR-TB isolates were subjected to second-line drug susceptibility testing, detection of mutations conferring resistance to aminoglycosides and fluoroquinolone, followed by 24-loci mycobacterial interspersed repetitive unit-variable number of tandem repeat typing and spoligotyping. Overall, 83 isolates were identified as MDR-TB, and 13 (15.7%) isolates showed resistance to second-line drugs. Moxifloxacin (low level) showed higher resistant rates (10.8%) followed by ofloxacin (7.2%), capreomycin (3.6%), kanamycin (3.6%), and amikacin (2.4%). Overall fluoroquinolone resistance was 12%, whereas aminoglycoside resistance was 7.2%. Predominant mutations conferring resistance to fluoroquinolone were found in gyrA A90V and D94G, whereas aminoglycoside resistance was observed only with rrs gene A1401G mutation. The corresponding strain lineages predominated with Indo-Oceanic and East-African Indian origin. Interestingly, none of the isolates with second-line drug resistance was defined as extensively drug-resistant TB (XDR-TB). Surprisingly, many isolates (50.6%) were panresistant to first-line drugs. Saudi Arabia faces considerable burden of fluoroquinolone- and aminoglycoside-resistant MDR-TB. Higher incidence of panresistant MDR-TB reveals a threat for the emergence of XDR-TB strains in the near future.

Background Clinical relevance of nontuberculous mycobacteria (NTM) is increasing worldwide including in Saudi Arabia. A high species diversity of NTM’s has been noticed in a recent study. However, the identification in diagnostic laboratories is mostly limited to common species. The impact of NTM species diversity on clinical outcome is so far neglected in most of the clinical settings. Methodology/Principal Findings During April 2014 to September 2015, a nationwide collection of suspected NTM clinical isolates with clinical and demographical data were carried out. Primary identification was performed by commercial line probe assays. Isolates identified up to Mycobacterium species level by line probe assays only were included and subjected to sequencing of 16S rRNA, rpoB, hsp65 and 16S-23S ITS region genes. The sequence data were subjected to BLAST analysis in GenBank and Ez-Taxon databases. Male Saudi nationals were dominated in the study population and falling majorly into the 46–59 years age group. Pulmonary cases were 59.3% with a surprising clinical relevance of 75% based on American Thoracic Society guidelines. Among the 40.7% extra-pulmonary cases, 50% of them were skin infections. The identification revealed 16 species and all of them are reporting for the first time in Saudi Arabia. The major species obtained were Mycobacterium monascence (18.5%), M. cosmeticum (11.1%), M. kubicae (11.1%), M. duvalli (7.4%), M.terrae (7.4%) and M. triplex (7.4%). This is the first report on clinical relevance of M. kubicae, M. tusciae, M.yongonense, M. arupense and M.iranicum causing pulmonary disease and M. monascence, M. duvalli, M. perigrinum, M. insubricum, M. holsaticum and M. kyorinense causing various extra-pulmonary diseases in Saudi Arabia. Ascites caused by M. monascence and cecum infection by M. holsaticum were the rarest incidents. Conclusions/Significance To the first time in the country, clinical significance of various rare NTM’s are well explored and the finding warrants a new threat to the Saudi Arabian clinical settings., Author Summary Nontuberculous mycobacteria (NTM) are ubiquitous in nature and they are opportunistic pathogens. In the last decade, infections caused by NTM’s increased—around the world in immune-suppressed and immune-competent individuals and Saudi Arabia is not an exception. Developments in diagnostic technologies increased the identification of several new or rare species of NTM’s. Indeed, the species diversity of NTM has a direct impact on clinical outcome and therapies. Saudi Arabian clinics so far report only the common species of NTM’s and rare species are mostly neglected due to the lack of proper infrastructure or ignorance. To the first time in the country, an exploration on the existence of clinically relevant rare NTM species was conducted on a nationwide level. The findings showed a huge diversity of rare NTM species causing both pulmonary and extra-pulmonary diseases. Clinical relevance of pulmonary infection based on American Thoracic Society guidelines was confirmed as an aggressive 75%, which is really alarming. Interestingly, 16 species of NTM’s were isolated in the study, and all of them are reporting for the first time in country. Overall finding shows Saudi Arabia faces serious threat from rare NTM species with high clinical significance and warrants the immediate need for more advanced infrastructure.

