|Year : 2020 | Volume
| Issue : 1 | Page : 62-70
An overview of pulmonary infections due to rapidly growing mycobacteria in South Asia and impressions from a subtropical region
Kamal Shrivastava1, Chanchal Kumar1, Anupriya Singh1, Anshika Narang1, Astha Giri1, Naresh Kumar Sharma1, Shraddha Gupta1, Varsha Chauhan1, Jayanthi Gunasekaran1, Viswesvaran Balasubramanian2, Anil Chaudhry3, Rupak Singla4, Rajendra Prasad2, Mandira Varma-Basil1
1 Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
2 Pulmonary Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
3 Department of Pulmonary Medicine, Rajan Babu Institute of Pulmonary Medicine and Tuberculosis, Delhi, India
4 Department of TB and Respiratory Diseases, National Institute of Tuberculosis and Respiratory Diseases, Delhi, India
|Date of Submission||15-Nov-2019|
|Date of Acceptance||23-Nov-2019|
|Date of Web Publication||6-Mar-2020|
Department of Microbiology, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi - 110 007
Source of Support: None, Conflict of Interest: None
Background: Rapidly growing mycobacteria (RGM) comprise nearly half of the validated species of nontuberculous mycobacteria (NTM) and have been reported to have a higher incidence in Asia as compared to Europe and America. There is limited information on RGM infections from South Asia. Hence, the present study aimed to ascertain the incidence of pulmonary infections due to RGM in Delhi and to review the status of available information on the prevalence of RGM in South Asia, a region endemic for tuberculosis. Methods: We analyzed 933 mycobacterial isolates obtained from pulmonary samples in Delhi and performed species identification by polymerase chain reaction (PCR)-restriction analysis (restriction fragment length polymorphism) and line probe assay. Drug susceptibility testing (DST) was performed by broth microdilution method. We also reviewed reports available on pulmonary infections in South Asia, attributed to RGM. Results: Of the 933 mycobacterial isolates studied, NTM were identified in 152 (16.3%). Of these, 65/152 (42.8%) were RGM comprising Mycobacterium fortuitum (34/65; 52.3%), Mycobacterium abscessus (25/65; 38.5%), Mycobacterium chelonae (3/65; 4.61%), Mycobacterium mucogenicum (2/65; 3.1%), and Mycobacterium smegmatis (1/65; 1.5%). On applying the American Thoracic Society/Infectious Diseases Society of America guidelines, 11/25 (44%) M. abscessus, 3/3 (100%) M. chelonae, and both isolates of M. mucogenicum were found to be clinically relevant. DST revealed that maximum susceptibility of the RGM was seen to linezolid, clarithromycin, and amikacin. Conclusions: Of the RGM isolated in the present study, 16/65 (24.6%) were found to be clinically relevant. Hence, it is important to recognize these organisms as potential pathogens to identify patients with RGM disease to initiate appropriate therapy.
Keywords: India, nontuberculous mycobacteria, rapidly growing mycobacteria, rapidly growing mycobacteria pulmonary infections, South Asia
|How to cite this article:|
Shrivastava K, Kumar C, Singh A, Narang A, Giri A, Sharma NK, Gupta S, Chauhan V, Gunasekaran J, Balasubramanian V, Chaudhry A, Singla R, Prasad R, Varma-Basil M. An overview of pulmonary infections due to rapidly growing mycobacteria in South Asia and impressions from a subtropical region. Int J Mycobacteriol 2020;9:62-70
|How to cite this URL:|
Shrivastava K, Kumar C, Singh A, Narang A, Giri A, Sharma NK, Gupta S, Chauhan V, Gunasekaran J, Balasubramanian V, Chaudhry A, Singla R, Prasad R, Varma-Basil M. An overview of pulmonary infections due to rapidly growing mycobacteria in South Asia and impressions from a subtropical region. Int J Mycobacteriol [serial online] 2020 [cited 2020 Mar 30];9:62-70. Available from: http://www.ijmyco.org/text.asp?2020/9/1/62/280138
| Introduction|| |
Rapidly growing mycobacteria (RGM) are ubiquitous organisms isolated from soil, dust, rocks, and water and are characterized by visible growth on solid media within 7 days. Although generally of low virulence, RGM especially, Mycobacterium abscessus, Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium mucogenicum, are being increasingly seen to cause a wide spectrum of diseases including pulmonary, skin, soft tissue, and disseminated infections.,,, Moreover, the high hydrophobicity of RGM, and other nontuberculous mycobacteria (NTM), favors the formation of biofilms, accounting for their resistance to antibiotics and commonly used disinfectants. Dispersal of the organisms from biofilms may also be a source of nosocomial infection in patients through water pipes or other devices. In fact, it has been reported that hospital-acquired infections due to NTM are most commonly associated with RGM. However, due to their ubiquitous nature, isolation of RGM from clinical specimens does not necessarily indicate NTM disease and was until recently, often ignored. The recent progress in the development of rapid molecular methods in clinical microbiology has led to increased isolation and identification of these organisms from clinical specimens.,, Consequently, a number of new species have been identified and some species previously considered to be contaminants, are now recognized as pathogens. With increasing awareness of the importance of RGM, clinicians are facing challenges while treating patients with RGM infection, especially if the RGM has been recently identified as a pathogen.
