Case report
Bubonic lymphogranuloma venereum with multidrug treatment failure
International Journal of STD & AIDS 2014, Vol. 25(4) 306–308 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462413501158 std.sagepub.com
Martı´ Vall-Mayans1, Jenny Isaksson2, Estrella Caballero3, Beatriz Salle´s4 and Bjo¨rn Herrmann2
Abstract A patient with proctitis and inguinal buboes diagnosed with lymphogranuloma venereum (LGV) was treated with doxycycline 21 days, azithromycin 20 days and moxifloxacin for a further 12 days because of progressive worsening of inguinal symptoms. Despite extensive antibiotic treatment, the inguinal LGV lesions persisted; however, the patient recovered spontaneously after three months.
Keyword Sexually transmitted infection, Chlamydia trachomatis, lymphogranuloma venereum, LGV, bubo, treatment failure Date received: 3 May 2013; accepted: 13 July 2013
A 47-year-old man who had sex with men (MSM) presented to our clinic with anal pain and large volume inguinal lymphadenitis for 45 days. He reported unprotected anal intercourse 2 months previously with a casual partner. Clinical examination found enlarged bilateral lymphadenopathies, 3 3 cm in size, that were tender; the one on the left side being of a firm, non-fluctuant consistency (Figure 1(a)). Proctoscopy showed a copious mucopurulent exudate with blood from where Chlamydia trachomatis was detected by PCR (Artus C. trachomatis Plus, Qiagen Diagnostics GmbH, Germany) and lymphogranuloma venereum (LGV) was confirmed using an in-house real-time PCR.1 The patient was started immediately with doxycycline treatment 200 mg/day for 21 days. After completion of that regimen his rectal symptoms improved but the lymph nodes remained tender, enlarged, with progressive inflammation. The patient was then treated with azithromycin 1 g/day, and after 10 days, a lymph node aspiration was performed, with purulent exudate obtained from which LGV DNA was detected. An ultrasound at this time (Figure 1c) showed an irregularly shaped adenomatous mass with hypoechoic areas suggesting intranodal necrosis, and node matting with surrounding soft tissue oedema. Deeper (Figure 1(c), left), inflammatory enlarged regular oval-shaped lymph nodes (8–20 mm) with an echogenic center were found. The patient continued with azithromycin 0.5 g/day for 10 more days. Around this time, rectal
LGV DNA was no longer detected. Biochemistry and haematological tests were within normal limits, with the exception of ESR ¼ 79, and mild elevations of IgA and IgG. Serology for HIV, syphilis, HCV and HBV was negative. Despite extension of antibiotic treatment with azithromycin, the nodes progressed to fluctuant buboes of a purplish colour with cellulitis. Treatment failure was suspected and hence moxifloxacin 400 mg/day was started for 12 days. After seven days on that regimen, the patient developed a thin discharging inguinal sinus (Figure 1(d)) from where C. trachomatis was detected (LGV DNA could not be confirmed due to inhibition of the technique). The patient had been compliant with all the treatments and reinfection was ruled out. One month later, the patient was recovering without external signs of inflammation or discharge from 1
STI Unit, University Hospital Vall d’Hebron, Barcelona, Catalonia, Spain Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden 3 Microbiology Service, University Hospital Vall d’Hebron, Barcelona, Catalonia, Spain 4 Immage Diagnosis Service (SDPI) Drassanes, Barcelona, Catalonia, Spain 2
Presented in part at the 27th IUSTI Europe Congress, Antalya (Turkey), 6–8 September 2012 (AbsRef: 0244). For MLST profiles, see database at Uppsala University: http://mlstdb.bmc.uu.se Corresponding author: Martı´ Vall-Mayans, STI Unit, University Hospital Vall d’Hebron, Av Drassanes 17-21, 08001 Barcelona, Catalonia, Spain. Email: [email protected]
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
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Figure 1. Left inguinal bubo at days 53, 80 and 99 (a, b and d), respectively, since the beginning of symptoms. (c) Ultrasound of bubo from image at (b).
