Mycobacterium Africanum, an Emerging Disease in High-Income Countries?

Mycobacterium africanum, an emerging disease in high-income countries?

M. C. Isea-Peña,* M. F. Brezmes-Valdivieso,† M. C. González-Velasco,‡ M. A. Lezcano-Carrera,§ L. López-Urrutia-Lorente,† N. Martín-Casabona,¶ M. L. Monforte-Cirac,§ J. J. Palacios,# A. Penedo-Pallares,# A. Ramirez-Rosales,** R. Sánchez-Silos,†† T. Tórtola-Fernández,¶ J. Viñuelas-Bayón,‡‡ A. Vitoria-Agreda,§§ Red de Laboratorios de Microbiología Servicio de Salud del Principado de Asturias (SESPA),*** J. Esteban* * Department of Clinical Microbiology, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, † Hospital Virgen de la Concha, Zamora, ‡ Hospital de Don Benito-Villanueva de la Serena, Badajoz, § Servicio de Microbiología y Parasitología, Hospital Universitario Miguel Servet, Zaragoza, ¶ Hospital Universitario Vall d’Hebron, Universidad Autónoma de Barcelona, Barcelona, # Unidad de Referencia Regional de Micobacterias, Hospital Universitario Central de Asturias, Oviedo, ** Hospital Universitario Son Dureta, Palma de Mallorca, †† Hospital Infanta Cristina de Badajoz, Badajoz, ‡‡ Hospital San Pedro de Alcántara, Cáceres, §§ Servicio de Microbiología, Hospital Universitario ‘Lozano Blesa’, Zaragoza, Spain

SUMMARY

BACKGROUND: Mycobacterium africanum is a cause Forty-four cases were from Africa, 1 from the Philip- of tuberculosis (TB) that has mainly been described in pines, 1 from India, and 4 from Spain, while the country Africa, but immigration and travel patterns have con- of origin was unknown in 7 cases. The most frequent tributed to the spread of the disease to other countries. site of infection was the lung (58.3%). Four cases (6.9%) METHODS: We retrospectively reviewed TB cases due were resistant to at least one first-line anti-tuberculosis to M. africanum during 2000–2010 in seven Spanish drug. hospitals. Selected clinical charts were reviewed using a CONCLUSIONS: Disease due to M. africanum in indus- predefined protocol that included demographical, clini- trialised countries is mainly associated with immigra- cal and microbiological data and outcome. tion from endemic areas, although some cases also occur RESULTS: Although 57 cases were diagnosed, only 36 among native-born populations. clinical charts were available for review: 82.8% were KEY WORDS: Mycobacterium africanum; tuberculosis; men and the mean age was 31.6 years (range 12–81). high-income

MYCOBACTERIUM AFRICANUM was fi rst de- like properties.6,8–10 However, subtype II has recently scribed in Senegal in 1968 by Castets and Savot1 as been described as M. tuberculosis,5,11 thus leaving the an endemic agent causing human infection in West West African type as the only M. africanum strain. African and other sub-Saharan African countries,2–5 This group was divided into subtype I (MAF1), for where it causes almost half of smear-positive cases strains found around the Gulf of Guinea, and sub- of pulmonary tuberculosis (TB).6,7 Included in the type II (MAF2), for those prevalent in the western part M. tuberculosis complex, M. africanum is estimated of West Africa.12 Both groups include the classical to have lost about 68 kilobases compared with the phenotypic characteristics and specifi c genetic mark- M. tuberculosis genome.8 ers, which consist of a lack of region of difference M. africanum strains were previously classifi ed into (RD) 9, the presence of RD12 and a specifi c gyrB gene two major subgroups per geographic origin and bio- polymorphism. Subtype MAF2 also has deletions of chemical properties: M. africanum subtype I (Clus- RD7, RD8 and RD10.5,12 Identifi cation of M. afri- ter G) from West Africa, which exhibits M. bovis-like canum is now possible using commercial kits,13 al- properties, and M. africanum subtype II from East though they do not distinguish between MAF1 and Africa (Cluster F), which exhibits M. tuberculosis- MAF2. M. africanum disease is rare in industrialised countries and is commonly diagnosed in immigrants from *** Red de Laboratorios de Microbiología SESPA: M I Blanco, L Barreiro, H Villar, A Torreblanca, E Hidalgo, J Diaz-Gigante, Africa. Cases have been described in countries outside F Hidalgo, S Calzón. Africa, such as the United States,14 Brazil,15 China,16

