• View in gallery

    Leprosy skin lesions two months after introduction of antiretroviral therapy in a human immunodeficiency virus–infected patient from Côte d'Ivoire living in France. This figure appears in color at www.ajtmh.org.

  • View in gallery

    Skin biopsy specimen from the patient showing A, a dense infiltrate extended throughout the dermis, with collection of epithelioid cells, lymphocytes, and plasmocytes (magnification ×5) and B, non-caseating epithelioid granulomas (magnification ×40). (Hematoxylin and eosin stained.) This figure appears in color at www.ajtmh.org.

  • 1.

    DeSimone JA, Pomerantz RJ, Babinchak TJ, 2000. Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 133: 447454.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ustianowski AP, Lawn SD, Lockwood DN, 2006. Interactions between HIV infection and leprosy: a paradox. Lancet Infect Dis 6: 350360.

  • 3.

    Batista MD, Porro AM, Maeda SM, Gomes EE, Yoshioka MC, Enokihara MM, Tomimori J, 2008. Leprosy reversal reaction as immune reconstitution inflammatory syndrome in patients with AIDS. Clin Infect Dis 46: e56e60.

    • Search Google Scholar
    • Export Citation
  • 4.

    Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, Elliott JH, Murdoch D, Wilkinson RJ, Seyler C, John L, van der Loeff MS, Reiss P, Lynen L, Janoff EN, Gilks C, Colebunders R, 2008. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 8: 516523.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bourgarit A, Carcelain G, Samri A, Parizot C, Lafaurie M, Abgrall S, Delcey V, Vicaut E, Sereni D, Autran B, 2009. Tuberculosis-associated immune restoration syndrome in HIV-1-infected patients involves tuberculin-specific CD4 Th1 cells and KIR-negative gammadelta T cells. J Immunol 183: 39153923.

    • Search Google Scholar
    • Export Citation
  • 6.

    Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC Jr, Hamill RJ, 2005. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19: 399406.

    • Search Google Scholar
    • Export Citation
  • 7.

    Couppie P, Domergue V, Clyti E, El Guedj M, Vaz T, Sainte-Marie D, Marty C, Nacher M, 2009. Increased incidence of leprosy following HAART initiation: a manifestation of the immune reconstitution disease. AIDS 23: 15991600.

    • Search Google Scholar
    • Export Citation
  • 8.

    Lortholary O, Fontanet A, Memain N, Martin A, Sitbon K, Dromer F, 2005. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 19: 10431049.

    • Search Google Scholar
    • Export Citation
  • 9.

    Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, Huerre M, Dromer F, Dupont B, Lortholary O, 2006. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 20: 119121.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Unmasking Leprosy: An Unusual Immune Reconstitution Inflammatory Syndrome in a Patient Infected with Human Immunodeficiency Virus

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  • Service de Maladies Infectieuses et Tropicales, et Service de Microbiologie, Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; Service de Dermatologie, et Service d'Anatomie et Cytologie Pathologiques, Université Paris Nord, Hôpital Avicenne, Bobigny, France; Groupe Microorganismes et Barrières de l'Hôte, Institut National de la Santé et de la Recherche Médicale Unité Avenir 604, Institut Pasteur, Paris, France

Immune reconstitution inflammatory syndrome (IRIS) has become a frequent and potentially severe complication after initiation of following antiretroviral therapy (ART) in patients infected with human immunodeficiency virus (HIV). IRIS can unmask a previously clinically silent infection, such as tuberculosis, as recently described for Mycobacterium infections. We describe a case in a patient from Côte d'Ivoire living in France in whom skin papular lesions developed after initiation of ART. These lesions were associated with microbiologically proven leprosy. Thus, latent leprosy can appear as IRIS, and leprosy-associated IRIS should be considered in HIV-infected patients from areas endemic for leprosy.

New clinical symptoms may occur soon after introduction of antiretroviral therapy (ART) in patients infected with human immunodeficiency virus (HIV) as immune reconstitution inflammatory syndrome (IRIS).1 IRIS has been initially reported as a paradoxical exacerbation of a pre-existing, treated, opportunistic infection after ART introduction in the absence of treatment failure, or as any new opportunistic infection seen as an immune response improvement.1 It may also reflect emergence of a previously clinically silent infection in the course of immunologic restoration. Diagnosis of these underlying infections may constitute a challenge for the clinician. We report an HIV-infected patient from Africa living in France in whom skin lesions developed after initiation of ART. These lesions were caused by Mycobacterium leprae.