For the first time in Saudi Arabia, the impact of a patient's ethnic background on mutations conferring resistance to rifampicin (RIF) and isoniazid (INH) in Mycobacterium tuberculosis isolates was analyzed on a nationwide sample collection. Four hundred fifteen isolates were subjected to drug susceptibility testing, mutation analysis, spoligotyping, and 24 loci-based Mycobacterial Interspersed Repetitive Units-Variable Number Tandem Repeat typing, respectively. Phenotypically, 41 (9.9%) isolates were resistant to RIF, 239 (57.6%) to INH, and 135 (32.5%) to both RIF and INH, respectively. Forty (9.6%), 236 (56.8%), and 133 (32%) isolates were determined as resistant to RIF, INH, and to both by molecular assay. Codon 531 (S531L) mutations (69.4%) in the rpoB gene and codon 315 (S315T) mutations (67.2%) in the katG gene were the most prominent among RIF- and INH-resistant isolates, respectively. The autochthonous population showed a predominance of rpoB codon 516 and 526 mutations, while the inhA promoter position -15 and -8 mutations were prominent among immigrants. A strain cluster ratio of 32% (30 clusters) was observed and 24 clusters displayed identical mutations. Overall, Euro-American lineages were predominant. However, Beijing (56.7%) and EAI (42.7%) were noticed with the highest cluster rate. In Saudi Arabia, the occurrence of mutations responsible for INH and RIF resistance was significantly associated with the ethnic origin of the patient.

It is well known that the number of people with Tuberculosis (TB) and those who develop multidrug resistance (MDR) are the fundamental components that affect the total cost of treatment of TB. This paper has two-fold objectives. Firstly, we use the Generalized Linear Regression Models (GLM) to predict the future count of persons with TB and MDR. Due to the fact that assessment of TB cost is methodologically difficult, and compounded with the lack of concrete information about the treatment cost in Saudi Arabia, our second objective is to use cost information from the EU countries as proxy to estimate the cost of treating TB. The cost predictions provide essential information that is part of the evidence needed for budgeting and financing the health care facilities of TB services, especially with respect to avoiding under-estimation of the cost of TB-MDR treatment.

Endogenous reactivation and exogenous reinfection of tuberculosis were studied for the first time in Saudi Arabia after enrolling a total of 39 patients with multiple episodes of tuberculosis between 2009 and 2010. All of the primary and subsequent isolates enrolled were subjected to spoligotyping, 24 loci based MIRU-VNTR typing and first line anti-tuberculosis drug susceptibility testing. The primary episode isolates from patients born outside Saudi Arabia were dominated by lineages which are prevalent in their country of origin (e.g. Ghana, Cameroon, Uganda-I, among African patients/Delhi/CAS and EAI among Asian patients). On the other hand, in Saudi Arabian patients, (median age of 67 years) Delhi/CAS, TUR and S lineages were predominant. The second episode of infection was mainly caused by the lineages Delhi/CAS, EAI, Uganda-I, Haarlem, and LAM which are currently disseminating in the country. Surprisingly, all of the first episode isolates were pan-susceptible, while 35.9% of the re-infected cases were drug resistant. Reactivation of a remote infection eventually followed by an exogenous reinfection was confirmed among patients, particularly those of African origin. Immediate actions to break the cycle of transmission of drug resistant tuberculosis are greatly needed in Saudi Arabia.

Drug susceptibility testing (DST) of Mycobacterium tuberculosis is a crucial procedure to determine the effective drug regimen for patients’ treatment. Reporting of erroneous DST results to the treating physician has adulterous effects on patients. As a first study of its type, the inconsistencies in reporting DST results of rifampicin and isoniazid from Saudi Arabia were assessed. An automated liquid culture-based DST and a molecular mutation detection technique were used. Performance of first-line drug susceptibility testing of 1904 clinical isolates showed 44 inconsistent results. The majority of the cases reported as MDR-TB from the referral laboratories could not reproduce the same results at a different site (Mycobacteriology Research Section). Of the 44 cases, 16 (36.3%) showed false resistance to isoniazid and rifampicin and on the other hand, 14 (31.8%) cases showed false susceptibility to the same drugs. The possible causes for the inconsistencies and recommendations to overcome the biases based on this experience are discussed.