Species-level identification of RGM is recommended as the susceptibility pattern varies among different species. Since conventional biochemical tests are time-consuming and cumbersome, laboratorians rely on molecular methods of identification such as polymerase chain reaction restriction analysis (PRA), line probe assay (LPA), and sequencing of hsp65 or16s rRNA. Furthermore, most RGM are resistant to first-line antituberculous drugs. In fact, M. abscessus is the most difficult to treat. Hence, drug susceptibility has been recommended for all RGM found to be clinically relevant.,
Although reports on the incidence of RGM infection are increasing, most of the reports come from industrialized nations of the world., There is still a paucity of data on RGM infections from South Asia, a region that is also endemic for tuberculosis (TB)., Here, we report our experience with RGM associated with pulmonary infections in Delhi, India, and present an overview of clinically significant RGM identified in South Asia, to understand the extent of awareness of these pathogens in this region.
| Methods|| |
A review of the reports on RGM in South Asia was conducted in accordance with PRISMA guidelines. The overall aim of this review was to determine the prevalence of clinically significant RGM in patients with pulmonary infection in South Asia. We included Afghanistan, Bangladesh, Bhutan, Nepal, India, Pakistan, Sri Lanka, and the Maldives in the South Asian region. We searched PubMed, Scopus, EMBASE, and Copernicus for publications on RGM involved in pulmonary infection in South Asia from January 2002 to June 2018 using various combinations of the search terms NTM, atypical mycobacteria, RGM, South Asia, Afghanistan, Bangladesh, Bhutan, Nepal, India, Pakistan, Sri Lanka, Maldives, and pulmonary infections.
Selection process and data abstraction
The titles and abstracts of all the articles obtained in the database search were screened and full-text copies of those found to be relevant to our search obtained. For all relevant articles, we extracted the following data using a data extraction sheet: research setting, study period, population tested and numbers, NTM species isolated, method for NTM identification, prevalence of pulmonary NTM isolation/disease, HIV coinfection rate, and risk factors for NTM acquisition. At least two authors reviewed each article.
In estimating country-level and overall prevalence of NTM in South Asia, a pooled estimate was computed based on the reported prevalence. We checked all retrieved articles for application of the American Thoracic Society (ATS) diagnostic criteria for clinically relevant RGM and recorded the proportion of patients meeting these criteria and NTM species responsible for infection.
Reporting the rapidly growing mycobacteria associated with pulmonary infections in Delhi, India
Clinical specimens and mycobacterial isolates
A total of 933 isolates were obtained from patients suspected of suffering from pulmonary mycobacterial disease between January 2014 and April 2019 at the Department of Microbiology, Vallabhbhai Patel Chest Institute, Delhi, India, after approval from the Institutional ethical committee. The patients had reported to the outpatient unit of Vallabhbhai Patel Chest Institute, Rajan Babu Institute of Pulmonary Medicine and TB of Delhi, or National Institute of TB and Respiratory Diseases, Delhi, India. The clinical isolates obtained were characterized by their colony morphology on Lowenstein–Jensen medium and were subjected to biochemical identification by niacin, nitrate reduction, and semi-quantitative catalase tests. Further characterization of the isolates was performed by PRA of the hsp65 gene using the enzymes NruI and BamHIas previously described.
