Histoplasmosis in two human immunodeficiency virus-positive immigrants to Italy: clinical features and management in the highly active antiretroviral therapy era.

Abstract: We report two cases of histoplasmosis occurring in human immunodeficiency virus-positive patients who immigrated to Italy, and focus our attention on the clinical features and therapeutic aspects, with particular emphasis on secondary prophylaxis. The patients had comparable human immunodeficiency virus baseline parameters, but had a completely different compliance over therapeutic regimens. The two patients were followed in two different city hospitals of our region, Padua and Verona, and the diagnosis was made on the basis of instrumental, histologic, and microbiologic findings. One of them was treated with corticosteroids because of nephrotic syndrome.

Key Words: highly active antiretroviral therapy, histoplasmosis, human immunodeficiency virus, immigrants, Italy

**********

The risk and severity of histoplasmosis, which is now recognized as an important infection in patients with acquired immunodeficiency syndrome (AIDS), increase as immune function declines. (1) Disseminated histoplasmosis is more likely to be encountered in patients with CD4 cell counts below 200 cells/[mm.sup.3], suggesting that cell-mediated immunity plays a key role against Histoplasma capsulatum. (2) After acute treatment, human immunodeficiency virus (HIV)-infected persons generally receive lifelong suppressive therapy with itraconazole (200 mg bid), (3) but insufficient data exist regarding the necessity of prolonged secondary prophylaxis. We report two cases of histoplasmosis occurring in HIV-positive patients who immigrated to Italy, and focus our attention on the clinical features and therapeutic aspects, with particular emphasis on secondary prophylaxis.

Case Reports

Patient 1

A 40-year-old woman emigrated from Nigeria to Italy in December 2001. Diagnosis of AIDS, based on detection of Candida esophagitis, was made in February 2002, when her CD4 cell count was 12 cells/[mm.sup.3] (1.6%) and her plasma HIV viral load was 290,000 copies/mL. She was put on highly active antiretroviral therapy (HAART) with DDI (200 mg administered once daily), D4T (40 mg administered twice daily), and NFV (750 mg tid) and prophylaxis against pneumocystosis and toxoplasmosis with co-trimoxazole. In the same period, treatment with corticosteroids (prednisone, 30 mg administered daily) was started because of nephrotic syndrome.

In July 2002, the patient came to our attention with multiple, umbilicated warts diffused on the face, trunk, and upper extremities and important edema of nasal mucosae and of the orbicularis ori region. No other pathologic clinical signs were present. The patient's CD4 cell count was 39 cells/[mm.sup.3] (2.2%) and her HIV plasma viral load was 179 copies/mL. The patient was still on both antiretroviral therapy and prednisone.

The diagnosis of histoplasmosis was definitively made on histologic examination of three cutaneous lesions (Fig. 1). Histoplasma capsulatum variety capsulatum was identified by polymerase chain reaction and culture findings. (4,5) The patient was treated with itraconazole oral solution (400 mg/d) for 12 weeks followed by itraconazole 200 mg/d as secondary prophylaxis. Clinical symptoms disappeared. Prednisone was then reduced to 15 mg/d after improved renal function.

The patient was lost to follow-up for some weeks and came back to our observation 105 days later, showing again a few lesions located on the perioral region and similar to the ones described previously. She had interrupted both prophylaxis and HAART. After psychological counseling, the patient restarted therapy with itraconazole and antiretroviral treatment, with complete remission of the lesions due to Histoplasma. The latest CD4 cell count showed 107 cells/[mm.sup.3] (4.5%) and her HIV load was less than 50 copies/mL.

Patient 2

A 29-year-old Colombian HIV-positive man, living in Italy from July 2000, was admitted to the Infectious Diseases Department of Padua University because of suspected pulmonary tuberculosis in November 2000. He had been treated for 6 months for pulmonary tuberculosis 3 years before. At admission, he complained of a 20-day history of dyspnea, cough, and fever; he had lost 10 kg in weight in the previous 2 months. Physical examination showed swollen lymph nodes in the right axillary region, pulmonary rales, hepatic and splenic enlargement, and oropharyngeal candidiasis.

Laboratory findings revealed high-level immunosuppression (CD4 lymphocytes, 22 cells/[mm.sup.3]), an HIV viral load of 16,800 copies/mL, anemia (hemoglobin level, 10 g/dL), thrombocytopenia (88,000 cells/[mm.sup.3]), hyperferritinemia (2,905 [micro]g/L), and high serum lactate dehydrogenase (1,451 U/L). A chest computed tomographic scan showed diffuse, bilateral, nodular, interstitial infiltrates with wide mediastinal lymphadenopathy (Fig. 2). A bronchoscopic evaluation with bronchoalveolar lavage was performed. Smear microbiologic examinations were negative. Empiric treatment against Mycobacterium tuberculosis and Pneumocystis carinii was started. Because of the presence of oral candidiasis, the patient also began antimycotic therapy with fluconazole. HAART was postponed.

