Borgdorff, M.W.

de Haas, P.

Kremer, K.

van Soolingen, D.

English

International Migration, Integration and Social Cohesion online publications

UvA-DARE is a service provided by the library of the University of Amsterdam (https://dare.uva.nl)UvA-DARE (Digital Academic Repository)Mycobacterium tubercuiosis Beijing genotype, the NetherlandsBorgdorff, M.W.; de Haas, P.; Kremer, K.; van Soolingen, D.Publication date2003Published inEmerging Infectious DiseasesLink to publicationCitation for published version (APA):Borgdorff, M. W., de Haas, P., Kremer, K., & van Soolingen, D. (2003). Mycobacteriumtubercuiosis Beijing genotype, the Netherlands. Emerging Infectious Diseases, 9(10), 1310-1313.General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s)and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an opencontent license (like Creative Commons).Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, pleaselet the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the materialinaccessible and/or remove it from the website. Please Ask the Library: https://uba.uva.nl/en/contact, or a letterto: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. Youwill be contacted as soon as possible.Download date:11 Nov 2022MycobacteriumtuberculosisBeijing Genotype,the NetherlandsMartien W. Borgdorff,*† Petra de Haas,‡ Kristin Kremer,‡ and Dick van Soolingen‡To determine whether the Beijing genotype ofMycobacterium tuberculosis is emerging in theNetherlands, we collected data on 6,829 patients during1993 to 2000. Six percent had the Beijing genotype. Thisgenotype was associated with diagnosis in recent years,young age, nationality, and multidrug resistance. The Beijing genotype is found frequently in Asia (1–3)but also in outbreaks of multidrug-resistant tuberculo-sis (MDRTB) in various parts of the world, includingCuba, Germany, Russia, and Estonia (4–7). The largestknown epidemic of MDRTB in North America was causedby the W strain, a variant of the Beijing genotype (8–9). Arecent study showed this strain’s emergence and associa-tion with drug resistance in Vietnam (10). The Beijinggenotype was also responsible for a recent outbreak oftuberculosis (TB) on the Canary Islands (11).The relatively high degree of genetic conservation ofBeijing genotype strains found in a widespread area (12)suggests a recent dissemination and, hence, selectiveadvantages associated with this genotype ofMycobacterium tuberculosis. Recently, Beijing genotypebacteria were reported to carry mutations in putative muta-tor genes, which may explain a higher adaptability of thesebacteria under stress conditions such as exposure to theintracellular environment or anti-TB drugs (13). Thesemutations may also be the basis of differential interactionbetween Beijing genotype bacteria and the host immunedefense system suggested in a recent study in Indonesia(14).In the Netherlands, MDRTB is affecting <1% of newTB patients, in particular immigrants (15–17). The inci-dence of the Beijing genotype has not yet been described.The goal of our study was to determine whether the Beijinggenotype is emerging in the Netherlands and whether thisgenotype is associated with multidrug resistance.The StudyPatient data were obtained from the NetherlandsTuberculosis Register, which is maintained by the RoyalNetherlands Tuberculosis Association and has been inplace since 1993. Municipal health services, which areresponsible for the followup of all TB patients, send infor-mation using standardized, precoded forms on all reportedTB cases to the register. The register includes informationon demographic characteristics, case detection, riskgroups, type of disease, treatment, and treatment outcome.Isolates obtained from all 8,210 culture-positivepatients underwent restriction fragment length polymor-phism (RFLP)–typing with IS6110 as a probe at theNational Institute of Public Health and the Environment.The Beijing genotype was defined on the basis of spoligo-type (no spacers 1–34; at least 4 of spacers 35–43) and aspecific region A insertion (18). Certain IS6110 RFLP-genotype families (clades 47 and 61) were consistentlyfound to be Beijing genotype (18). Isolates were assignedto the Beijing genotype on the basis of the IS6110 RFLPpattern (18). If any doubt about clade membership existed,we used spoligotyping for the final allocation.The RFLP results for the period 1993–2000 werematched to patient data on the basis of date of birth, postalarea code, and sex, resulting in a perfect match for 5,994(73%) patients and a near-perfect match for 835 (10%)patients; overall, 83% of the samples matched (6,829patients). During this period, the Beijing genotype wasobserved in 516 cultures, representing 6% of the 8,210patients. In the matched dataset, 415 (6%) of 6,829 were ofthe Beijing genotype. The number of TB cases attributableto the Beijing genotype tended to increase over time(Figure; p>0.05). This tendency was observed both amongDutch patients (r=0.66, 95% confidence interval [CI]–0.08 to 0.93) and non-Dutch patients (r=0.59, 95% CI–0.20 to 0.91) (Figure). While the increase in the numberof cases among immigrants may be associated with anoverall increase of immigrants to the Netherlands during1310 Emerging Infectious Diseases • Vol. 9, No. 10, October 2003DISPATCHES*Royal Netherlands Tuberculosis Association, the Hague, theNetherlands; †University of Amsterdam, Amsterdam, theNetherlands; and ‡National Institute of Public Health and theEnvironment (RIVM), the Hague, the NetherlandsFigure. Number of tuberculosis cases with the Beijing genotype,Netherlands, 1993–2000.Emerging Infectious Diseases • Vol. 9, No. 10, October 2003 1311DISPATCHESTable. Risk factors for the Beijing genotype of Mycobacterium tuberculosis, the Netherlands, 1993–2000  Odds ratio Risk factor Beijing genotype Total % Crude Adjustedb (95% confidence intervals) Y of diagnosis  1993 23 669 3 1.09 1.08 (1.03 to 1.13)  1994 41 941 4                             (per year)  1995 56 863 6    1996 50 946 5    1997 64 872 7    1998 58 804 7    1999 74 879 8    2000 49 855 6   Sex  Male 254 4,135 6 1   Female 161 2,694 6 0.97  Age group  <25 120 1,522 8 1 1  25–34 123 1,925 6 0.80 0.69 (0.53 to 0.91)  35–44 64 1,080 6 0.74 0.60 (0.43 to 0.83)  45–54 23 614 4 0.45 0.36 (0.23 to 0.57)  55–64 24 493 5 0.60 0.55 (0.35 to 0.88)  65–74 40 517 8 0.98 0.78 (0.52 to 1.15)  75+ 21 678 3 0.37 0.30 (0.18 to 0.50) Nationality  Netherlands 160 2,825 6 1 1  Europe (central and eastern)  20 231 9 1.58 1.27 (0.77 to 2.09)  Turkey 3 339 1 0.15 0.12 (0.04 to 0.38)  Morocco 19 650 3 0.50 0.41 (0.25 to 0.68)  Somalia 21 957 2 0.37 0.27 (0.17 to 0.44)  Africa (other)  28 594 5 0.82 0.63 (0.41 to 0.96)  Asia 140 786 18 3.61 3.01 (2.32 to 3.91)  Other 19 345 6 0.97 0.86 (0.53 to 1.42)  Unknown 5 102 5 0.86 0.73 (0.29 to 1.84) RFLP clusteringa  No 212 3,227 7 1   Yes, first case 57 1,052 5 0.81   Yes, later case 146 2,550 6 0.86  Localization  Pulmonary 268 4,064 7 1   Extrapulmonary 113 2,122 5 0.80  Pulmonary and extrapulmonary 34 643 5 0.79  Residing in Netherlands  <6 months 46 641 7 1  6–11 mo 12 301 4 0.54  12–23 mo 28 358 8 1.10  2–4 y 53 767 7 0.96  >5 y 122 1,710 7 0.99  Born in Netherlands 117 2,437 5 0.65  No information 37 615 6 0.83  Drug resistance Susceptible 332 5,910 6 1  H only 11 227 5 0.86  S only 34 358 9 1.76  Other patterns 26 221 12 2.24  Multidrug-resistant 9 53 17 3.44  Unknown 3 60 5 0.88  Multidrug resistance Yes 9 53 17 3.21 2.64 (1.22 to 5.74) No 406 6,776 6 1 1 HIV infection Yes 14 294 5 0.76  No 401 6,535 6 1  aRFLP, restriction fragment length polymorphism. bAdjusted for year of diagnosis, age, nationality, and multidrug resistance.  