Correspondence to: Jaime Esteban, Department of Clinical Microbiology, IIS Fundación Jiménez Díaz, Av Reyes Católicos 2, 28040 Madrid, Spain. Tel: (+34) 915 504 900. Fax: (+34) 549 4764. e-mail: [email protected] Article submitted 21 February 2012. Final version accepted 29 April 2012. Mycobacterium africanum disease 1401

Australia,17 Turkey,18 Denmark,19 Italy,20 Germany,21,22 tal Universitario Central de Asturias and Hospital the United Kingdom,23,24 France,25 Portugal26 and Vall d’Hebron) that had received strains from other Spain,27 and also in animals in Norway,28 Croatia29 sites for identifi cation and DST. Full clinical charts and Bangladesh.30 In the present study, we provide a were available for 36 patients, although some data review of cases found in different geographical areas were available from all patients. The characteristics in Spain over a 10-year period. of those patients with full data are shown in the Ta- ble; 82.75% of all patients were males, and based on the 51 patients for whom age was available, the mean MATERIAL AND METHODS age was 31.64 years (range 12–81). Four patients originated from Spain; of the remaining 53, the coun- A retrospective, multicentre study to evaluate the try of origin of 7 was unknown, while the remaining clinical characteristics of patients with M. africanum 46 cases were immigrants. The highest number of infection between 2000 and 2010 was performed in cases came from Africa (n = 44): 36 were from West seven hospitals in different geographical areas in Africa, including Senegal (n = 15), the Gambia (n = Spain. Laboratory records from the mycobacteriol- 11), Guinea Bissau (n = 2), Mali (n = 4), Sierra Leone ogy laboratories of the participating centres were re- (n = 2), Ghana (n = 1) and Cape Verde (n = 1); 4 viewed. All patients with at least one isolate identifi ed were from Central Africa (Equatorial Guinea [n = 3] as M. africanum were selected for the study. and Nigeria [n = 1]), while the remaining 4 cases The study was approved by the ethical committee were from unspecifi ed countries in Africa. One case of the centre coordinating the study (Fundacion Ji- was from the Philippines and one from India. Of the menez Diaz). Spanish patients, three were homeless, and one lived in During the study period, different methods were an area with a high concentration of immigrants. No used to identify the strains as M. africanum. These history of travel was recorded in the clinical charts of include the use of a combination of DNA probes these patients, and the retrospective nature of our (AccuProbe Mycobacterium tuberculosis Complex study made it impossible to obtain more specifi c data. Culture Identifi cation Test, Gen-Probe, San Diego, CA, Five of the 36 patients were human immuno- USA) and biochemical tests (3 centres); polymerase defi ciency virus (HIV) positive. Two were under anti- chain reaction (PCR) hybridisation based commer- retroviral treatment (ART), and