Nontuberculous Mycobacteria (NTM) are causing growing health problems worldwide. This is indicated by an increasing amount of scientific reports showing not only well-identified species reemerging but also emergence of new species. The emergence and reemergence of NTM are particularly worrying in developing countries due to scarce published data and improper identification. Here we aimed to examine the main epidemiological aspects and diagnostic challenges associated with NTM in countries of the Gulf Cooperation Council (GCC) and compare these findings to the international arena findings. Data revealed that countries of the GCC are largely dominated by rapidly growing mycobacteria species such asM. fortuitum(29%) andM. abscessus(17%) with high rate of definitive respiratory diseases. On the other hand, most of the developed countries are dominated by slowly growing mycobacteria such as MAC,M. kansasii, andM. gordonae. More efforts are needed, however, to gain insights into NTM issues in countries of the GCC.

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration., We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.).

The outcome of infection with Mycobacterium tuberculosis (MTB) is largely influenced by the host–pathogen interaction in which both the human host and the MTB genetic backgrounds play an important role. Whether this interaction also influences the selection and expansion of drug-resistant MTB strains is the primary focus of this review. We first outline the main and recent findings regarding MTB determinants implicated in the development of drug resistance. Second, we examine data regarding human genetic factors that may play a role in TB drug resistance. We highlight interesting openings for TB research and therapy.

Health care workers (HCW’s) are always at an increased risk of contracting tuberculosis (TB) infection. In Saudi Arabia, Interferon Gamma Release Assay (IGRA) has not been evaluated as a screening tool for latent TB infection (LTBI) among HCW’s considering their high demographic diversity. During February 2012 to January 2015 a cross sectional study has been conducted in a tertiary care center with maximum demographically diverse staff population in the capital city-Riyadh. After a short interview and consenting, all the candidates were subjected to tuberculin skin test (TST) and QuantiFERON TB gold In-tube test (QFT). A logistic regression analysis was carried out for establishing the associations between putative risk factors and the diagnostic tests. The candidates were classified according to geographical origin and a detailed analysis was conducted on the impact of their origin towards the results of TST and QFT. Of the 1595 candidates enrolled, 90.6% were BCG vaccinated, female (67.9%) and mainly nurses (53.2%). Candidates with high risk of suspected or confirmed TB patient exposure were 56.1% and 76.5% of them had

Data on the genetic variation of isolates of Mycobacterium tuberculosis and spectrum of mutations determining resistance to principal anti-tuberculosis drugs isoniazid (INH) and rifampicin (RIF) have not yet been studied in Saudi Arabia. One hundred and fifty-one clinical isolates of M. tuberculosis from different regions in the country showing resistance to RIF and INH were subjected to drug susceptibility testing, characterization of mutations conferring drug resistance and genotyping. Phenotypically 17 (11.3%) isolates were resistance to RIF, 75 (49.6%) were resistant to INH and 59 (39.1%) were resistant to both RIF and INH, respectively. Sixteen (10.6%), 74 (49%) and 56 (37.1%) were determined as resistant to RIF, INH and to both by line probe assay. High frequency of rpoB 531 mutations (67.1%) in RIF resistant strains and katG 315 mutations (65.2%) in INH resistant strains were found. Mutations responsible for INH resistance, katG 315 (P value0.001, odds ratio: 1.81, 95% CI [1.51, 2.18]) and inhA-15 (P value - 0.004, odds ratio: 1.48, 95% CI [1.22, 1.8]) were predominant among the newly diagnosed cases. Beijing strains were significantly associated with multi drug resistance and mutations in combination of rpoB531 and katG315 (P value -0.001, odds ratio: 6.83, 95% CI [2.65, 17.58]). In addition multi drug resistance was significantly associated with treatment history (P value0.001, odds ratio: 3.16, 95% CI [2.14, 4.67]). Furthermore, a higher rate (39.3%) of clustering among the multidrug resistant strains particularly with Beijing family (52.9%) was observed. Saudi Arabia harbors highly diverse drug resistant M. tuberculosis population with an ongoing transmission which needs to be immediately managed.

