In HIV-infected patients, highly active antiretroviral therapy (HAART) produces a partial recovery of cellular immunity . Nevertheless, this may also induce unexpected clinical manifestations classified as immune reconstitution inflammatory syndrome (IRIS) [2–4]. We describe the occurrence of IRIS in HIV-infected patients with disseminated histoplasmosis.
A 34-year-old man living in Surinam presented in October 2001 with a disseminated histoplasmosis with meningitis, capsular cerebral lesion and colic involvement. HIV serology was positive, the CD4 cell count was 69 cells/mm3 and the HIV-RNA level was greater than 500 000 copies/ml. Colonoscopy showed multiple ulcerations, and biopsy revealed ulcerative colitis with granulomatous inflammation including histiocytic infitrates filled with numerous yeasts suggestive of Histoplasma capsulatum var. capsulatum. Treatment with amphotericin B followed by itraconazole was administered, with a rapid cessation of fever and diarrhoea, normalization of cerebrospinal fluid and improvement of neurological deficit. In January 2002, HAART was initiated. Fifteen days later the patient presented with fever, weight loss, cholestatic hepatitis and neurological deterioration. The CD4 cell count was 177 cells/mm3 and HIV-RNA level was 628 copies/ml. Cerebral magnetic resonance imaging revealed the appearance of a contrast enhancement surrounding the capsular lesion and meningeal inflammation. Abdominal computed tomography scan revealed the appearance of mesenteric lymphadenopathies and of contrast enhancing liver abscesses. Liver biopsy revealed epithelioid and giant cells forming a rather well-formed granuloma (Fig. 1a). Grocott staining and fungal cultures of liver biopsy were negative. Immunohistochemistry using a polyclonal antibody against Histoplasma (Institut Pasteur, Paris, France) showed diffuse staining of the granuloma. Antiretroviral treatment and itraconazole were continued, and naproxen was administered with a rapid favourable outcome without relapse after a follow-up of 18 months.
A 20-year-old woman originating from the Ivory Coast and living in France for one year presented in November 2001 with a disseminated histoplasmosis with cerebral, cutaneous and medullar involvement. HIV serology was positive, the CD4 cell count was 4 cells/mm3 and the HIV-RNA level was 109 700 copies/ml. Cultures from skin and bone marrow biopsies were positive for Histoplasma spp. Amphotericin B was administered followed by itraconazole, with a rapid improvement. Cerebral magnetic resonance imaging showed the disappearance of the cerebellar lesion. In January 2002, HAART was initiated. One month later, she presented with fever, left wrist and left knee arthritis, and granulomatous uveitis. Synovial aspirate culture was positive for Histoplasma spp. The CD4 cell count was 108 cells/mm3 and the HIV-RNA level was 25 000 copies/ml. Antiretroviral treatment and itraconazole were continued, and local ocular steroid treatment was administered, with a favourable outcome. She was then lost to follow-up.
First IRIS: A 41-year-old HIV-infected man originating from the Congo and living in France for 15 years was admitted in September 1996 for fever, cervical lymphadenitis, a facial palsy and papulous skin lesions. The CD4 cell count was 136 cells/mm3. HAART had been initiated in June 1996 (CD4 cell count 38 cells/mm3). Skin and lymph node biopsies revealed well-formed epithelioid and giant cell granulomas with necrosis and large intracellular yeasts suggestive of H. capsulatum var. duboisii after Grocott staining. Cultures were positive for Histoplasma spp. Facial palsy was attributed to nerve compression by enlarged lymphadenitis. Treatment with amphotericin B switched to itraconazole was administered with a favourable outcome.
Second IRIS: In December 1996, the CD4 cell count decreased to 32 cells/mm3 and the HAART regimen was modified. In November 1997, he presented with a recurrence of cervical lymph node enlargement. The CD4 cell count was 117 cells/mm3 and the HIV-RNA level was less than 200 copies/ml. Lymph node biopsy revealed well-formed epithelioid and giant cell granulomas with caseation containing large yeast cells. Fungal and mycobacterial cultures were sterile. Antiretroviral treatment and itraconazole were continued without modification, and outcome was favourable without relapse after a follow-up of 6.5 years.
