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In the early 1990s, a multidrug-resistant Mycobacterium tuberculosis strain was identified in New York (1). This strain, designated “W,” which was associated with large institutional outbreaks of tuberculosis (TB) and many deaths, was later identified in other parts of the United States (2,3). In 1995, a large proportion of the M. tuberculosis strains in the Beijing area of China was reported to have mutually highly similar multi-banded IS6110 restriction fragment-length polymorphism (RFLP) patterns; these “Beijing” strains were also present in many other populations (4). The New York City multidrug-resistant “W” strain was, in the second half of the 1990s, recognized as a member of the “Beijing” genotype family of M. tuberculosis strains (5–7). The W strain is recognized by a specific IS6110 fingerprint pattern, by multiplex polymerase chain reaction (PCR) targeted at specific insertions, or both (2,3). W family strains have IS6110 patterns closely related to that of W, although the degree of similarity in different studies has not always been specified. Beijing strains, including the W variants, have an insertion of IS6110 in the genomic dnaA-dnaN locus (5,7). All W family strains have a characteristic spoligotype that is shared with the whole Beijing family of strains and seems to be specific for this family (4,8,9). Spoligotyping is based on DNA polymorphism in the direct repeat region, and “Beijing” spoligotypes only contain spacers 35–43.

e genomic dnaA-dnaN locus (5,7). All W family strains have a characteristic spoligotype that is shared with the whole Beijing family of strains and seems to be specific for this family (4,8,9). Spoligotyping is based on DNA polymorphism in the direct repeat region, and “Beijing” spoligotypes only contain spacers 35–43. The combination of a widespread family of strains and, in some situations, the association with multidrug resistance has led to concern that these strains may be spreading and may have a predilection for acquiring drug resistance. Many recent studies have recorded “Beijing-like” or “W-like” strains. We have conducted a systematic review of published reports to assess how widespread the family of strains is, whether there is any evidence that it is spreading, and whether it is associated with drug resistance.

ection for acquiring drug resistance. Many recent studies have recorded “Beijing-like” or “W-like” strains. We have conducted a systematic review of published reports to assess how widespread the family of strains is, whether there is any evidence that it is spreading, and whether it is associated with drug resistance. Methods Relevant studies were identified through computerized searches of Medline (January 1, 1990–November 1, 2001) and PubMed (January 1, 2000–November 1, 2001), manually searching key journals, searching the Internet, and cross-checking references with collections of articles on Beijing strains compiled by researchers in the field. The computerized searches used both thesaurus and free-text terms to search for tuberculosis and any of the following: molecular epidemiology, DNA fingerprinting, DNA fingerprint*, typing, type, types, restriction fragment-length polymorphism, RFLP, spoligotyping, spoligotyp*, strain, and strains. The International Journal of Tuberculosis and Lung Disease, its predecessor Tuberculosis and Lung Disease, and the Journal of Clinical Microbiology were searched manually back to January 1990. A request for relevant articles was sent to all 32 participants in the European Union Concerted Action project on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis. An Internet search, using Google, used the term “Beijing strain tuberculosis.” The reference lists of all included articles were searched for additional relevant studies.

nts in the European Union Concerted Action project on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis. An Internet search, using Google, used the term “Beijing strain tuberculosis.” The reference lists of all included articles were searched for additional relevant studies. Articles were included if they contained information allowing estimation of the proportion of TB patients included with the Beijing or W strains. Articles were excluded if they were limited to a particular outbreak, if they included only drug-resistant strains, or if <30 TB patients were included. Identified articles were subdivided into those that used spoligotyping to identify Beijing family strains and those that used other methods. Where spoligotypes were shown, estimates based on the spoligotype were used rather than any estimate given in the papers, using the proportion with spacers 35–43. Studies identifying only W strains or other W-like strains with a single IS6110 fingerprint pattern will underestimate the prevalence of Beijing strains, since they identify only part of the family of strains. The method of patient selection was recorded when stated. In all studies, any evidence of changes over time or by age group or of any association between strain type and drug resistance was recorded.