the buboes. He was seen again after three months and all symptoms had resolved, leaving minor scarring on the left inguinal side. The clinical evolution of buboes in this case was similar to the evolution of cases described decades ago.2 We further analyzed the LGV strain by using a multilocus sequence typing (MLST) system based on five highly variable gene regions and we also sequenced the ompA gene.3 In both rectal and nodal specimens it showed the MLST sequence type 58 with allele profile 27,13,17, 13, 28 that is the predominant sequence type amongst MSM3 and in ompA the L2 strain was found, which is different from the prevalent L2b variant in contemporary LGV cases.4 A similar case with L2 serotype that was cured with moxifloxacin treatment after failure of extended treatment with doxycycline has been reported.5 Another case with L2 in the rectum had ‘significant’ lymphadenopathy, while almost all of the other cases from that study were L2b with clinical proctitis.6 It is of interest that the reference L2 strain L2/ 434/Bu was originally isolated from an inguinal bubo and that in earlier studies,7 it was said that systemic signs and symptoms accompanied the inguinal syndrome more frequently than the genito-anorectal syndrome. Although L2 might seem more virulent than L2b, the determinants of tropism and invasiveness of LGV8 and other C. trachomatis isolates9 are likely to be multifactorial and complex. Also, the difference in ompA between strains L2b and L2/434/Bu is only one nucleotide and the complete sequence of both genomes are almost identical.8 All of this favours the view that
L2b would be a classical L2 isolate that has been circulating in humans for a long time causing a new disease.10 C. trachomatis is naturally sensitive to tetracyclines, macrolides and fluoroquinolones.11,12 The French case cited above failed doxycycline treatment, but recovered after moxifloxacin, when inguinal sinuses had already discharged and had been drained.5 Our case showed multidrug treatment failure to cure the lymphangitis but not the proctitis. This rules out true drug resistance. Similar to the French case, our patient also began to improve clinically at the inguinal level with moxifloxacin after spontaneous draining of buboes. As showed in a case series from the mid-1960s, the aspiration of buboes prevented rupture, minimized complications and hastened recovery.7 So, without further evidence from an antibiogram or other molecular studies, it would be inappropriate to consider our case as well as the French case5 as drug resistance. Probably, host factors, drug penetration and immunological response must play some role in selected cases. In patients with an LGV inguinal syndrome, doxycycline has been effective13 but early aspiration of fluctuant buboes has also to be considered.12 In conclusion, clinicians must be vigilant for the evolving presentations of LGV and be prepared to recognize all manifestations of this disease.14 Acknowledgements The authors acknowledge their colleagues at the STI Unit, University Hospital Vall d’Hebron, Barcelona for comments on this case.
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
308
International Journal of STD & AIDS 25(4)
Conflict of interest The authors declare no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Chen CY, Chi KH, Alexander S, et al. The molecular diagnosis of lymphogranuloma venereum: evaluation of a real-time multiplex polymerase chain reaction test using rectal and urethral specimens. Sex Transm Dis 2007; 34: 451–455. 2. Coutts WE. Lymphogranuloma venereum. A general review. Bull World Hlth Org 1950; 2: 545–562. 3. Christerson L, de Vries HJC, de Barbeyrac B, et al. Typing of lymphogranuloma venereum Chlamydia trachomatis strains. Emerg Infect Dis 2010; 16: 1777–1779. 4. Spaargaren J, Fennema HS, Morre SA, et al. New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam. Emerg Infect Dis 2005; 7: 1090–1092. 5. Me´chaı¨ F, de Barbeyrac B, Aoun O, et al. Doxycycline failure in lymphogranuloma venereum. Sex Transm Infect 2010; 86: 278–279. 6. Korhonen S, Hiltunen-Back E and Puolakkainen M. Genotyping of Chlamydia trachomatis in rectal and pharyngeal specimens: identification of LGV genotypes in Finland. Sex Transm Infect 2012; 88: 465–469.
7. Abrams AJ. Lymphogranuloma venereum. JAMA 1968; 205: 59–62. 8. Thomson NR, Holden MTG, Carder C, et al. Chlamydia trachomatis: genome sequence analysis of lymphogranuloma isolates. Genome Res 2008; 18: 161–171. 9. Christerson L, Bom RJ, Bruisten SM, et al. Chlamydia trachomatis strains show specific clustering for men who have sex with men compared to heterosexual transmission in Sweden, the Netherlands and the United States. J Clin Microbiol 2012; 50: 3548–3555. 10. Spaargaren J, Schachter J, Moncada J, et al. Slow epidemic of lymphogranuloma venereum L2b strain. Emerg Infect Dis 2005; 11: 1787–1788. 11. McLean C, Stoner BP and Workowski KA. Treatment of lymphogranuloma venereum. Clin Infect Dis 2007; 44(Suppl 3): S147–S152. 12. de Vries HJC, Zingoni A, Kreuter A, et al. IUSTI European guideline on the management of lymphogranuloma venereum, http://www.iusti.org/regions/Europe/ euroguidelines.htm (2013, accessed 25 June 2013). 13. Sethi G, Allason-Jones E, Richens J, et al. Lymphogranuloma venereum presenting as genital ulceration and inguinal syndrome in men who have sex with men in London, UK. Sex Transm Infect 2009; 85: 165–170. 14. Vall-Mayans M, Caballero E and Sanz B. The emergence of lymphogranuloma venereum in Europe. Lancet 2009; 374: 356.