Species identification by line probe assay
Species identification of the isolates identified as NTM was performed by GenoType Mycobacterium CM/AS (Hain Lifescience GmbH, Germany).
Species identification of a subset of the clinical isolates was confirmed by Sanger sequencing of heat-shock protein-65 (hsp65) gene in an Applied Biosystems Automated Sequencer (Ocimum Biosolutions, Bengaluru, India). Sequences were identified by similarity using Blastn available at National Center for Biotechnology Information (NCBI) (www.blast.ncbi.nlm.nih.gov/blast.cgi). Species identification was confirmed if 97% match was obtained with a sequence deposited in the database, according to the criteria proposed by McNabb et al.
Clinical relevance of rapidly growing mycobacteria
Clinical records of patients were reviewed to assess the clinical relevance of the NTM isolated according to ATS guidelines.
Minimum inhibitory concentration
Minimum inhibitory concentrations (MICs) of the clinically relevant RGM were performed by broth microdilution method described by Li et al. in U-bottomed microtiter plates (Falcon, New York) using streptomycin (STR), isoniazid (INH), ethambutol (EMB), ciprofloxacin (CIP), clarithromycin (CLR), amikacin (AMK), cefoxitin (FOX), linezolid (LZD), doxycycline (DOX), imipenem (IPM), sulfamethoxazole (SFX), levofloxacin (LVX), tetracycline, and clofazimine (Sigma Aldrich, St. Louis, MO, USA) and rifampicin (RIF) (MP Biomedicals, Santa Ana, CA, USA). Various concentrations of the drugs [Table 1], dissolved in an appropriate solvent, were added to microtiter plates in triplicates, followed by the addition of 100 μl of the test inoculum that had been adjusted to 0.5 McFarland's standard. The microtiter plates were sealed with parafilm and incubated at 37°C for 72 h. Freshly prepared 30 μl of Alamar Blue reagent (0.2 mg/ml) was added to the wells after 3 days. The plates were reincubated at 37°C for 24 h, and the color change in all wells, from blue to pink indicating the growth of bacteria, was recorded. MIC was recorded as the lowest concentration of drug preventing color change.
|Table 1: Antimicrobials tested against rapidly growing mycobacteria in the present study|
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Written informed consent and detailed history of contact were taken from each patient prior to the collection of samples, following approval of the study by the Institutional Ethics Committee of Vallabhbhai Patel Chest Institute. All experiments were performed in accordance with the ethical standards of the Declaration of Helsinki.
| Results|| |
Description of included studies
We conducted a review of the literature focusing on RGM reported in South Asia. With the search terms nontuberculous mycobacteria, atypical mycobacteria, rapidly growing mycobacteria, South Asia, Afghanistan, Bangladesh, Bhutan, Nepal, India, Pakistan, Sri Lanka, Maldives, pulmonary infections, we identified 81 reports from South Asia and excluded case reports, reviews, and editorials. We also excluded publications where the isolates had not been clearly differentiated as pulmonary or extrapulmonary, identification had not been done up to species level, where the RGM described were reported only from extrapulmonary sites or from the environment. Thus, 17 articles were selected [Table S1]a and [Table S1]b, of which the maximum number of reports was from India (14/17; 82.3%) [Table 2].,,,,,,,,,,,,, Pakistan, Sri Lanka, and Nepal had one study each (1/17; 5.8%) [Table 2].,, The most common method used for species identification was the difference in growth and biochemical characteristics observed in 15/17 (88.2%) articles. Of these, 8/15 (53%) also used a molecular assay. Investigators used the MPT64 antigen immunochromatography test in 2/17 (11.7%) studies to differentiate between Mycobacterium tuberculosis complex (MTBC) and NTM [Table 2].