nt pattern will underestimate the prevalence of Beijing strains, since they identify only part of the family of strains. The method of patient selection was recorded when stated. In all studies, any evidence of changes over time or by age group or of any association between strain type and drug resistance was recorded. Results Five thousand nineteen articles were selected from the initial search of Medline and PubMed. The titles and abstracts of these articles were scanned for relevant information, and 4,909 articles were rejected, leaving 110 articles for full text review. No further articles were identified by manual searching, but one recently published article was identified in the article collections that had not yet been indexed in the databases (10). One additional article was identified from reference list check that was published in a Vietnamese journal not indexed by Medline, EMBASE, or Web of Science, and we have been unable to locate it. Another article was found from an Internet search, in an electronic journal (11). Of the 112 articles reviewed in full, 26 fulfilled the inclusion criteria of this review, including 16 that gave results based on spoligotyping and several that reported results from more than one area (Tables 1,2; Figure). Studies that described patients who were apparently included in other reports have been excluded (31,32).

2 articles reviewed in full, 26 fulfilled the inclusion criteria of this review, including 16 that gave results based on spoligotyping and several that reported results from more than one area (Tables 1,2; Figure). Studies that described patients who were apparently included in other reports have been excluded (31,32). Table 1 Prevalence of Beijing family strains in studies that have used spoligotypinga Reference Setting Yrs Population New TB or new + old Prevalence Beijing strain N/N (%) Asia 12 Beijing and Hebei province, China 1956–1960 Stored lung biopsy samples from pneumonectomies ? Both 9/10 (90) 1969–1970 8/9 (89) 1979–1980 18/18 (100) 1989–1990 10/12 (83) 1956–1990 45/49 (92) 4 Beijing, China 1992–1994 ? selection method ? Both 45/49 (92) 13 Hong Kong 1998–1999 Random sample ? New 337/500 (67) 14 Ho Chi Minh City, and Hanoi, Vietnam 1998–1999 ? All patients New 301/563 (53) 15 Bangkok, Thailand 1999–2000 One hospital ? selection method ? Both 90/204 (44) 8 Jakarta, Indonesia 1998–1999 Consecutive patients one clinic ? Both 31/92 (34) Africa 16 Senegal 1994–1995 ? selection method (all Beijing were relapses) Both 8/69 (12) Middle East 17 Fars Province and Tehran, Iran 1995–1996 All from Shiraz; ? random for others Both 10/97 (10) Europe 11 Northwest region, Russia 1997–1998 ? selection method Both 22/100 (22) 10 Azerbaijan 1995–1996 Prison ? selection method Both 46/65 (71) 18 Estonia 1994 Two hospitals, pulmonary TB New 61/209 (29) 4 Netherlands 1993–1994 Whole population Both 82/2594 (3) 19 Gran Canaria, Spain 1991–1992 Whole island ? Both 0/85 (0) 1993 10/179 (5.5) 1994 12/148 (8.1) 1995 18/110 (16) 1996 35/129 (27) 1999 9/40 (23) USA 9 New Jersey 1996–1998 Whole population Both 68/1,207 (6) 20 Houston, Texas 1994–1999 Whole population ? Both 326/1,283 (25) Caribbean 21 Cuba, outside Havana 1994–1995 Whole population ? Both 20/157 (13) 22 Guadeloupe 1994–1996 Whole island ? Both 1/95 (1) 22 Martinique 1995–1996 Whole island ? Both 0/31 0 South America 22 French Guiana 1995–1996 Whole country ? Both 0/76 0 aN/N, number with Beijing strain/ total number of patients; ?, not clear from report.