Background Incidences of nontuberculous mycobacteria (NTM) causing pulmonary and extrapulmonary diseases are reportedly increasing globally and the current epidemiologic situation in Saudi Arabia remains unclear. To study such trend, we carried out a nationwide systematic epidemiological study focusing on NTM diseases for the first time in the country. Methods/Principle findings A nationwide collection of NTM isolates with clinical and demographical data was conducted for a period of 24 months. Primary species identification was carried out by line probe assays followed by sequencing of 16S rRNA, 16S-23S ITS region, rpoB and hsp65 genes. The laboratory findings were comprehensively analysed against demographical and clinical data. A total of 527 isolates were enrolled with a higher proportion of Saudi citizens (76.5%), elderly (>60 years) patients (34.2%), and male gender (65.3%) respectively. Overall, 75.1% isolates were pulmonary origin with a proven clinical significance of 44.7%. In total, 34 NTM species including 17 rare species were identified, in addition to 8 ‘undefined’ isolates. M.simiae (22.6%), M.fortuitum (18.1%) and M.abscessus (17.8%) were predominant species. Interestingly, 27 new cases of clinically relevant M.riyadhense were also noticed (Primary data on emergence of rare NTM species and M.riyadhense has been recently reported). Results showed, rare clinical events such as mycobacteremia, cecum abscess, peritonitis and ascites caused by M.wolinskyi, M.holsaticum, M.duvalii and M.monacence respectively. Diabetes mellitus (P value-0.04) and previous history of tuberculosis (P value- 0.001) were identified as independent risk factors associated with NTM diseases. Conclusions/Significance NTM disease spectrum and pathogen diversity is an emerging challenge to any nation, including Saudi Arabia. Therefore, more priorities will be given to NTM’s with an immediate initiative to develop diagnostic infrastructures and disease management plans., Author summary Non-tuberculous mycobacteria (NTM) are opportunistic pathogens and saprophytes found largely in wet soil, marshland, streams, rivers and estuaries. Pulmonary and extrapulmonary Infections caused by NTM’s increased globally in immune-suppressed and immune-competent individuals without an exemption to Saudi Arabia. However, recent developments in diagnostic platforms improved the identification of several new and rare species of NTM’s. Interestingly, recent studies linked the direct impact of species spectrum on clinical outcome and therapies. To date, in Saudi Arabia, no systematic nationwide surveillance study was conducted on the challenges of NTM causing diseases. Therefore, for the first time, a nationwide inventory study on the spectrum of clinically relevant pulmonary and extra pulmonary diseases with an attempt to explore epidemiological data has been carried out. The study results showed a huge species spectrum of NTM’s causing highly diverse clinical manifestations. Clinical relevance pulmonary infection was relatively high and several very rare extrapulmonary infections also were observed. The study reported the emergence of a rare pathogen, Mycobacterium riyadhense and predominance of Mycobacterium simiae as the most common species. As the first large scale study from the GCC region, the findings cements the growing potential of various NTM species to cause significant clinical implications in the country and warrants an immediate change on disease management priorities.

F ive Mycobacterium tuberculosis isolates were obtained from three body sites from a Dutch patient. The isolates displayed a single genotype by 24-locus MIRU-VNTR typing (except for a single locus not amplified from one isolate) but were differentiated by small variations in IS 6110 fingerprints, spoligotypes, 6 hypervariable MIRU-VNTR loci, and/or DiversiLab profiles, revealing patterns of microevolution in a clonal infection.

Objective : To investigate the prevalence of Beijing genotype strains of Mycobacterium tuberculosis in the Kingdom of Saudi Arabia. Methods : We analyzed the available data on a total of 1505 strains isolated during 2002-2005. Results : Spoligotyping results revealed that Beijing family isolates represented 4.5% of all the isolates. Existence of Beijing clade is alarming as this family is known to be multi-drug resistant and transmissible. Conclusions : This study showed that the occurrence of Beijing genotype is associated with young age and drug resistance. The Beijing strains affected both Saudi nationals as well as migrants originating in Asia. The Beijing clade could be responsible for the ongoing transmission of tuberculosis within the community.

Contains fulltext : 79827.pdf (Publisher’s version ) (Open Access) A non-chromogenic, slowly growing Mycobacterium strain was isolated from a maxillary sinus lavage from a symptomatic patient in Riyadh, Saudi Arabia. It was initially identified as a member of the Mycobacterium tuberculosis complex by a commercial line-probe assay. Its 16S rRNA, hsp65 and rpoB gene and 16S-23S internal transcribed spacer sequences were unique; phylogenetic analysis based on the 16S rRNA gene sequence groups this organism close to Mycobacterium szulgai and Mycobacterium malmoense. Its unique biochemical properties and mycolic acid profile support separate species status. We propose the name Mycobacterium riyadhense sp. nov. to accommodate this strain. The type strain is NLA000201958(T) (=CIP 109808(T) =DSM 45176(T)).

An extra-pulmonary tuberculosis (EPTB) infection rate of 30% in Saudi Arabia remains above the global rate. A variable rate of infection in each province has been reported and the involvement of most organs has been cited. Nationwide collective data on the current trends of infection are scarce and the factors behind the increased rate of EPTB are perplexing. This review endeavors to shed light into the epidemiology of EPTB, various types of infections sites, geographical differences in the infection rate, known risk factors, and challenges in the diagnosis and management of EPTB in Saudi Arabia.