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
Bubonic lymphogranuloma venereum with multidrug treatment failure
International Journal of STD & AIDS 2014, Vol. 25(4) 306–308 ! The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0956462413501158 std.sagepub.com
Martı´ Vall-Mayans1, Jenny Isaksson2, Estrella Caballero3, Beatriz Salle´s4 and Bjo¨rn Herrmann2
Abstract A patient with proctitis and inguinal buboes diagnosed with lymphogranuloma venereum (LGV) was treated with doxycycline 21 days, azithromycin 20 days and moxifloxacin for a further 12 days because of progressive worsening of inguinal symptoms. Despite extensive antibiotic treatment, the inguinal LGV lesions persisted; however, the patient recovered spontaneously after three months.
Keyword Sexually transmitted infection, Chlamydia trachomatis, lymphogranuloma venereum, LGV, bubo, treatment failure Date received: 3 May 2013; accepted: 13 July 2013
A 47-year-old man who had sex with men (MSM) presented to our clinic with anal pain and large volume inguinal lymphadenitis for 45 days. He reported unprotected anal intercourse 2 months previously with a casual partner. Clinical examination found enlarged bilateral lymphadenopathies, 3 3 cm in size, that were tender; the one on the left side being of a firm, non-fluctuant consistency (Figure 1(a)). Proctoscopy showed a copious mucopurulent exudate with blood from where Chlamydia trachomatis was detected by PCR (Artus C. trachomatis Plus, Qiagen Diagnostics GmbH, Germany) and lymphogranuloma venereum (LGV) was confirmed using an in-house real-time PCR.1 The patient was started immediately with doxycycline treatment 200 mg/day for 21 days. After completion of that regimen his rectal symptoms improved but the lymph nodes remained tender, enlarged, with progressive inflammation. The patient was then treated with azithromycin 1 g/day, and after 10 days, a lymph node aspiration was performed, with purulent exudate obtained from which LGV DNA was detected. An ultrasound at this time (Figure 1c) showed an irregularly shaped adenomatous mass with hypoechoic areas suggesting intranodal necrosis, and node matting with surrounding soft tissue oedema. Deeper (Figure 1(c), left), inflammatory enlarged regular oval-shaped lymph nodes (8–20 mm) with an echogenic center were found. The patient continued with azithromycin 0.5 g/day for 10 more days. Around this time, rectal
LGV DNA was no longer detected. Biochemistry and haematological tests were within normal limits, with the exception of ESR ¼ 79, and mild elevations of IgA and IgG. Serology for HIV, syphilis, HCV and HBV was negative. Despite extension of antibiotic treatment with azithromycin, the nodes progressed to fluctuant buboes of a purplish colour with cellulitis. Treatment failure was suspected and hence moxifloxacin 400 mg/day was started for 12 days. After seven days on that regimen, the patient developed a thin discharging inguinal sinus (Figure 1(d)) from where C. trachomatis was detected (LGV DNA could not be confirmed due to inhibition of the technique). The patient had been compliant with all the treatments and reinfection was ruled out. One month later, the patient was recovering without external signs of inflammation or discharge from 1
STI Unit, University Hospital Vall d’Hebron, Barcelona, Catalonia, Spain Section of Clinical Bacteriology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden 3 Microbiology Service, University Hospital Vall d’Hebron, Barcelona, Catalonia, Spain 4 Immage Diagnosis Service (SDPI) Drassanes, Barcelona, Catalonia, Spain 2
Presented in part at the 27th IUSTI Europe Congress, Antalya (Turkey), 6–8 September 2012 (AbsRef: 0244). For MLST profiles, see database at Uppsala University: http://mlstdb.bmc.uu.se Corresponding author: Martı´ Vall-Mayans, STI Unit, University Hospital Vall d’Hebron, Av Drassanes 17-21, 08001 Barcelona, Catalonia, Spain. Email: [email protected]
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
Vall-Mayans et al.
307
Figure 1. Left inguinal bubo at days 53, 80 and 99 (a, b and d), respectively, since the beginning of symptoms. (c) Ultrasound of bubo from image at (b).