Of the 1324 NTM identified, 852 (64.35%) were rapid growers. The most common RGM was M. fortuitum (333/852; 39.08%), followed by M. abscessus (250/852; 29.34%) and M. chelonae (173/852; 20.3%). Of the 470 RGM isolated from pulmonary NTM disease, M. fortuitum (181/470; 38.5%) was the most common, followed by M. abscessus (146/470; 31%). M. abscessus pulmonary disease was reported in India, though the report from Pakistan reported the occurrence of M. chelonae–M. abscessus. In Pakistan, Mycobacterium smegmatis (11/64; 17.19%) and M. mucogenicum (9/64; 14.06%), were the most common RGM found in pulmonary samples after M. fortuitum (16/64; 25%) [Figure 1].
|Figure 1: Rapidly growing mycobacteria causing pulmonary infections in South Asia.,,,,,,,,,,,,,,,, Highlighted box shows the rapidly growing mycobacteria isolated from pulmonary infections in the present study|
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Clinical relevance of nontuberculous mycobacteria
For the analysis, we excluded articles where specific criteria for identifying clinical relevance of NTM (viz., ATS guidelines) had not been followed and nine articles were selected.,,,,,,,, However, clinically relevant RGM were identified in only eight studies. The ninth study isolated only one RGM, Mycobacterium flavescens, which was not clinically relevant. Out of the eight studies included in the final analysis, maximum number of reports was from India (6/8; 75%). Pakistan and Sri Lanka had one study each (1/8; 12.5%) [Table 2].
Of the 238 clinically significant NTM isolated from pulmonary specimens, 122 (51.26%) were rapid growers. The most common RGM was M. chelonae (46/122; 37.7%), followed by M. fortuitum (45/122; 36.89%) and M. abscessus (18/122; 14.75%) [Figure 2].
|Figure 2: Clinically relevant rapidly growing mycobacteria isolated from pulmonary specimens in South Asia.,,,,,,,, Highlighted box shows the clinically relevant rapidly growing mycobacteria isolated from pulmonary infections in the present study|
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Drug susceptibility profile of the clinically relevant rapidly growing mycobacteria in the included studies
The eight articles that identified clinically relevant RGM were also screened for reports of drug susceptibility profile of the RGM and five articles reporting drug susceptibility testing (DST) were selected for analysis.,,,, Of these, 3/5 (60%) studies were from India and 1/5 (20%) each were from Pakistan and Sri Lanka. Studies that did not report species-specific susceptibility pattern were not included in the final analysis.
The DST pattern revealed that no uniform methodology was used in the five studies that reported the DST. Two studies each (2/5; 40%) used broth microdilution assay and disc diffusion assay and one (1/5; 20%) used Etest. A varying resistance pattern was observed to all the antibiotics tested [Table 3].
|Table 3: Drug resistance profile of the clinically relevant rapidly growing mycobacteria isolated from pulmonary samples in the studies included from South Asia|
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Rapidly growing mycobacteria associated with pulmonary infections in Delhi, India
Clinical isolates (n = 933) were subjected to primary screening by PRA to differentiate between MTBC and NTM. Of these, 152/933 (16.3%) isolates were identified as NTM.
Speciation of the isolated nontuberculous mycobacteria and establishment of clinical relevance of the rapidly growing mycobacteria
Of all the NTM isolated, RGM were identified in 65/152 (42.8%) isolates and the remaining were slow growers. Majority of the RGM (34/65; 52.3%) were M. fortuitum, followed by M. abscessus (25/65; 38.5%), M. chelonae (3/65; 4.6%), M. mucogenicum (2/65; 3%), and M. smegmatis (1/65; 1.5%). Mycobacterium intracellulare was the most common (45/87; 51.7%) slow-growing NTM isolated, followed by Mycobacterium kansasii (24/87; 27.6%), Mycobacterium simiae (15/87; 17.2%), Mycobacterium celatum (1/87; 1.1%), and Mycobacterium malmoense (1/87; 1.1%). One slow-growing NTM could not be speciated.