After 3 weeks, the patient left the hospital, with an apparent improvement of his clinical conditions. After 2 months, the patient was again hospitalized because of a maculopapular rash on the face and on the left shoulder. One ulcerative lesion was also present on the palate. Treatments against tuberculosis and pneumocystosis were interrupted and HAART (D4T, 30 mg administered twice daily; 3TC, 150 mg administered twice daily; and NVP, 200 mg administered twice daily) was started. Skin lesion biopsies and Histoplasma serology were performed. Histologic examination and cultural findings revealed Histoplasma capsulatum var. capsulatum. Serology was also positive. Treatment with itraconazole was started.

After a month of continuous antiretroviral treatment and an antimycotic regimen, skin and mucosal lesions disappeared. His CD4 cell count was 84 cells/[mm.sup.3] and his HIV RNA load was less than 40 copies/mL. At the end of February 2001, the patient was discharged. A month later, he came back to medical attention without signs of relapse. He had stopped without medical advice both secondary prophylaxis against histoplasmosis and primary prophylaxis against Pneumocystis carinii pneumonia. Twelve months later (in February 2002), his CD4 cell count was 112 cells/[mm.sup.3] and his HIV load was less than 40 copies/mL. In October 2002, his CD4 cell count was 220 cells/[mm.sup.3] and his HIV load was less than 40 copies/mL. Clinically, there were no signs of relapse.

Discussion

AIDS-related disseminated histoplasmosis is relatively common in highly endemic areas of North and Central America and Africa (6) and is rarely observed in nonendemic regions such as Europe, where it is generally observed only as an immigration-associated disease. (7) The cases in this article stress the role of immigration of people infected in their native country who have symptoms in other countries. Many factors, such as the low index of clinical suspicion, the fastidious growth requirements, and the limited usefulness of serologic and skin testing, can contribute, as in our experience, to a delayed diagnosis, which often relies on invasive procedures carried out to obtain material for histopathologic examination or cultural identification. The cases that we observed outline the importance of HAART adherence and the role of chronic maintenance therapy in patients with HIV infection.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

In the first case, the voluntary interruption of HAART and antimycotic maintenance therapy led to a new episode of acute histoplasmosis. In the latter case, the strict adherence to a highly active antiretroviral regimen had permitted the interruption of the maintenance therapy (the patient's own decision) without any relapse of Histoplasma capsulatum infection until recently (20-month disease-free interval). We stress that many immigrants from Africa suffer from nephrotic syndrome and are on prolonged therapy with corticosteroids, an adjunctive, independent cause of activation of "native-country-acquired" diseases, such as histoplasmosis.

Conclusion

After acute treatment for histoplasmosis, HIV-infected persons generally receive lifelong suppressive therapy with itraconazole (200 mg administered twice daily), but insufficient data exist regarding the necessity of prolonged secondary prophylaxis, and with our little experience, we want to stress the role of compliance in the management of therapeutics in HIV-infected persons.

Accepted May 20, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9704-0398

References

1. Wheat J. Endemic mycoses in AIDS: a clinical review. Clin Microbiol Rev 1995;8:146-159.

2. Wheat LJ, Connolly-Stringfield PA, Baker RL, et al. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature. Medicine (Baltimore) 1990;69:361-374.

3. Wheat J, Hafner R, Wulfsohn M, et al. Prevention of relapse of histoplasmosis with itraconazole in patients with the acquired immunodeficiency syndrome: The National Institute of Allergy and Infectious Diseases Clinical Trials and Mycoses Study Group Collaborators. Ann Intern Med 1993;118:610-616.

4. de Hoog GS, Guarro J, Gene J, et al. Atlas of Clinical Fungi. Utrecht, The Netherlands, Centraalbureau voor Schimmelcultures, 2000, ed 2.

5. Porta A, Colonna-Romano S, Callebaut I, et al. An homologue of the human 100-kDa protein (p100) is differentially expressed by Histoplasma capsulatum during infection of murine macrophages. Biochem Biophys Res Commun 1999;254:605-613.

6. Sarosi GA, Johnson PC. Disseminated histoplasmosis in patients infected with human immunodeficiency virus. Clin Infect Dis 1992;14(Suppl 1):S60-S67.

7. Manfredi R, Mazzoni A, Nanetti A, et al. Histoplasmosis capsulati and duboisii in Europe: the impact of the HIV pandemic, travel and immigration. Eur J Epidemiol 1994;10:675-681.

RELATED ARTICLE: Key Points

* Histoplasmosis is now recognized as an important infection in patients with acquired immunodeficiency syndrome.

* Disseminated histoplasmosis is likely to be encountered in patients with CD4 cell counts below 200 cells/[mm.sup.3].

* After acute treatment, human immunodeficiency virus-infected patients generally receive secondary prophylaxis, but insufficient data exist on the management of lifelong suppressive antimycotic therapy.

Federica Faggian, MD, Massimiliano Lanzafame, MD, Emanuela Lattuada, MD, PierLuigi Brugnaro, MD, Giovanni Carretta, MD, Paolo Cadrobbi, MD, and Ercole Concia, MD

From the Clinical Division of Infectious Diseases, Major Civil Hospital, B.go Trento, Verona, Italy, and the Clinical Division of Infectious Diseases, Civil Hospital, Padua, Italy.

We have no commercial or proprietary interest in any drug, device, or equipment mentioned in this article and received no financial support.

Reprint requests to Federica Faggian, MD, Via Sirtori no. 10, 37126 Verona, Italy. Email: [e-mail]