Background Saudi Arabia annually reports a relatively higher proportion (28–32%) of extrapulmonary tuberculosis (EPTB) cases in comparison to other global regions. However, there were few studies conducted so far to determine the sociodemographic factors and clinical manifestations associated with EPTB at a nationwide level. Methodology A retrospective analysis on culture positive EPTB isolates collected from all the provinces of the country were conducted for a period of 12 months to determine the spectrum of diversity in EPTB infection sites and the confounding factors. A detailed clinical and demographical data analysis was carried out along with first line drug susceptibility testing. Principal Findings Intra-thoracic and extra-thoracic lymph nodes (44.6%) were the most common sites of infection followed by gastrointestinal (17.3%) and central nervous systems (11.8%). Male patients were mostly infected (58.8%), in contrary to the global trend. Any drug resistance was observed in 23.1% isolates with a 2.1% of multi-drug resistance. HIV reactivity was found only in 2.2% cases. A higher proportion of Saudi nationals (58.8%) were infected compared to the immigrants, descending mostly from South Asia (34.4%) and South East Asia (31.2%). The Saudi population predominated with all forms of EPTB while immigrants showed no significant variations. Conclusions Saudi Arabia faces a serious threat from EPTB, particularly to the central nervous system and gastrointestinal systems. More effective diagnostic strategies and control measures must be implemented to reduce the high rate of EPTB in the country. In addition, these findings warrant further detailed research to explore all related comorbid conditions of EPTB development, particularly the host-related factors.

Mycobacterium abscessus is a rapidly growing non-tuberculous mycobacterium that is a common water contaminant, and an exclusive opportunistic pathogen in immunosuppressed patients; however, it occasionally causes lung infections in immunocompetent persons as well. We report two cases of chronic pulmonary infection caused by M abscessus in two young migrant workers; they were nonreactive to HIV antigen, without any history of pulmonary disorders and no evidence of any immunocompromized status. Both were initially suspected as having pulmonary tuberculosis, and antituberculosis drugs were administered. The preliminary culture found the isolate as a rapidly growing nontuberculous mycobacteria and later by advanced molecular genotyping of the isolates revealed it as M abscessus. The patients were treated with multiple drugs including clarithromycin. The symptoms resolved slowly, the smears and culture became negative, and they recovered completely. This is the first case of its type to be reported from Saudi Arabia.

Background Latent tuberculosis (TB) infection (LTBI) is screened by using clinical assessment, tuberculin skin test (TST), chest radiography and recently by interferon-gamma release assays (IGRA). The objective of this study was to evaluate the diagnostic potential of QuantiFERON®-TB Gold In-Tube test (QFT) for diagnosing LTBI in patients planned for kidney transplantation. Methods All adult patients with end-stage renal disease, evaluated for kidney transplantation in a referral center from August 2008 till May 2013, were enrolled, after consenting in a prospective, observational, non-interventional study. LTBI diagnosis was conducted by TST, chest x-ray and clinical assessment followed by IGRA by QFT. Results Overall, 278 patients were enrolled and kidney transplantation was performed in 173 patients. Contributed follow-up was 836.5 patient-years, and TB-free transplant duration was 478.5 patient-years. By standard methods, LTBI was diagnosed in 14 patients. Peri-transplant chemoprophylaxis was given to 53 patients, which included recipients of organs from all deceased donors and living donors with LTBI. QFT was positive in 70 patients, negative in 200 patients, and indeterminate in 8. The agreement between LTBI diagnosis using standard methods and IGRA by QFT was poor (kappa: 0.089 + 0.046, P-value = .017). Twenty-seven of the QFT-positive patients were transplanted and only 1 was given isoniazid preventive therapy. None of the transplant recipients developed TB after a median follow-up of 25 months (range 2-58 months, mean 27 months). Conclusions The agreement of the QFT with standard diagnosis of LTBI in kidney transplant recipients was poor. This article is protected by copyright. All rights reserved.

