Amoroso, Anthony

Barcena, Carmen

Giulieri, Stefano G.

Hauser, Philippe M.

Meylan, Pascal

Moulin, Estelle

Rey, Laure-Emilie

Zaugg, Thomas

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A N S W E R T O T H E P H O T O Q U I ZAnthony Amoroso, Section EditorA 53-Year-Old Woman With an Unusual Etiology of Joint Pain(See page 76 for the Photo Quiz.)Diagnosis: Disseminated Histoplasma capsulatum var. duboisiiinfection (African histoplasmosis).Silver staining of lymph node biopsy showed several yeasts(Figure 1A and 1B). Broad-range fungal polymerase chain reac-tion (PCR) targeting the 18S ribosomal RNA gene was positivebut failed to distinguish Histoplasma capsulatum from Blasto-myces dermatidis. The polymorphisms detected in the OLEgene (delta-9 fatty acid desaturase) allowed the differentiationbetween the 2 dimorphic fungi as well as the identiﬁcation ofthe variety duboisii of H. capsulatum (Figure 1C). Clinical in-volvement of liver and bone marrow was suspected because ofelevated liver enzymes and leukopenia. The patient was treatedwith liposomal amphotericin B (3 mg/kg daily) for 2 weeks, fol-lowed by itraconazole (200 mg 3 times daily for 3 days, then200 mg twice daily), with blood concentrations >1 µg/mL.Prednisone was reduced to 10 mg daily and the immunosup-pressive treatment was substituted for hydroxychloroquine.On antifungal treatment, the patient became afebrile, withmarked improvement of shoulder pain and swelling. Liver en-zymes and white blood cell count returned to normal values. Incontrast to the general favorable outcome, painful swelling ofthe left wrist persisted.Magnetic resonance imaging (MRI) of theleft hand showed osteomyelitis of carpal bones, wrist arthritis,and wrist extensor tenosynovitis. One month after hospitalization,a left wrist synovectomy and proximal row carpectomy was per-formed. On surgery, severe synovitis involving the extensor ten-dons was observed (Figure 1D). Because of persistent wristswelling with limited range of motion, a second synovectomyFigure 1. A, Necrotizing granulomatous lymphadenitis, with encaspulated yeast cells (arrows) ( periodic acid-Schiff coloration). B, Grocott methenaminesilver staining of lymph node biopsy showing numerous yeasts and the “ﬁgure 8” budding typical of Histoplasma capsulatum var. duboisii (n = 83; meanlength [major axis], 3.5 µm; SD, 0.5; range, 2.4–5.0). C, Dimorphic fungus culture: H. capsulatum var. duboisii (lactophenol cotton blue coloration). D, Statusduring surgical procedure: diffuse synovitis that extended to the common extensor III and IV.ANSWER TO THE PHOTO QUIZ • CID 2015:61 (1 July) • 129was performed 3 months after start of antifungal treatment. Sil-ver staining showed several yeasts, but fungal cultures were ster-ile. On the last follow-up 6 months after start of antifungaltreatment, the patient had no signs of active infection but hadsevere sequelae on both hands with rupture of several extensortendons (third and fourth extensor of the left wrist, subluxationof the second metacarpophalangeal joint of the right hand).This case is an example of the triple tropism (lymphadenop-athy and skin and bone involvement) of H. capsulatum var.duboisii [1, 2], an organism prevalent in West Africa and Mad-agascar, in contrast to H. capsulatum var. capsulatum, whichoccurs commonly in the southern and midwestern UnitedStates and in Central America [3] and more frequently affectsinternal organs. Three hundred cases of African histoplasmosisare described in the literature [4], but its true prevalence is un-known. Disseminated disease is associated with poor immuno-logic status in patients infected with human immunodeﬁciencyvirus (HIV) (CD4 count <50 cells/µL). Patients typically