the buboes. He was seen again after three months and all symptoms had resolved, leaving minor scarring on the left inguinal side. The clinical evolution of buboes in this case was similar to the evolution of cases described decades ago.2 We further analyzed the LGV strain by using a multilocus sequence typing (MLST) system based on five highly variable gene regions and we also sequenced the ompA gene.3 In both rectal and nodal specimens it showed the MLST sequence type 58 with allele profile 27,13,17, 13, 28 that is the predominant sequence type amongst MSM3 and in ompA the L2 strain was found, which is different from the prevalent L2b variant in contemporary LGV cases.4 A similar case with L2 serotype that was cured with moxifloxacin treatment after failure of extended treatment with doxycycline has been reported.5 Another case with L2 in the rectum had ‘significant’ lymphadenopathy, while almost all of the other cases from that study were L2b with clinical proctitis.6 It is of interest that the reference L2 strain L2/ 434/Bu was originally isolated from an inguinal bubo and that in earlier studies,7 it was said that systemic signs and symptoms accompanied the inguinal syndrome more frequently than the genito-anorectal syndrome. Although L2 might seem more virulent than L2b, the determinants of tropism and invasiveness of LGV8 and other C. trachomatis isolates9 are likely to be multifactorial and complex. Also, the difference in ompA between strains L2b and L2/434/Bu is only one nucleotide and the complete sequence of both genomes are almost identical.8 All of this favours the view that
L2b would be a classical L2 isolate that has been circulating in humans for a long time causing a new disease.10 C. trachomatis is naturally sensitive to tetracyclines, macrolides and fluoroquinolones.11,12 The French case cited above failed doxycycline treatment, but recovered after moxifloxacin, when inguinal sinuses had already discharged and had been drained.5 Our case showed multidrug treatment failure to cure the lymphangitis but not the proctitis. This rules out true drug resistance. Similar to the French case, our patient also began to improve clinically at the inguinal level with moxifloxacin after spontaneous draining of buboes. As showed in a case series from the mid-1960s, the aspiration of buboes prevented rupture, minimized complications and hastened recovery.7 So, without further evidence from an antibiogram or other molecular studies, it would be inappropriate to consider our case as well as the French case5 as drug resistance. Probably, host factors, drug penetration and immunological response must play some role in selected cases. In patients with an LGV inguinal syndrome, doxycycline has been effective13 but early aspiration of fluctuant buboes has also to be considered.12 In conclusion, clinicians must be vigilant for the evolving presentations of LGV and be prepared to recognize all manifestations of this disease.14 Acknowledgements The authors acknowledge their colleagues at the STI Unit, University Hospital Vall d’Hebron, Barcelona for comments on this case.
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
308
International Journal of STD & AIDS 25(4)
Conflict of interest The authors declare no conflict of interest.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Chen CY, Chi KH, Alexander S, et al. The molecular diagnosis of lymphogranuloma venereum: evaluation of a real-time multiplex polymerase chain reaction test using rectal and urethral specimens. Sex Transm Dis 2007; 34: 451–455. 2. Coutts WE. Lymphogranuloma venereum. A general review. Bull World Hlth Org 1950; 2: 545–562. 3. Christerson L, de Vries HJC, de Barbeyrac B, et al. Typing of lymphogranuloma venereum Chlamydia trachomatis strains. Emerg Infect Dis 2010; 16: 1777–1779. 4. Spaargaren J, Fennema HS, Morre SA, et al. New lymphogranuloma venereum Chlamydia trachomatis variant, Amsterdam. Emerg Infect Dis 2005; 7: 1090–1092. 5. Me´chaı¨ F, de Barbeyrac B, Aoun O, et al. Doxycycline failure in lymphogranuloma venereum. Sex Transm Infect 2010; 86: 278–279. 6. Korhonen S, Hiltunen-Back E and Puolakkainen M. Genotyping of Chlamydia trachomatis in rectal and pharyngeal specimens: identification of LGV genotypes in Finland. Sex Transm Infect 2012; 88: 465–469.
7. Abrams AJ. Lymphogranuloma venereum. JAMA 1968; 205: 59–62. 8. Thomson NR, Holden MTG, Carder C, et al. Chlamydia trachomatis: genome sequence analysis of lymphogranuloma isolates. Genome Res 2008; 18: 161–171. 9. Christerson L, Bom RJ, Bruisten SM, et al. Chlamydia trachomatis strains show specific clustering for men who have sex with men compared to heterosexual transmission in Sweden, the Netherlands and the United States. J Clin Microbiol 2012; 50: 3548–3555. 10. Spaargaren J, Schachter J, Moncada J, et al. Slow epidemic of lymphogranuloma venereum L2b strain. Emerg Infect Dis 2005; 11: 1787–1788. 11. McLean C, Stoner BP and Workowski KA. Treatment of lymphogranuloma venereum. Clin Infect Dis 2007; 44(Suppl 3): S147–S152. 12. de Vries HJC, Zingoni A, Kreuter A, et al. IUSTI European guideline on the management of lymphogranuloma venereum, http://www.iusti.org/regions/Europe/ euroguidelines.htm (2013, accessed 25 June 2013). 13. Sethi G, Allason-Jones E, Richens J, et al. Lymphogranuloma venereum presenting as genital ulceration and inguinal syndrome in men who have sex with men in London, UK. Sex Transm Infect 2009; 85: 165–170. 14. Vall-Mayans M, Caballero E and Sanz B. The emergence of lymphogranuloma venereum in Europe. Lancet 2009; 374: 356.
Downloaded from std.sagepub.com at UNIV OF MICHIGAN on July 3, 2015