outside Havana 1994–1995 Whole population ? Both 20/157 (13) 22 Guadeloupe 1994–1996 Whole island ? Both 1/95 (1) 22 Martinique 1995–1996 Whole island ? Both 0/31 0 South America 22 French Guiana 1995–1996 Whole country ? Both 0/76 0 aN/N, number with Beijing strain/ total number of patients; ?, not clear from report. Table 2 Prevalence of Beijing and W-like strains in studies not based on spoligotypinga Reference Setting Yrs Population New TB or new + old Typing methods and definitions used Prevalence of Beijing strain N/N (%) Asia 23 Henan Province, China ? No information given ? RFLP +3.6kb Pvu II fragment 59/64 (92) 23 Philippines ? No information given ? RFLP +3.6kb Pvu II fragment 34/34 (100) 23 Hanoi, Vietnam ? No information given ? RFLP +3.6kb Pvu II fragment 20/50 (40) 23 Korea 1995 No information given ? RFLP +3.6kb Pvu II fragment 99/138 (72) 23 Thailand ? No information given ? RFLP +3.6kb Pvu II fragment 31/49 (63) 24 Bangkok Nonthaburi, Thailand 1994–1995 Patients from 3 hospitals ? how selected. Half extrapulmonary ? Both RFLP + comparison with Dutch database 80/211 (37) 23 Malaysia ? No information given ? RFLP +3.6kb Pvu II fragment 17/48 (35) 25 Malaysia 1993–1994 Random 3% sample from whole population ? Both RFLP “similar” to Beijing family 83/439 (19) Africa 26 Cape Town, South Africa 1993–1997 Whole population Both RFLP “strain U”, (W-like) Two closely related patterns only 17/650 (2.6) USA 27 New York City 1992–1994 Patients from 5 hospitals ? Both RFLP, strain W only 6/302 (2.0) 3 New York City 1990–1995 ? selection method ? Both RFLP, “W-like” 273/1,953 (14) 28 Central Los Angeles 1994–1996 Consecutive patients ? Both RFLP, strain 210 (W-related) 43/162 (27) 29 California 1992–1995 All cases from specific locations ? Both RFLP, strain 210 (W-related) 39/522 (7) 16/546 (3) 2/256 (0.8) Texas 1993–1995 Colorado 1989–1994 2 United States (excluding NY) and Puerto Rico 1992–1997 All notified cases Both RFLP and/or PCR probe. Multidrug resistant W only 23/104,549 (0.02) South America 30 Buenaventura, Colombia 1997–1998 34 treatment failure + 73 new ? selection method Both RFLP + PCR probe. “Similar” to W 11/107 (10) (? 8 in new) aN/N, number with Beijing strain/total number of patient; ?, not clear from report; the different typing methods are described in the introduction. RFLP restriction fragment length polymorphism (RFLP) using IS6110. Polymerase chain reaction (PCR) probe is a multiplex PCR probe targeted at specific insertions.

8 in new) aN/N, number with Beijing strain/total number of patient; ?, not clear from report; the different typing methods are described in the introduction. RFLP restriction fragment length polymorphism (RFLP) using IS6110. Polymerase chain reaction (PCR) probe is a multiplex PCR probe targeted at specific insertions. The 3.6 kb pvuII fragment was identified by IS1081 fingerprinting. Figure Percentage of tuberculosis due to Beijing strains. Data from studies based on spoligotyping (Table 1). The Beijing strain was most common in the Beijing area of China, accounting for 92% of strains (4,12). The strain was common in all the Asian studies (4,8,12–15,23–25) and also in Houston, Texas (25%), and Estonia (29%) (18,20). Some examples of the Beijing family were seen in almost all the populations studied (Tables 1 and 2).

g strain was most common in the Beijing area of China, accounting for 92% of strains (4,12). The strain was common in all the Asian studies (4,8,12–15,23–25) and also in Houston, Texas (25%), and Estonia (29%) (18,20). Some examples of the Beijing family were seen in almost all the populations studied (Tables 1 and 2). Two studies looked at trends over time (Table 1). In China, the proportion of TB due to Beijing family strains in stored specimens going back to the 1950s was similar to the proportion among more recent specimens (12). In Gran Canaria, a dramatic increase was seen from 1992 to 1996, traced to an outbreak originating from a noncompliant patient with laryngeal TB (19). In studies over a short period, variations with age can be studied as a proxy for time trends. In Vietnam, among new cases of TB, the proportion due to Beijing strains was 71% in those <25 years of age, decreasing to 41% in those >55 years (p < 0.001, chi square test for trend) (14). In Bangkok, little difference was seen with age in two studies (15,24). In Hong Kong (13), Jakarta, Indonesia (8), and Estonia (18), there was no association between age and disease due to the Beijing strain. In New Jersey, among those with tuberculosis due to W-like strains, 70% of patients were <50 years old, compared with 63% of those with other strains (p=0.2) (9). In Gran Canaria, the median age of cases with the Beijing strain was similar to that of all cases (19). No other studies have presented results by age.