presentwith fever, weight loss, pancytopenia, lymphadenopathy, lunginﬁltrates, hepatosplenomegaly, and cutaneous and mucosal le-sions. Mortality is high, up to 80% in septic shock with multipleorgan dysfunctions [5, 6].African histoplasmosis is transmitted by inhalation of micro-conidia found in soil containing bird or rat droppings, althougha primary pulmonary infection has not been reported. Al-thoughH. capsulatum var. duboisii yeast cells are generally larg-er (8–15 vs 2–4 µm) [7], the mean diameter of yeast in thepresent case and in a previously published case [6] was <4µm. Histoplasma capsulatum var. duboisii is often seen in thecytoplasma of giant cells, with a thicker wall that can preventneutrophilic phagocytosis; well-organized granulomas with ca-seous centers, characteristic of H. capsulatum var. capsulatum,are not observed [4].Diagnosis is performed by direct examina-tion and fungal cultures, which is considered to be the goldstandard. PCR identiﬁcation of the variety duboisii is possibleby sequencing of the polymorphic gene OLE, and its use canshorten the time to the diagnosis [6].Standard treatment with amphotericin B, followed by main-tenance therapy with itraconazole, should be given by analogywith H. capsulatum var. capsulatum disseminated infections[8], but there are no speciﬁc recommendations for antifungaltreatment of osteoarticular histoplasmosis. A recent review ofthe literature reported 10 cases of tenosynovitis (4/10) andcarpal tunnel syndrome (6/10) caused by H. capsulatum (var.capsulatum) [9]. The best response to treatment was achievedwith the combination of surgical debridement and antifungaltherapy with liposomal amphotericin B.We reviewed 18 published cases of H. capsulatum var. duboi-sii bone infections [10–18]. All patients came from West Africa,the median age was 28 years (range, 2–65 years), and 9 were fe-male. HIV coinfection was reported in 3 cases. The majorityhad disseminated disease, and only 4 patients presented local-ized (bone) infection. Eight patients had a favorable outcome, 2died, 3 recovered with severe sequelae, and 2 had an unfavorableevolution under treatment (cutaneous extension and possibleimmune reconstitution inﬂammatory syndrome). Only 6 casesrequired surgery (debridement, bone reconstruction), probablybecause of limited access to surgical procedures and loss to fol-low-up. In our opinion, surgery should be recommended in os-teoarticular involvement in cases of insufﬁcient response toantifungal treatment and should be guided by osteoarticular im-aging (eg, MRI), with the aim of decreasing fungal load, remov-ing necrotic foci, and preserving joint function.NotePotential conﬂicts of interest. S. G. G. has received travel grants fromGilead Sciences and Merck and has served as an advisory board memberfor Merck. P. M. H. has received personal fees fromMerck. All other authorsreport no potential conﬂicts.All authors have submitted the ICMJE Form for Disclosure of PotentialConﬂicts of Interest. Conﬂicts that the editors consider relevant to the con-tent of the manuscript have been disclosed.Estelle Moulin,1 Philippe M. Hauser,2 Laure-Emilie Rey,3 Thomas Zaugg,4Carmen Barcena,5 Pascal Meylan,1,2 and Stefano G. Giulieri11Infectious Diseases Service, Department of Medicine, 2Institute of Microbiology,Department of Laboratories, 3Plastic Surgery Service, Department of theMusculoskeletal System, 4Internal Medicine Service, Department of Medicine, and5Institute of Pathology, Department of Laboratories, Lausanne UniversityHospital, SwitzerlandReferences1. Manfredi R, Mazzoni A, Nanetti A, Chiodo F. Histoplasmosis capsulatiand duboisii in Europe: the impact of the HIV pandemic, travel and im-migration. Eur J Epidemiol 1994; 