two began ART after cial kit (GenoType, Hain, Nehren, Germany; 5 cen- the diagnosis of M. africanum disease. The mean tres); PCR-restriction fragment length polymorphism CD4+ count was 121.8 mm3 (range 17–450). of the gyrB gene, detection of RD9 or RD1 (2 cen- The sites of infection were the lungs 52.8% (n = tres); spoligotyping (3 centres); and 16S rDNA se- 19), lymph nodes 13.9% (n = 5), bone 11.1% (n = 4), quencing (1 centre). All strains identifi ed with bio- disseminated 8.3% (n = 3), the central nervous sys- chemical tests and DNA probes were sent to the tem 5.5% (n = 2), skin and soft tissue 2.8% (n = 1), Mycobacterial Reference Laboratory of the National peritoneum 2.8% (n = 1) and pleura 2.8% (n = 1; Microbiology Centre (Majadahonda, Madrid, Spain) data available from 36 charts reviewed). Thorax ra- for confi rmation by molecular methods. Drug sus- diography revealed visible changes in two thirds of ceptibility testing (DST) of the isolates has been per- the patients (n = 24). Eight patients began treatment formed using commercial liquid automated systems with three drugs (isoniazid [H, INH] + rifampicin [R, (MGIT™ 960, BD, Sparks, MD, USA) in all hospitals, RMP] + pyrazinamide [Z, PZA]), 1 patient was ad- and Versatrek (bioMérieux, Marcy l’Etoile, France) ministered INH+RMP+ethambutol (E, EMB), 24 re- in one hospital, since 2009. Only those patients with ceived four drugs (HRZE) and no data were available M. africanum sensu stricto strains (M. africanum for 3 patients. On follow-up, 80.6% of the patients type I) were included in the study. had a positive outcome and 5.6% had died (Table). The clinical charts of the selected patients (n = 36) Diagnostic delay, defi ned as time elapsed from were reviewed using a pre-designed protocol that in- the onset of symptoms to fi nal diagnosis (data avail- cluded demographics, including country of origin able in 26 patients), was 102.34 days (range 2–730). and date of arrival in Spain, risk factors, underlying Acid-fast stain results were positive in respiratory diseases, delay in diagnosis, clinical onset and data of samples from 89.5% of the patients with lung dis- the present disease, treatment and outcome (Table). ease. Four cases showed in vitro resistance to at least one fi rst-line anti-tuberculosis drug: one to RMP+ EMB+streptomycin (S, SM), one to SM+INH, one RESULTS to PZA, and one to INH+EMB+SM+PZA. All resis- During the study period, 57 patients were diagnosed tant strains came from the Supranational Reference as having M. africanum disease: Asturias (n = 4), Laboratory of the World Health Organization in Bar- Badajoz (n = 3), Catalonia-Balearic Islands (n = 22), celona, including one from the Balearic Islands, which Madrid (n = 9), Zamora (n = 2) and Saragossa (n = had been submitted for identifi cation and DST from 17). Two of these were reference laboratories (Hospi- other hospitals. 1402 The International Journal of Tuberculosis and Lung Disease