Of the 65 isolates of RGM, clinical relevance was attributed to 16/65 (24.6%) isolates on the basis of ATS guidelines. Of the 25 M. abscessus identified, 11/25 (44%) were clinically relevant and were recovered repeatedly from five patients. Two M. mucogenicum isolates were obtained from repeated samples of a single patient with symptoms of prolonged cough, fever, and loss of appetite. Two isolates of M. chelonae were also repeatedly isolated from a single patient with tracheostomy. The third isolate of M. chelonae was a repeat isolate obtained from a patient with complaints of cough and weight loss.
Antimicrobial susceptibility testing
The isolates were categorized into sensitive, intermediate, and resistant according to the breakpoint described previously. Antimicrobial susceptibility testing was performed for the clinically relevant RGM. Since multiple isolates were obtained from patients, a single isolate from each patient was taken up for DST. One isolate of M. abscessus was lost during subculture, thus antimicrobial susceptibility testing was performed for four isolates of M. abscessus, two isolates of M. chelonae, and one isolate of M. mucogenicum. All the four isolates of M. abscessus were resistant to STR, INH, RIF, EMB, DOX, and SFX [Table 4]. None of the isolates were resistant to CLR and LZD. M. mucogenicum (n = 1) and M. chelonae (n = 2) were also resistant to STR, INH, RIF, EMB, and SFX [Table 4]. M. mucogenicum was susceptible to AMK, FOX, CLR, CIP, LZD, and LVX, while M. chelonae showed susceptibility only to AMK, CLR, and LZD.
|Table 4: Drug resistance profile of the rapidly growing mycobacteria isolated from pulmonary samples in the present study|
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| Discussion|| |
RGM comprise nearly half of the validated mycobacterial species known till date and have been grouped into six major taxonomic groups on the basis of their phenotypic and genotypic characters, namely, M. fortuitum, M. chelonae/M. abscessus complex, M. smegmatis, M. mucogenicum, Mycobacterium mageritense/Mycobacterium wolinskyi, and the pigmented RGM. Although ubiquitous in nature, RGM can lead to a wide spectrum of diseases ranging from asymptomatic illness to soft-tissue infections to chronic pulmonary infections. In fact, RGM were first implicated in human disease in 1938 when da Costa Cruz attributed a postinoculation abscess to an RGM that he described and named M. fortuitum. Since then, RGM have increasingly been implicated as pathogens and reports have further increased with the advent of molecular assays.
Like other NTM, the distribution of RGM also varies by region. Although geographic diversity has been studied by some investigators, there are very little data from South Asia. Hence, we reviewed the available literature from eight countries in South Asia, namely, Afghanistan, Bangladesh, Bhutan, Nepal, India, Pakistan, Sri Lanka, and the Maldives.
We obtained 81 reports from this region, of which we analyzed 17 reports that had given details of the source of samples collected. No data were available from Afghanistan, Bhutan, Bangladesh, or Maldives. A maximum number of reports were from India, followed by Pakistan [Table 2]. Of the 17 articles retrieved, the most common method used for identification was difference in growth and biochemical characteristics observed in 15/17 (88.2%) articles, of which 8/15 (53%) used a molecular assay in addition to conventional techniques. The number of articles reporting use of molecular assays alone or in conjunction with an immunochromatographic technique was lower (2/17; 11.7%) than the studies using conventional techniques alone (7/17; 41.18) (Fisher's exact test >P = 0.05). Given the improvement in molecular diagnostics in the last decade and the availability of rapid results, we expected a greater number of investigators using molecular diagnostic tools. However, the popularity of the conventional methods of diagnostics was probably due to the higher cost of molecular tests which are not easily accessible in several regions of South Asia.
The most common molecular tests used were PRA (7/17; 41.18%) and line probe hybridization assays (3/17; 17.65%). Sequencing was used only in four studies (23.53%) [Table 2]. Sequencing is not easily accessible to several laboratories, while PRA is a sensitive and specific technique which is more cost-effective than the currently available commercial assays, which may account for it being used more frequently than sequencing. Of the studies using LPAs, one study used an in-house reverse line blot hybridization assay, while two used the genotype CM/AS assay.,
Of the 1324 NTM identified in the 17 articles retrieved from South Asia, 852 (64.35%) were RGM. Although RGM comprise about 50% of the currently validated NTM species encountered in clinical settings, in various surveys conducted previously, RGM were found to vary from 3% to 14% of the clinically relevant NTM isolated from pulmonary samples., However, in their review of NTM isolation from Asia, Simons et al. reported that RGM were responsible for 14% of pulmonary NTM infections, except in India, Taiwan, South Korea, where they were responsible for >30% of infections. Simons et al. hypothesized that the fact that RGM were frequently found in pulmonary samples in Asia, could reflect ethnic susceptibility, laboratory practices, or higher environmental exposure to RGM in Asia.