10:675–81.2. Drouhet E. Clinical aspects of African histoplasmosis [in French]. AnnSoc Belg Med Trop 1972; 52:391–405.3. Kauffman CA. Histoplasmosis: a clinical and laboratory update. ClinMicrobiol Rev 2007; 20:115–32.4. Gugnani HC, Muotoe-Okafor F. African histoplasmosis: a review. RevIberoam Micol 1997; 14:155–9.5. Cavassini M, Lepori M, Baur AS, Bille J, SchallerMD,Marchetti O. Dissem-inated histoplasmosis in Switzerland: an unexpected cause of septic shockand multiple organ dysfunction. Intensive Care Med 2002; 28:1501–2.6. Pellaton C, Cavassini M, Jaton-Ogay K, et al. Histoplasma capsulatumvar. duboisii infection in a patient with AIDS: rapid diagnosis usingpolymerase chain reaction-sequencing. Diagn Microbiol Infect Dis2009; 64:85–9.7. Brandt ME, Gomez BL, Warnock DW. Histoplasma, Blastomyces,Coccidioides, and other dimorphic fungi causing systemic mycoses.In: Versalovic J, Carroll KC, Funke G, Jorgensen JH, Landry ML,Warnock DW, eds. Manual of clinical microbiology. 10th ed. Washing-ton, DC: ASM Press, 2012:1902–19.8. Wheat LJ, Freifeld AG, Kleiman MB, et al. Clinical practice guidelinesfor the management of patients with histoplasmosis: 2007 update bythe Infectious Diseases Society of America. Clin Infect Dis 2007; 45:807–25.9. Cucurull E, Sarwar H, Williams CST, Espinoza LR. Localized tenosyn-ovitis caused by Histoplasma capsulatum: case report and review of theliterature. Arthritis Rheum 2005; 53:129–32.130 • CID 2015:61 (1 July) • ANSWER TO THE PHOTO QUIZ10. Minta DK, Sylla M, Traore AM, et al. Malian ﬁrst observation of dis-seminated African histoplasmosis with predominant bone localizationsin an HIV-negative child in Bamako (Mali). Review of the literature [inFrench]. J Mycol Med 2014; 24:152–7.11. Ngatse-Oko A, Peko JF, Ntsiba H, et al. Pathological fracture revealingan osseous histoplasmosis. A case report on a 60-year patient [inFrench]. Bull Soc Pathol Exot 2006; 99:227–9.12. Thompson EM, Ellert J, Peters LL, Ajdukiewicz A, Mabey D. Histoplas-ma duboisii infection of bone. Br J Radiol 1981; 54:518–21.13. Andre C, Badoual J, Kalifa G, Dubousset J. African histoplasmosis. Acase [in French]. Arch Fr Pediatr 1984; 41:429–31.14. Bankole Sanni R, Denoulet C, Coulibaly B, et al. Apropos of 1 Ivoiriancase of osseus and cutaneous histoplasmosis byHistoplasma capsulatumvar. duboisii [in French]. Bull Soc Pathol Exot 1998; 91:151–3.15. Chandenier J, Goma D, Moyen G, et al. African histoplasmosis due toHistoplasma capsulatum var. duboisii: relationship with AIDS in recentCongolese cases [in French]. Sante 1995; 5:227–34.16. Loulergue P, Bastides F, Baudouin V, et al. Literature review and casehistories of Histoplasma capsulatum var. duboisii infections in HIV-infected patients. Emerg Infect Dis 2007; 13:1647–52.17. Nethercott JR, Schachter RK, Givan KF, Ryder DE. Histoplasmosis dueto Histoplasma capsulatum var duboisii in a Canadian immigrant. ArchDermatol 1978; 114:595–8.18. Onwuasoigwe O, Gugnani HC. African histoplasmosis: osteomyelitis ofthe radius. Mycoses 1998; 41:105–7.Correspondence: Stefano G. Giulieri, MD, Infectious Diseases Service, Department of Medicine,Lausanne University Hospital (CHUV), Rue du Bugnon 46, CH-1011 Lausanne, Switzerland(stefano.giulieri@chuv.ch).Clinical Infectious Diseases® 2015;61(1):129–31© The Author 2015. Published by Oxford University Press on behalf of the Infectious DiseasesSociety of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/civ136ANSWER TO THE PHOTO QUIZ • CID 2015:61 (1 July) • 131

A 53-Year-Old Woman With an Unusual Etiology of Joint Pain

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A 53-Year-Old Woman With an Unusual Etiology of Joint Pain

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