the study period, the increasing numbers among Dutchpatients likely reflect an increasing incidence rate.The proportion of TB patients who had the Beijinggenotype was significantly associated in univariate analy-sis with a later year of diagnosis, young age, nationality(increased among immigrants from Asia and decreasedamong those from Morocco, Turkey, Somalia, and otherAfrican countries, compared with Dutch citizens), andmultidrug resistance (Table). These associations persistedin multivariate analysis (Table). The association between the proportion of TB caseswith the Beijing genotype and age was observed in partic-ular in Dutch patients (chi squaretrend 15.5; p<0.0001), andwas not clear among non-Dutch patients (chi squaretrend0.8; p>0.2). Among Dutch patients, the Beijing genotypewas more commonly found in new cases (6%, 133/2,130)than among retreated cases (4%, 18/498; p<0.05). Amongnon-Dutch patients, the Beijing genotype was slightlymore common in retreated cases (8%, 19/229) than in newcases (6%, 204/3,218); however, this occurrence was notsignificant (p>0.2). The incidence pattern by person andtime appears consistent with transmission of the Beijinggenotype from immigrants to the Dutch population (19).The proportion of TB cases with the Beijing genotypewas not substantially associated with HIV infection, pul-monary localization, RFLP clustering, or duration of stayin the Netherlands (Table). The lack of association withRFLP-clustering suggests that the Beijing genotype is notspreading more quickly than other M. tuberculosis strains.Of the nine patients with the Beijing genotype and mul-tidrug resistance, four were from central and easternEurope, three from Asia, one from Africa, and one fromthe Netherlands. One of these nine patients was RFLP-clustered; the other patient in that RFLP cluster had beendiagnosed previously and had isolated isoniazid resistance.During 1993 to 2000 in the Netherlands, the Beijinggenotype represented 6% of TB cases. The Beijing geno-type was associated with recent diagnoses, young age (inparticular among Dutch citizens), nationality (EasternEurope and Asia), and multidrug resistance. Although theBeijing genotype was associated with multidrug resist-ance, the number of MDRTB cases was small. No second-ary cases were observed with the Beijing genotype andMDRTB. Of the nine cases of MDRTB, only one case mayhave been caused by transmission within the Netherlandsfrom a case-patient who had isoniazid resistance at thestart of treatment and may have acquired rifampicin resist-ance during treatment. However, the spread of the Beijinggenotype among young people suggests the possible emer-gence of multidrug resistance and emphasizes the need forcontinued surveillance.AcknowledgmentsWe thank all municipal health services in the Netherlandsfor their contribution to the Netherlands Tuberculosis Register.This study was performed within the framework ofConcerted Action project QLK2-2000-00630 on MolecularEpidemiology of Tuberculosis. Dr. Borgdorff is the chief epidemiologist of the RoyalNetherlands Tuberculosis Association (KNCV) and professor ofinternational health with special reference to tuberculosis at theUniversity of Amsterdam. His areas of interest include the molecu-lar epidemiology of tuberculosis and other communicable diseases. 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Kremer K, van den Brandt A, Kurepina NE, Glynn J, Bifani PJ, vanSoolingen D. Definition of the Mycobacterium tuberculosis Beijinggenotype. European Union Concerted Action project meeting,Cascais, May 27–30, 2002. Abstract 019. 19. Borgdorff MW, Nagelkerke NJ, De Haas PE, Van Soolingen D.Transmission of tuberculosis depending on the age and sex of sourcecases. Am J Epidemiol 2001;154:934–43.Address for correspondence: M.W. Borgdorff, Royal NetherlandsTuberculosis Association (KNCV), P.O. Box 146, 2501 CC the Hague,the Netherlands; fax: +31 70 3584004; email: borgdorffm@kncvtbc.nlEmerging Infectious Diseases • Vol. 9, No. 10, October 2003 1313DISPATCHESAll material published in Emerging Infectious Diseases is in thepublic domain and may be used and reprinted without special per-mission; proper citation, however, is appreciated.Search past issues of EID at www.cdc.gov/eid

Mycobacterium tubercuiosis Beijing genotype, the Netherlands

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Mycobacterium tubercuiosis Beijing genotype, the Netherlands

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