Table Data of patients with M. africanum disease

Patient Age, Country Diagnostic Years/months Diagnostic HIV CXR no. years of origin Sex year in Spain delay, days status changes Diagnosis Treatment Outcome 1 37 Senegal Male 2000 Unknown 3 Negative Yes Pulmonary 2RHZ/4RH Cured 2 39 Sierra Leone Male 2001 Unknown 2 Positive Yes Pulmonary 2RHZ/4RH Lost to follow-up 3 34 Philippines Male 2002 2 90 Negative No Lymph node 2RHE/4RH Lost to follow-up 4 35 Senegal Male 2006 5 months 2 Negative Yes Pulmonary 2RHZ/4RH Lost to follow-up 5 18 Equatorial Male 2008 1 90 Negative Yes Pulmonary 2RHZE/4RH Cured Guinea 6 26 Mali Male 2009 5 30 Negative Yes Lymph node 2RHZ/4RH Cured 7 19 Senegal Male 2010 1 Unknown Negative No Cerebral 2RHZ/4RH Cured 8 44 Senegal Male 2010 9 30 Negative Yes Disseminated 2RHZ/4RH Cured 9 22 Gambia Male 2010 2 15 Negative No Cerebral 2RHZE/4RH Cured 10 29 Senegal Male 2009 2 45 Negative Yes Pulmonary 2RHZE/4RH Cured 11 55 Spain Male 2008 NA Unknown Unknown Yes Pulmonary 2RHZE/4RH Cured 12 52 Equatorial Male 2008 10 months 730 Positive Yes Pulmonary 2RHZE/4RH Cured Guinea 13 24 Senegal Male 2008 3 Unknown Negative No Bone 2RHZE/4RH Cured 14 30 Senegal Male 2003 3 120 Negative Yes Lymph node 2RHZE/4RH Cured 15 32 Senegal Male 2006 Unknown 300 Positive Yes Pulmonary 2RHZE/4RH Lost to follow-up 16 37 Spain Male 2007 NA Unknown Negative Yes Pulmonary 2RHZE/4RH Cured 17 30 Senegal Male 2009 2 300 Negative Yes Pulmonary 2RHZE/4RH Cured 18 28 African Male 2009 Unknown Unknown Unknown Yes Pleural 2RHZE/4RH Lost to follow-up 19 24 African Male 2009 Unknown Unknown Unknown Yes Bone 2RHZE/4RH Cured 20 35 Senegal Male 2010 2 90 Negative Yes Lymph node 2RHZE/4RH Cured 21 30 Gambia Male 2004 6 30 Negative Yes Pulmonary 2RHZE/4RH Cured 22 35 Equatorial Male 2006 1 month 60 Positive No Pulmonary 2RHZE/4RH Cured Guinea 23 31 Ghana Male 2007 10 4 Positive No Lymph node 2RHZE/4RH Cured 24 27 Gambia Male 2009 8 60 Negative No Disseminated 2RHZE/4RH Cured 25 26 Gambia Male 2009 2 Unknown Negative No Skin and 2RHZE/4RH Cured soft tissue 26 27 Spain Male 2008 NA 120 Negative No Pulmonary Not available Cured 27 37 Gambia Male 2008 Unknown Unknown Negative Yes Pulmonary 2RHZE/4RH Cured 28 21 Nigeria Male 2006 3 Unknown Negative No Bone 2RHZE/4RH Cured 29 48 Cape Verde Male 2010 8 20 Negative No Peritonitis 2RHZE/4RH Cured 30 24 African Male 2008 Unknown 30 Unknown Yes Pulmonary Not available Cured 31 21 Mali Male 2006 1 month 15 Negative Yes Pulmonary 2RHZ/4RH Cured 32 81 Spain Male 2001 NA 365 Unknown Yes Pulmonary 2RHZ/4RH Died 33 20 Sierra Leone Female 2004 8 months 30 Negative Yes Pulmonary 2RHZE/4RH Cured 34 20 Gambia Male 2007 2 months 20 Negative Yes Pulmonary 2RHZE/4RH Cured 35 52 Senegal Male 2010 Unknown Unknown Unknown Yes Disseminated Not available Died 36 28 Senegal Male 2010 4 60 Negative No Bone 2RHZE/4RH Cured

HIV = human immunodeficiency virus; CXR = chest X-ray; R = rifampicin; H = isoniazid; Z = pyrazinamide; E = ethambutol; NA = not applicable (Spanish patients).

DISCUSSION age of the study patients suggests that the patients ac- quired the infection at early stages of life in their M. africanum is a pathogen described mainly in a spe- country of origin,23 but we cannot dismiss the possi- cifi c geographic area, although some data have been bility of recent acquisition in Spain, as some cases published on its isolation in other countries.4,14,22– emerged several years after arrival. 25,27,31–39 Its isolation in industrialised countries has Disease caused by M. africanum is very similar to been related to immigration from endemic countries. that caused by M. tuberculosis.7 A number of studies In our series, we found that most cases were indeed have described and evaluated both diseases: one re- immigrants from such areas, but we also observed port4 showed no differences between the two species; patients from other geographic areas (Asia) and even however, M. africanum had fewer clustering cases and four cases in Spanish patients. Although no informa- involvement of the lower lobe of the lung was less tion about contact with tuberculous patients, travel frequent than in M. tuberculosis among HIV-negative or other epidemiological data were available from patients.4 Other reports have evaluated age, HIV co- these patients, it is possible that the disease was ac- infection and X-ray fi ndings, showing that M. afri- quired in Spain when the cases came into contact canum patients were older, more likely to be mal- with patients with active M. africanum infection, as nourished, had HIV more frequently, and had more has been described for TB in our area.27,40 The mean severe chest X-ray patterns.2 Patients with associated Mycobacterium africanum disease 1403