Background Bacillus Calmette Guerin (BCG) is the only available vaccine for tuberculosis (TB). Low grade complications in healthy recipients and disseminated vaccine associated complications among immuno-suppressed individuals were noticed globally after administration. Recently a series of clinically suspected BCG associated suppurative and non-suppurative lymphadenitis cases were reported from different regions of Saudi Arabia. However a molecular confirmative analysis was lacking to prove these claims. Methodology During 2009–2010, 42 Mycobacterium bovis BCG suspected clinical isolates from children diagnosed with suppurative lymphadenitis from different provinces of the country were collected and subjected to 24 loci based MIRU-VNTR typing, spoligotyping and first line anti-TB drugs susceptibility testing. Principal Findings Of the total 42 cases, 41 (97.6%) were Saudi nationals and particularly male (64.3%). Majority of the cases were aged below 6 months (83.3%) with a median of age 4 months. All the enrolled subjects showed left axillary mass which suppurated in a median of 4 months after vaccination. Among the study subjects, 1 (2.4%) case was reactive to HIV antigen and 2 (4.8%) case had severe combined immunodeficiency. Genotyping results showed that, 41 (97.6%) isolates were identical to the vaccine strain Danish 1331 and one to Tokyo 172-1. Phylogenetic analysis revealed all the Danish 1331 isolates in a single cluster. Conclusion Elevated proportion of suppurative lymphadenitis caused by M. bovis BCG reported in the country recently is majorly related to the vaccine strain Danish 1331. However lack of nationwide data on real magnitude of BCG related adverse events warrants population centric, long term future studies.

The real magnitude of antituberculosis (anti-TB) drug resistance in Saudi Arabia is still unknown because the available data are based on retrospective laboratory studies that were limited to hospitals or cities. A representative national survey was therefore conducted to investigate the levels and patterns of anti-TB drug resistance and explore risk factors. Between August 2009 and July 2010, all culture-positive TB patients diagnosed in any of the tuberculosis reference laboratories of the country were enrolled. Isolates obtained from each patient were tested for susceptibility to first-line anti-TB drugs by the automated Bactec MGIT 960 method. Of the 2,235 patients enrolled, 75 cases (3.4%) were lost due to culture contamination and 256 (11.5%) yielded nontuberculous mycobacteria (NTM). Finally, 1,904 patients (85.2% of those enrolled) had available drug susceptibility testing results. Monoresistance to streptomycin (8.1%; 95% confidence interval [CI], 7.2 to 9.1), isoniazid (5.4%; 95% CI, 4.7 to 6.2), rifampin (1%; 95% CI, 0.7 to 1.3) and ethambutol (0.8%; 95% CI, 0.5 to 1.2) were observed. Multidrug-resistant TB (MDR-TB) was found in 1.8% (95% CI, 1.4 to 2.4) and 15.9% (95% CI, 15.4 to 16.5) of new and previously treated TB cases, respectively. A treatment history of active TB, being foreign-born, having pulmonary TB, and living in the Western part of the country were the strongest independent predictors of MDR-TB. Results from the first representative national anti-TB drug resistance survey in Saudi Arabia suggest that the proportion of MDR-TB is relatively low, though there is a higher primary drug resistance. A strengthened continuous surveillance system to monitor trends over time and second-line anti-TB drug resistance as well as implementation of innovative control measures, particularly among immigrants, is warranted.

Item does not contain fulltext Data are scarce on demographical factors related to the population structure of Mycobacterium tuberculosis in Saudi Arabia. A study was conducted on 902 clinical isolates to explore current trends in the phylogeography and associated demographical factors of tuberculosis by using spoligotyping and 24 loci based MIRU-VNTR typing. Young male patients (aged 16-29 and 30-44) were predominant in this cohort. The phylogenetic diversity among M. tuberculosis isolates was found high, as almost all known genetic lineages were identified. Delhi/CAS (26.4%), EAI (13.7%) and Haarlem (11.3%) were the most common lineages observed, particularly among the low age groups (16-29 and 30-44 years), whereas elderly patients (>60 years) showed a predominance in the lineages S, Ghana, TUR and Uganda-I. A statistically significant association was observed between gender of the patients and lineages of EAI (p value 0.026) and LAM (p value 0.005). Overall, molecular strain cluster rate was 34.4% with an elevated rate among patients aged below 15 years (43.1%), while cases among the elderly (>60 years) showed the lowest degree of clustering (12.5%). The largest level of clustering was noticed among cases caused by strains of the lineages Haarlem (59.8%), Beijing (55.8%) and LAM (42.8%). The current population structure of M. tuberculosis in Saudi Arabia is highly diverse with significant associations to demography, transmission dynamics and origin of the patients. The difference in genotype distributions among low and high aged patients reflects the ongoing change in the strain population structure in the country. 01 juni 2013