rain. In New Jersey, among those with tuberculosis due to W-like strains, 70% of patients were <50 years old, compared with 63% of those with other strains (p=0.2) (9). In Gran Canaria, the median age of cases with the Beijing strain was similar to that of all cases (19). No other studies have presented results by age. Several studies reported associations with drug resistance (Table 3). Some studies found high rates of drug resistance among Beijing strains, but others found no difference in drug resistance profiles between Beijing and the other local strains.

rain. In New Jersey, among those with tuberculosis due to W-like strains, 70% of patients were <50 years old, compared with 63% of those with other strains (p=0.2) (9). In Gran Canaria, the median age of cases with the Beijing strain was similar to that of all cases (19). No other studies have presented results by age. Several studies reported associations with drug resistance (Table 3). Some studies found high rates of drug resistance among Beijing strains, but others found no difference in drug resistance profiles between Beijing and the other local strains. Table 3 Association between Beijing family strains of Mycobacterium tuberculosis and drug resistancea Reference Place, yr Strain % Drug resistance Comparison of Beijing vs. non-Beijing by drugb RR 95% CIb Beijing Non-Beijing Any I S MDR Beijing Non-Beijing Beijing Non-Beijing Beijing Non-Beijing Beijing Non-Beijing 13 Hong Kong, 1998–1999 310 181 6 12 10 13 I 0.54 (0.30 to 0.97) S 0.76 (0.46 to 1.3) 14 Ho Chi Minh City, 1998–1999 264 235 28 19 42 19 3 2 I 1.5 (1.1 to 2.0) S 2.2 (1.6 to 3.0) MDR 1.4 (0.47 to 4.3) 15 Bangkok, 1999–2000 90 114 No assoc 8 Jakarta, 1998–1999 27 56 41 25 37 20 15 5 Any 1.6 (0.86 to 3.1) I 1.9 (0.92 to 3.9) S 2.8 (0.67 to 11.5) 16 Senegal, 1994–1995 8 61 No assoc 11 NW Russia, 1997–1998 22 78 77 58 MDR 1.3 (1.0 to 1.8) 10 Azerbaijan, 1995–1996 46 19 89 68 80 68 83 58 61 32 Any 1.3 (0.94 to 1.8) I 1.2 (0.84 to 1.6) S 1.4 (0.95 to 2.1) MDR 1.9 (0.96 to 3.9) 18 Estonia, 1994 61 148 70 14 34 2 Any 5.0 (3.2 to 7.6) MDR 17.0 (5.3 to 54.9) 19 Gran Canaria, 1991–1996 75 576 0 ? 3 New York, 1990–1995 273 (W-like) 1,680 (not W like) 93b ?0 p <0.001 21d Cuba, 1994–1995 20 137 55–65 4–5 55–60 4 0–10 0.7–2 0 0.7 Any 10.8 (4.7 to 24.5) I 15.1 (5.8 to 38.9) 30 Colombia, 1997–1998 11 70 27 23 MDR 1.2 (0.41 to 3.4) aI, isoniazid; S, streptomycin; MDR, multidrug resistant (at least isoniazid and rifampicin); blank spaces indicate that data are not available. bRelative risks (RR) were calculated when possible from the data presented. These are shown with 95% confidence intervals. c Resistant to at least four drugs. Includes 206 W strains and 40 W1 strains. Identified by RFLP, not spoligotyping. dExact numbers not clear since drug resistance data only given by strain number for IS6110 defined clusters, and two Beijing strains were not clustered. For the relative risk calculation, the minimum proportion resistant among the Beijing strains was used.

rains and 40 W1 strains. Identified by RFLP, not spoligotyping. dExact numbers not clear since drug resistance data only given by strain number for IS6110 defined clusters, and two Beijing strains were not clustered. For the relative risk calculation, the minimum proportion resistant among the Beijing strains was used. An association between the successful spread of Beijing strains and BCG vaccination has been suggested (4). In Jakarta, Indonesia (8), 26% of those with Beijing strains and 23% of other patients had a BCG scar. In Vietnam, although a higher proportion of those with Beijing strains than with other strains had a BCG scar, this association was no longer apparent after the data were adjusted for age (14).