The most common RGM isolated from pulmonary specimens, identified in the 17 articles included in this review, was M. fortuitum (181/470; 38.5%), followed by M. abscessus (146/470; 31%) [Figure 1]. The rare RGM, M. thermoresistibile was isolated in one study from Pakistan. However, the source of these isolates was not mentioned, hence the study was not included in the final analysis. Although M. thermoresistibile has been isolated earlier in Iran, no cases have yet been reported from South Asia, other than Pakistan. It may be noted, that of the 17 studies included, only nine studies had followed the clinical guidelines (namely, ATS guidelines) to identify clinically relevant RGM.
Drug susceptibility profile was reported in five studies that demonstrated isolation of clinically relevant RGM. It was observed that no uniform method of DST was used in these studies. Two studies each (2/5; 40%) used broth microdilution assay and disc diffusion assay and one (1/5; 20%) used E test. Although a varying resistance pattern was observed to all the antibiotics tested, maximum susceptibility was observed to AMK [Table 3].
In our own investigation, we identified RGM in 65 (42.8%) of the 152 NTM isolated from clinical specimens. On applying the ATS guidelines for clinical relevance, 11 of the M. abscessus were clinically relevant, as they were isolated from multiple samples of five patients. Two isolates of M. mucogenicum were isolated repeatedly from the respiratory secretions of a single patient. M. mucogenicum has rarely been reported from South Asia. One study in Pakistan isolated nine isolates of M. mucogenicum from pulmonary samples and three from extrapulmonary samples. In India, M. mucogenicum was reported to be clinically relevant in a sample from pleural tap in one study. Sankar et al. reported the drug susceptibility of a single clinical isolate of M. mucogenicum. However, the source of this isolate was not mentioned. The ATS guidelines recommend routine susceptibility testing for both taxonomic identification and treatment of M. fortuitum, M abscessus, and M. chelonae with AMK, DOX, fluorinated quinolones, a sulfonamide or trimethoprim-SFX, FOX, CLR, and LZD. Testing against IPM is recommended only for M. fortuitum and M. mucogenicum, as it is reproducible. Hence, in the present study, we tested IPM only against M. mucogenicum (n = 1) and found it to be resistant.
The investigations conducted in our laboratory revealed high susceptibility of M. abscessus to LZD, CLR, and AMK [Table 4]. Similarly, high susceptibility of M. abscessus to CLR and AMK has been reported in other studies also.,
The two isolates of M. chelonae were susceptible to AMK, CLR, and LZD, consistent with the report of Goswami et al., though the latter had not reported the susceptibility of M. chelonae to LZD.
The Clinical and Laboratory Standards Institute recommends the broth microdilution method for DST of RGM. Agar-based methods and E test are not recommended due to inconsistent results. However, a number of articles we reviewed had used the Etest or Kirby–Bauer method for DST of RGM.,, The variation in the drug susceptibility patterns in various studies highlights the importance of using a uniform technique for drug susceptibility assays of RGM.
| Conclusions|| |
There is a large gap in our knowledge of RGM in South Asia. In fact, there are no reports from a number of regions. With the improvement in molecular diagnostic techniques and better awareness of the importance of RGM as potential pathogens, it is very important to generate data on the occurrence of these pathogens to be able to identify patients harboring these agents. It is also necessary to follow uniform methodology for DST to be able to treat these patients.
KS and CK would like to acknowledge the Department of Science and Technology and Indian Council of Medical Research, respectively, for providing fellowship.
Financial support and sponsorship
This work was supported by the Indian Council of Medical Research, India (No. 5/8/5/14/2013-ECD1).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]