A 40-year-old man was admitted to the Center d'Infectiologie Necker-Pasteur in Paris, France, for recent skin lesions. A native of Côte d'Ivoire, he had been living in France since 2003, and had returned to Côte d'Ivoire in 2006 and 2007. HIV-1 infection was diagnosed in 2004 with 106 CD4+ lymphocytes/mm3 (5%) and an HIV RNA viral load of 5.1 log10 copies/mL. The patient was treated with zidovudine/lamivudine and lopinavir/ritonavir, and then with abacavir, tenofovir, and lopinavir/ritonavir. However, he showed poor compliance with treatment, and viral load never decreased to less than 3.9 log10 copies/mL. ART was stopped by the patient in April 2008.

In March 2009, analyses showed 8 CD4+ lymphocytes/mm3 (1%) and a viral load of 5 log10 copies/mL. Treatment was then switched to lopinavir/ritonavir, tenofovir, and abacavir/lamivudine, according to viral resistance genotyping. The patient showed good compliance, and two months later the CD4+ cell count increased to 117 lymphocytes/mm3 (6%) and the viral load decreased to 2.4 log10 copies/mL.

In May 2009, he reported progressive occurrence of several painless, infiltrated, centimetric and non-pruriginous skin lesions. Clinical examination showed 11 erythematous papules, sometimes covered with gray squamae and located on the forehead, ears, eyelids, right internal canthus, and upper limbs (Figure 1). No other physical abnormality was found. The C-reactive protein level was 13 mg/L. Results of standard biological analyses were normal. A few acid-fast bacilli were found on a cutaneous smear after Ziehl staining (Supplemental Figure, available at www.ajtmh.org). Skin biopsy specimens showed non-caseating epithelioid granulomas. Ziehl, periodic acid–Schiff, Giemsa and Grocott stainings showed negative results on skin biopsy specimens (Figure 2). Results of a chest radiograph and abdominal computed tomography were normal. Results of tests for acid-fast bacilli in sputum and analysis of gastric fluid, urine, blood, and bone marrow were negative. A specific M. tuberculosis complex polymerase chain reaction performed on skin biopsy specimens showed negative results.

Figure 1.
Figure 1.

Leprosy skin lesions two months after introduction of antiretroviral therapy in a human immunodeficiency virus–infected patient from Côte d'Ivoire living in France. This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 1; 10.4269/ajtmh.2010.10-0071

Figure 2.
Figure 2.

Skin biopsy specimen from the patient showing A, a dense infiltrate extended throughout the dermis, with collection of epithelioid cells, lymphocytes, and plasmocytes (magnification ×5) and B, non-caseating epithelioid granulomas (magnification ×40). (Hematoxylin and eosin stained.) This figure appears in color at www.ajtmh.org.

Citation: The American Society of Tropical Medicine and Hygiene 83, 1; 10.4269/ajtmh.2010.10-0071

Treatment with clarithromycin, ethambutol, and rifabutin was started because an M. avium complex infection was suspected. A 16S–23S ribosomal RNA–specific polymerase chain reaction and sequencing performed on skin biopsy samples identified M. leprae. Electromyography showed damage on the right ulnar nerve. A diagnosis of a borderline lepromatous form of leprosy was made and treatment was changed to clarithromycin, ethionamide, and dapsone. Clarithromycin was given instead of rifampin because of major interactions with ART. Skin lesions progressively cleared but became hypoesthesic. The patient is still receiving therapy, with no other complication reported as of January 2010, after six months of treatment. We plan a minimal duration of treatment of 12 months.

Although HIV has never been shown to increase susceptibility to M. leprae, latent leprosy infections can be unmasked as IRIS after initiation of ART.2,3 The concept of silent infection becoming clinically patent upon rapid restoration of immune responses has been documented for other human pathogenic mycobacteria such as M. tuberculosis.4 In HIV-infected patients, IRIS caused by M. tuberculosis is associated with an increase in the number of activated tuberculin-specific effector memory CD4+ T cells and of a subpopulation of T cell antigen receptor γδ T cells.5 IRIS is more frequent in naive patients with a rapid decrease of HIV viral load after ART introduction and when ART is started near the time of diagnosis of an opportunistic infection.1,6 This reaction seems to be associated with an increase of T cell reactivity after ART initiation, with migration of CD4+ T cells into lesions and improvement of the Th1 reaction.2