has been suggested (4). In Jakarta, Indonesia (8), 26% of those with Beijing strains and 23% of other patients had a BCG scar. In Vietnam, although a higher proportion of those with Beijing strains than with other strains had a BCG scar, this association was no longer apparent after the data were adjusted for age (14). Discussion This review has confirmed the ubiquity of the Beijing family of strains. Only a few of the smaller studies (in Martinique and French Guiana) found no examples, and the proportion of TB due to Beijing strains in several Asian studies was >50%. However, studies could only be included in the review if they mentioned the Beijing strain or strain W or presented data showing spoligotypes. Some of the excluded studies may have found Beijing strains but not reported them as such (33,34). Others may have looked for Beijing strains but not reported negative findings. The only articles identified that reported not finding Beijing strains were studies including more than one study site. It is not known how unusual it is for a genotype family of M. tuberculosis to be as widespread as this. Comparable data are not available for other strains, although they are beginning to be gathered, and some other strains have also been found in several distinct settings (35).

dies including more than one study site. It is not known how unusual it is for a genotype family of M. tuberculosis to be as widespread as this. Comparable data are not available for other strains, although they are beginning to be gathered, and some other strains have also been found in several distinct settings (35). In many studies, the true proportion of TB attributable to the Beijing family of strains is hard to assess. Difficulties arise due to the variable strain definitions used and the way patients were selected for inclusion. Spoligotyping seems to be both sensitive and specific for the Beijing family and is also easily compared between studies (6). Although IS6110 fingerprinting can also be used to detect this genotype family, with results that correlate closely with the spoligotypes, most published studies have used narrow definitions, based on a single strain or a few closely related strains defined by IS6110 fingerprinting; such studies are thus likely to underestimate the prevalence of Beijing strains. Studies including drug resistance in the definition (2) and those that appear to have defined the strains after grouping by drug resistance (26) may also underestimate the prevalence.

osely related strains defined by IS6110 fingerprinting; such studies are thus likely to underestimate the prevalence of Beijing strains. Studies including drug resistance in the definition (2) and those that appear to have defined the strains after grouping by drug resistance (26) may also underestimate the prevalence. Some of the studies (those in the Netherlands, New Jersey, Houston, Texas, and French Guiana and the Caribbean islands) included information on all TB patients in the population and thus provide reliable estimates of prevalence. Others were less representative, and many did not state how the patients were selected (Table 1 and 2). Studies that included patients from particular hospitals may be representative of an area, but referral hospitals may be biased if they accept a high proportion of drug-resistant or complex cases. Similarly, convenience samples may not be representative of the community of TB patients, particularly if the samples were kept because they were interesting in some way (e.g., drug resistant or from epidemiologically related cases). TB patients in prison (10) may not have the same strains as those in the community. Some studies included only new patients, and others included both new patients and recurrent cases. This distinction, which was often not clear in the reports, could influence the results if relapse rates differ between strains.

cases). TB patients in prison (10) may not have the same strains as those in the community. Some studies included only new patients, and others included both new patients and recurrent cases. This distinction, which was often not clear in the reports, could influence the results if relapse rates differ between strains. In many studies, some culture-positive specimens are not typed because they are nonviable. IS6110 RFLP typing relies on large quantities of DNA and hence on viable strains, and theoretically some genotypes may survive better than others in vitro. Spoligotyping is PCR-based so does not require viable isolates, but it is sometimes used only as a secondary method in specimens that have already been typed by IS6110 RFLP.