HIV disease were considered to have an opportunis- Acknowledgements tic infection;2,3 however, another report found no The authors thank O Shaw for his help with the English language. such association.4 Local differences and host particu- Part of this research was presented at the XIV Meeting of the larities could be an explanation for such differences, Grupo Español de Micobacteriología. as the studies were performed in different countries with different types of patients. In our study there References was a low incidence of HIV co-infection (13.88%), and clinical manifestations and outcome after treat- 1 Castets M, Sarrat H. [Experimental study of the virulence of Mycobacterium africanum (preliminary note)]. Bull Soc Med ment were not different from those without HIV in- Afr Noire Lang Fr 1969; 14: 693–696. [French] fection. However, the lack of a specifi c control group 2 de Jong B C, Adetifa I, Walther B, et al. Differences between limits comparison between groups. Moreover, our tuberculosis cases infected with Mycobacterium africanum, fi ndings were from patients with disease caused by West African type 2, relative to Euro-American Mycobacte- M. africanum sensu stricto, according to the latest rium tuberculosis: an update. FEMS Immunol Med Microbiol 2010; 58: 102–105. taxonomic changes. As most of the previous refer- 3 de Jong B C, Hill P C, Brookes R H, et al. Mycobacterium afri- ences included both older type I and type II sub- canum: a new opportunistic pathogen in HIV infection? AIDS groups,3,6,23,41,42 it was often diffi cult to tell whether 2005; 19: 1714–1715. data were from M. africanum type I or II. Some of the 4 Meyer C G, Scarisbrick G, Niemann S, et al. Pulmonary tuber- studies evaluated type II strains. culosis: virulence of Mycobacterium africanum and relevance in HIV co-infection. Tuberculosis (Edinb) 2008; 88: 482–489. Most cases in our series appeared between 2006 5 Niemann S, Kubica T, Bange F C, et al. The species Mycobacte- and 2010. This could be due to the availability of rium africanum in the light of new molecular markers. J Clin new diagnostic techniques capable of discriminating Microbiol 2004; 42: 3958–3962. between the different species of the M. tuberculosis 6 Källenius G, Koivula T, Ghebremichael S, et al. Evolution and complex (notably, Hain’s GenoType MTBC system), clonal traits of Mycobacterium tuberculosis complex in Guinea- but it could also be a refl ection of the migratory his- Bissau. J Clin Microbiol 1999; 37: 3872–3878. 7 Bentley S D, Comas I, Bryant J M, et al. The genome of Myco- tory in Spain, where immigration has increased dur- bacterium africanum West African 2 reveals a lineage-specifi c ing the last decade, particularly from South America locus and genome erosion common to the M. tuberculosis and Africa. The coincidence of both circumstances complex. PLoS Negl Trop Dis 2012; 6: e1552. made it diffi cult to ascertain the relative importance 8 Mostowy S, Onipede A, Gagneux S, et al. Genomic analysis of each. distinguishes Mycobacterium africanum. J Clin Microbiol 2004; 42: 3594–3599. An interesting fi nding is the high proportion of 9 David H L, Jahan M T, Jumin A, Grandry J, Lehman E. Nu- smear positivity (89.5%). We hypothesise that these merical taxonomy analysis of Mycobacterium africanum. Int J results could be due to the lengthy diagnostic delay Systematic Bacteriol 1978; 28: 464–472. among these patients, which leads to increased dis- 10 Sola C, Rastogi N, Gutierrez M C, Vincent V, Brosch R, Par- ease severity and consequent bacterial load. It could sons L. Is Mycobacterium africanum subtype II (Uganda I and Uganda II) a genetically well-defi ned subspecies of the Myco- also be due to the more severe nature of M. africa- bacterium tuberculosis complex? J Clin Microbiol 2003; 41: num infection, as described by de Jong et al. for West 1345–1346; author reply 6–8. African strains.2 Unfortunately, the retrospective na- 11 Niemann S, Rüsch-Gerdes S, Joloba M L, et al. Mycobacterium ture of our study did not permit the collection of africanum subtype II is associated with two distinct genotypes microbiological data such as growth rate (described and is a major cause of human tuberculosis in Kampala, Uganda. J Clin Microbiol 2002; 40: 3398–3405. by Castets and Savot as being slower than that of 12 de Jong B C, Antonio M, Gagneux S. Mycobacterium africanum 1 M. tuberculosis). —review of an important cause of human tuberculosis in West All cases described to date have been reported as Africa. PLoS Neglected Trop Dis 2010; 4: e744. being susceptible to fi rst-line antimycobacterial treat- 13 Richter E, Weizenegger M, Fahr A M, Rüsch-Gerdes S. Use- ment, and no multidrug-resistant (MDR) M. afri- fulness of the GenoType MTBC assay for differentiating spe- canum cases or outbreaks have been described.7 In cies of the Mycobacterium tuberculosis complex in cultures obtained from clinical specimens. J Clin Microbiol 2004; 42: our series, we found four M. africanum cases resis- 4303–4306. tant to at least one TB drug, although no MDR- 14 Desmond E, Ahmed A T, Probert W S, et al. Mycobacterium M. africanum strain was detected. africanum cases, California. Emerg Infect Dis 2004; 10: 921– In conclusion, disease caused by M. africanum 923. clinically resembles disease due to M. tuberculosis, 15 Gomes H M, Elias A R, Oelemann M A, et al. Spoligotypes of Mycobacterium tuberculosis complex isolates from patients and the only proper method of diagnosis is by species- residents of 11 states of Brazil. Infection, genetics and evolu- level identifi cation among M. tuberculosis complex tion. Infect Genet Evol 2012; 12: 649–656. isolates. 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RÉSUMÉ