A 56-year-old man originating from French Guyana and living in metropolitan France for 10 years presented in October 2002 with a disseminated histoplasmosis with superficial and mesenteric lymphadenitis. HIV serology was positive, the CD4 cell count was 55 cells/mm3 and the HIV-RNA level was greater than 500 000 copies/ml. Lymph node biopsies revealed diffuse yeast-laden histiocytic infiltrates suggestive of H. capsulatum var. capsulatum and were positive for Histoplasma spp. in culture. Itraconazole and HAART were initiated simultaneously. One week later, the clinical outcome was favourable with the cessation of fever and abdominal pain. One month later, he presented with an acute abdominal pain. Laparotomy was performed revealing intestinal obstruction secondary to intestinal thickening and numerous peritoneal miliary nodules. Histological examination showed the presence of well-formed epithelioid and giant cell granulomas sometimes with caseation containing yeasts (Fig. 1b). The CD4 cell count was 436 cells/mm3 and the HIV-RNA level was less than 200 copies/ml. HAART was stopped and itraconazole was continued. A favourable outcome was observed after surgical treatment. HAART was resumed in January 2003 without relapse after a follow-up of 18 months.
We described IRIS complicating disseminated histoplasmosis as a consequence of HAART initiation. This diagnosis was suggested by the appearance of new manifestations or the worsening of previous manifestations related to histoplasmosis after an initial improvement with antifungal therapy. IRIS was documented by the increase in the CD4 cell count within the first months of HAART, and supported by the presence of granulomatous reactions. These tuberculoid granulomas including giant cells and necrosis surrounding intracellular yeasts are classically observed in immunocompetent patients , but not in severely immunocompromised HIV-infected patients with disseminated histoplasmosis [6,7]. The conversion from histiocytic infiltrates before HAART to well-formed epithelioid and giant cell granulomas after HAART was compatible with the restoration of T-cell-dependent macrophage activation .
In HIV-infected patients, successful antiretroviral therapy can induce IRIS. Generally, two different pathogenic mechanisms might explain its occurrence, both of which were found in the cases reported here. First, a paradoxical reaction to antigens of microbiologically inactive infectious agents can occur despite specific potent anti-infectious therapy [2–4]. Second, an inflammatory reaction unmasks smouldering but active infection [2–4]. One case illustrates a borderline reaction between these two different mechanisms. The timing, unusual clinical manifestations and favourable outcome without the modification of treatment suggested that clinical manifestations were probably linked to immunological changes associated with HAART. Interestingly, the unique unpublished histoplasmosis-associated IRIS case was comparable .
In conclusion, histoplasmosis broadens the spectrum of opportunistic pathogens inducing IRIS in HIV-infected patients.
The authors would like to thank Dr Nathalie Mémain who participated in the collection of data.
1. Autran B, Carcelain G, Li TS, Blanc C, Mathez E, Tubiana R, et al
. Positive effect of combinated antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277:112–116.
2. DeSimone JA, Pomerantz RJ, Babinchak TJ. Inflammatory reactions in HIV-1 infected persons after initiation of highly active antiretroviral therapy. Ann Intern Med 2000; 133:447–454.
3. Shelburne SA III, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DM, et al
. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002; 81:213–227.
4. French MA, Price P, Stone SF. Immune restoration disease after antiretroviral therapy. AIDS 2004; 18:1615–1627.
5. Goodwin RA, Loyd JE, Des Prez RM. Histoplasmosis in normal hosts. Medicine 1981; 60:231–266.
6. Wheat LJ, Connolly-Stringfield PA, Baker RL, Curfman MF, Eads ME, Israel KS, et al
. Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical finding, diagnosis and treatment, and review of the literature. Medicine 1990; 69:361–374.
7. Chandler FW, Watts JC. Histoplasmosis capsulati.
In: DH Connor, FW Chandler, editors. Pathology of infectious diseases
. Stanford, Connecticut: Appelton and Lange; 1987; pp. 1007–1015.
8. Lucas SB. Histopathology in clinical tuberculosis. London: Chapman and Hall; 1998. pp. 113–127.
9. Bottaro E, Elsner B, Cassetti Y. Histoplasmosis and HAART: appearance of adenomegaly during treatment [in Spanish].
In: Third Argentinean Congress on AIDS
. Mar del Plata, Argentina, 1997.