LP typing relies on large quantities of DNA and hence on viable strains, and theoretically some genotypes may survive better than others in vitro. Spoligotyping is PCR-based so does not require viable isolates, but it is sometimes used only as a secondary method in specimens that have already been typed by IS6110 RFLP. Associations with drug resistance were variable (Table 3): of the 12 studies with data available, only 4 found statistically significant increases in the proportions of drug resistance among those with Beijing strains. Of the Asian studies, only one found a statistically significant increase in drug resistance in Beijing strains (14), and in Hong Kong the Beijing strains were less likely than the others to be isoniazid resistant (13). In contrast, Beijing strains were strongly associated with drug resistance in New York, Cuba, and Estonia (3,18,21). In New York, the spread of the W strain, which was mainly nosocomial and institutional, has been attributed in part to drug resistance. Once a strain has become multidrug resistant, treatment is more complicated so patients may remain infectious for a longer period. Whether the Beijing family has a particularly high probability of acquiring drug resistance is not known but is suggested by the fact that these associations with the same strain family have been found in widely distributed areas.

ant, treatment is more complicated so patients may remain infectious for a longer period. Whether the Beijing family has a particularly high probability of acquiring drug resistance is not known but is suggested by the fact that these associations with the same strain family have been found in widely distributed areas. The published studies provided little direct evidence that the Beijing strain has been increasing. Of the two studies that included time trends, one found no increase in a population with a very high prevalence for many decades (12), and in the other the increase may be attributable to the characteristics of the index patient in the outbreak (19,36). In Vietnam, the proportion of new TB patients with the Beijing strain decreased with age, suggesting an increase in Beijing strains in the communities studied (14). No association with age was found anywhere else (8,9,13,15,18,19,24), including the two other studies restricted to new patients (13,18).

outbreak (19,36). In Vietnam, the proportion of new TB patients with the Beijing strain decreased with age, suggesting an increase in Beijing strains in the communities studied (14). No association with age was found anywhere else (8,9,13,15,18,19,24), including the two other studies restricted to new patients (13,18). On the other hand, the ubiquity of the Beijing strain and its frequent appearance in outbreaks, particularly of drug-resistant TB, suggest that it may have the potential to spread. In Estonia, although there was no association between Beijing strains and age, TB and particularly multidrug-resistant (MDR) TB have been increasing, and most MDR TB was found to be due to Beijing strains (18). The limited amount of information available from most areas of the world and the possible biases in many of the studies make definite conclusions about the extent of spread and associations with drug resistance impossible. Through the European Concerted Action on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis, a standard definition of the Beijing genotype is being finalized, by comparisons of large collections of strains typed with spoligotyping, IS6110 RFLP, and Region A RFLP, which visualizes insertion of IS6110 in the genomic dnaA-dnaN locus (ms. in preparation). Studies are planned to reanalyze available data worldwide by using standard definitions and approaches.

e is being finalized, by comparisons of large collections of strains typed with spoligotyping, IS6110 RFLP, and Region A RFLP, which visualizes insertion of IS6110 in the genomic dnaA-dnaN locus (ms. in preparation). Studies are planned to reanalyze available data worldwide by using standard definitions and approaches. Further studies are also needed to include more areas in an unbiased way, to study historical specimens if possible, and to investigate the virulence (8) and transmissibility of this potentially important family of M. tuberculosis strains. The question to be answered is if and to what extent Beijing genotype strains have selective advantages over other M. tuberculosis genotypes in the ability to gain resistance and to interact with the host immune defense system. If Beijing genotype strains represent a higher level of evolutionary development of M. tuberculosis being selected for as a result of the introduction of tuberculostatics, which inhibit the growth of M. tuberculosis, then consequences for the treatment of tuberculosis will be serious. Suggested citation for this article: Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis [serial online] 2002 Aug [date cited];8. Available from: URL: http://www.cdc.gov/ncidod/EID/vol8no8/02-0002.htm Acknowledgments We thank Martien Borgdorff for helpful comments on an earlier draft.

Suggested citation for this article: Glynn JR, Whiteley J, Bifani PJ, Kremer K, van Soolingen D. Worldwide occurrence of Beijing/W strains of Mycobacterium tuberculosis: a systematic review. Emerg Infect Dis [serial online] 2002 Aug [date cited];8. Available from: URL: http://www.cdc.gov/ncidod/EID/vol8no8/02-0002.htm Acknowledgments We thank Martien Borgdorff for helpful comments on an earlier draft. This paper was written as part of the EU Concerted Action project QLK2-CT-2000-00630. JRG is partially funded by the Department for International Development, United Kingdom. Dr. Glynn is a senior lecturer in epidemiology at the London School of Hygiene and Tropical Medicine, London, United Kingdom. Her research interests include tuberculosis, HIV, and molecular epidemiology.