Ustianowski and others reported nine patients with ART-unmasked leprosy.2 Clinical symptoms usually developed within three months after ART initiation. Such symptoms were occasionally severe and could require oral corticosteroids, along with therapy against M. leprae. Recent data underline the increased incidence of leprosy after initiation of ART.7 However, development of papular lesions in the setting of HIV infection is evocative of other several diagnoses (M. avium complex infection, syphilitic nodules, histoplasmosis, disseminated cryptococcosis [umbilicated lesions], Kaposi sarcoma, leishmaniasis, and sarcoidosis). Unmasking leprosy should also be considered in HIV-infected patients from Africa beginning ART, even long after they have left disease-endemic areas. Leprosy should be promptly differentiated from other tropical causes of IRIS such as tuberculosis, cryptococcosis, and histoplasmosis.4,8,9

  • 1.

    DeSimone JA, Pomerantz RJ, Babinchak TJ, 2000. Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 133: 447454.

    • Search Google Scholar
    • Export Citation
  • 2.

    Ustianowski AP, Lawn SD, Lockwood DN, 2006. Interactions between HIV infection and leprosy: a paradox. Lancet Infect Dis 6: 350360.

  • 3.

    Batista MD, Porro AM, Maeda SM, Gomes EE, Yoshioka MC, Enokihara MM, Tomimori J, 2008. Leprosy reversal reaction as immune reconstitution inflammatory syndrome in patients with AIDS. Clin Infect Dis 46: e56e60.

    • Search Google Scholar
    • Export Citation
  • 4.

    Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, Elliott JH, Murdoch D, Wilkinson RJ, Seyler C, John L, van der Loeff MS, Reiss P, Lynen L, Janoff EN, Gilks C, Colebunders R, 2008. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis 8: 516523.

    • Search Google Scholar
    • Export Citation
  • 5.

    Bourgarit A, Carcelain G, Samri A, Parizot C, Lafaurie M, Abgrall S, Delcey V, Vicaut E, Sereni D, Autran B, 2009. Tuberculosis-associated immune restoration syndrome in HIV-1-infected patients involves tuberculin-specific CD4 Th1 cells and KIR-negative gammadelta T cells. J Immunol 183: 39153923.

    • Search Google Scholar
    • Export Citation
  • 6.

    Shelburne SA, Visnegarwala F, Darcourt J, Graviss EA, Giordano TP, White AC Jr, Hamill RJ, 2005. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19: 399406.

    • Search Google Scholar
    • Export Citation
  • 7.

    Couppie P, Domergue V, Clyti E, El Guedj M, Vaz T, Sainte-Marie D, Marty C, Nacher M, 2009. Increased incidence of leprosy following HAART initiation: a manifestation of the immune reconstitution disease. AIDS 23: 15991600.

    • Search Google Scholar
    • Export Citation
  • 8.

    Lortholary O, Fontanet A, Memain N, Martin A, Sitbon K, Dromer F, 2005. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 19: 10431049.

    • Search Google Scholar
    • Export Citation
  • 9.

    Breton G, Adle-Biassette H, Therby A, Ramanoelina J, Choudat L, Bissuel F, Huerre M, Dromer F, Dupont B, Lortholary O, 2006. Immune reconstitution inflammatory syndrome in HIV-infected patients with disseminated histoplasmosis. AIDS 20: 119121.

    • Search Google Scholar
    • Export Citation

Author Notes

*Address correspondence to Caroline Charlier, Service de Maladies Infectieuses et Tropicales, Université Paris Descartes, Hôpital Necker-Enfants Malades, Centre d'Infectiologie Necker-Pasteur, 149 Rue de Sèvres, 75015 Paris, France. E-mail: caroline.charlier@nck.aphp.fr

Authors' addresses: Guillaume Bussone, Caroline Charlier, Jean-Paul Viard, and Olivier Lortholary, Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. Emmanuelle Bille, Service de Microbiologie, Université Paris Descartes, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France. Frédéric Caux, Service de Dermatologie, Université Paris Nord, Hôpital Avicenne, Bobigny, France. Annie Lévy, Service d'Anatomie et Cytologie Pathologiques, Université Paris Nord, Hôpital Avicenne, Bobigny, France. Marc Lecuit, Service de Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur, Université Paris Descartes, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France et Groupe Microorganismes et Barrières de l'Hôte, Institut National de la Santé et de la Recherche Médicale Avenir Unité 604, Institut Pasteur, Paris, France.

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