CONTEXTE : Mycobacterium africanum est une cause cas ; l’âge moyen a été de 31,6 ans (extrêmes : 12–81). de tuberculose (TB) décrite particulièrement en Afrique, Quarante-quatre cas provenaient d’Afrique, un des Phi- mais suite à l’immigration et les voyages on observe cette lippines et un de l’Inde. Quatre cas venaient d’Espagne maladie dans d’autres pays. et pour sept cas, le pays d’origine était inconnu. Le site MÉTHODES : Nous avons revu de manière rétrospective le plus fréquent d’infection s’est avéré les poumons les cas de maladie due à M. africanum au cours de la pé- (58,3%). Dans quatre cas (6,9%), il existait une résis- riode 2000–2010 dans sept hôpitaux différents d’Espagne. tance à l’égard d’au moins un antibiotique antitubercu- Les dossiers cliniques sélectionnés ont été revus au moyen leux de première ligne. d’un protocole prédéfini qui comporte des données démo- CONCLUSIONS : La maladie due à M. africanum peut graphiques, cliniques et microbiologiques ainsi que les être détectée dans les pays industrialisés, principalement résultats. en rapport avec l’immigration provenant de zones endé- RÉSULTATS : Le diagnostic a été porté dans 57 cas, mais miques, bien qu’elle puisse également être détectée dans 36 dossiers cliniques seulement ont été disponibles la population autochtone. pour la révision. Il s’agissait d’hommes dans 82,8% des

RESUMEN

MARCO DE REFERENCIA: Mycobacterium africanum 82,8% eran varones y la edad media fue de 31,6 años es la causa de casos de tuberculosis (TB) descritos espe- (rango 12–81). Cuarenta y cuatro casos eran de origen cialmente en África, pero debido a la inmigración y los africano, uno de Filipinas, uno de la India, cuatro de viajes a zonas endémicas esta enfermedad se detecta paci entes españoles y en siete no fue posible conocer el también en otros países. país de origen. La localización más frecuente de la enfer- MÉTODOS: Se revisaron retrospectivamente los casos de medad fue la pulmonar (58,3%). Cuatro de los aislados enfermedad causada por M. africanum durante el periodo fueron resistentes al menos a un antituberculoso de 2000–2010 en siete hospitales españoles. Se revisaron primera línea. las historias clínicas de los pacientes seleccionados em- CONCLUSIONES: Se puede detectar la presencia de en- pleando un protocolo predefinido que incluía datos de- fermedad por M. africanum en países desarrollados, mográficos, clínicos y microbiológicos, así como el re- asociada principalmente con la inmigración procedente sultado final de la enfermedad. de áreas endémicas, aunque puede detectarse también RESULTADOS: Se diagnosticaron 57 casos, de los cuales en población autóctona. estaban disponibles las historias clínicas de 36 de ellos;