A Case of Immune Reconstitution Syndrome to Disseminated Histoplasmosis

Abstract

Histoplasmosis is an uncommon cause of hepatosplenomegaly in South Africa. A case of immune reconstitution syndrome (IRS) to disseminated histoplasmosis in a patient presented to a tertiary hospital in Kwazulu-Natal, South Africa, is described.

Case Report

A 32-year-old male with fever, left flank pain, hepatosplenomegaly, and bicytopenia was referred from a local hospital to a tertiary hospital in Kwazulu-Natal, South Africa. The patient experienced an increase in abdominal circumference over 3 months. He had a 6-month history of gradual weight loss of approximately 10 kg with intermittent fever and rigors. He tested positive for HIV infection (CD4 count 20 cells/mm3) at his local hospital and was in the process of being prepared for the initiation of highly active antiretroviral therapy (HAART).

On examination, the patient was febrile (39.8°C). He was pale and had generalized lymphadenopathy (<0.5 cm in diameter). He had splenomegaly that extended 10 cm below the costal margin and a liver span of 16 cm. The full blood count showed a hemoglobin 6.6 g/dL (normochromic, normocytic anemia), platelets 173 × 109/L, and white cell count 1.6 × 109/L. Liver function tests revealed a hyperglobulinemia. He had an erythrocyte sedimentation rate (ESR) of 113 mm/h, and his urea and electrolytes were normal. Hepatitis screens were negative. The malaria smear was negative. The chest radiograph was normal. Ultrasound of the abdomen revealed abdominal lymphadenopathy in addition to hepatosplenomegaly. A bone marrow aspirate and trephine was done in the first instance to investigate the bicytopenia. The bone marrow aspirate and trephine showed granuloma and characteristics of histoplasmosis. Tuberculosis was excluded by the absence of acid fast bacilli on bone marrow and trephine and liver biopsy.

The patient was treated with intravenous amphotericin B (1 mg/kg per d) for 14 days followed by itraconazole 200 mg twice daily. Renal impairment, hypokalemia, and thrombophlebitis complicated his therapy with amphotericin B. After 7 days of itraconazole, he was commenced on HAART: lamivudine (3TC), stavudine (d4T), and efavirenz (EFV). On day 30 post commencement of HAART, he developed pyrexia and left upper quadrant pain. The spleen size had increased, and the actual size was unfortunately not documented. An ultrasound of the abdomen revealed an enlarged spleen with a splenic abscess and features suggesting impending splenic abscess rupture. He had a laporotomy with splenectomy and a wedge liver biopsy. The liver biopsy revealed histoplasmosis by eosin and hematoxylin staining. The splenic tissue histology could not be retrieved. The viral load at this admission was <400 copies/mL. The patient was recommenced on intravenous amphotericin B. This resulted in defervesce. After 10 days of amphotericin B, he was recommenced on itraconazole 200 mg twice daily.

Discussion

This case highlights the importance of considering uncommon infections associated with common clinical presentations, given the seroprevalance of HIV infection in South Africa. The diagnosis of disseminated histoplasmosis was not suspected clinically but was established by a stepwise approach to investigation. It further highlights the complexities of commencing HAART soon after the therapy for an opportunistic infection.

Histoplasmosis capsulatum has a worldwide prevalence but is endemic in North America and Latin America. ¹ In central Africa, Histoplasmosis capsulatum variant duboissii is endemic. ² This dimorphic fungus is an opportunistic infection in AIDS with severe disseminated infections occurring at CD4 counts <75 cells/mm³. The organism is found in soil laden with bat or bird excreta. ¹ The spores may be carried miles by air currents and the exposure may occur in individuals distant from the contaminated site. ¹

Histoplasmosis capsulatum usually causes an asymptomatic disease but can be fatal especially in the immunosupressed individual. ¹ Several clinical syndromes of histoplasmosis are described. These include acute and chronic pulmonary histoplasmosis, disseminated histoplasmosis, central nervous system histoplasmosis, granulomatous mediastinitis, fibrosing mediastinits, pericarditis, and rheumatological syndromes. ¹

Disseminated histoplasmosis is associated with fever, weight loss, and hepatosplenomegaly. ¹ Other sites of dissemination include oropharyngeal, gastrointestinal mucosa, skin, or adrenal glands. Individuals with underlying immunosuppression and extremes of age are at risk of disseminated histoplasmosis. ¹ Shock, respiratory distress, hepatic and renal failure, and coagulopathy may complicate the severity of the disease. ¹ Central nervous system involvement occurs in 5% to 20% of patients and may present as chronic meningitis or focal brain lesions. ¹

The differential diagnosis of hepatosplenomegaly includes malaria, schistosomiasis, miliary tuberculosis, cirrhosis with portal hypertension, typhoid fever, bacterial endocarditis, leishmaniasis, African trypanosomiasis, lymphoma, and leukemia.

The diagnosis of histoplasmosis depends on tissue diagnosis of infected tissue (liver, lymph node, and bone marrow) using hematoxylin and eosin stain. ¹ Other methods of diagnosis include culture of infected tissue, but this takes a long time and requires appropriate laboratory infection control measures. Antigen testing is more sensitive than serology and is faster than culture. ³ The urinary antigen test has a sensitivity of 95% as compared to blood (70%) in disseminated disease. ³ The limitations of the antigen test include cross-reactivity with Bacteroides dermatidis and paracoccidiodes. Unfortunately antigen testing is not routinely available. ³

There is a high mortality (80%) associated with disseminated histoplasmosis if untreated, but this may be reduced to <25% with antifungal therapy. ¹ The recommended treatment for AIDS-associated disseminated histoplasmosis includes a 12-week intensive phase to induce remission (with amphotericin B or itraconazole) and then followed by a chronic maintenance phase of therapy (itraconazole) to prevent relapse. ¹ Most patients respond rapidly to amphotericin B and can be transitioned to therapy with oral itraconazole. Lipid formulations of amphotericin B represent a recent advance in the therapy of disseminated fungal infections. Itraconazole takes a longer time to clear histoplasmosis and may interact with antiretroviral therapy (ART) in the setting of HIV infection. ¹

Patients with histoplasmosis receiving amphotericin B should be monitored for intercurrent infections (such as thrombophlebitis), renal impairment, hypokalemia, and hypomagnesemia. ¹ Response to therapy can be monitored by resolution of fever. The antigen test may also be used in monitoring therapy in disseminated histoplasmosis. Antigen concentrations decrease with therapy and increase with relapse. ¹

Histoplasmosis has protean clinical manifestations and is difficult to diagnose without tissue diagnosis. This infection should be suspected in immunocompromised patients with unexplained systemic illness. Furthermore, patients commenced on ART while still receiving treatment for an acute opportunistic infection should be closely monitored for immune reconstitution syndrome (IRS).

Immune reconstitution syndrome is a clinical syndrome that typically presents within a few weeks of starting ART. ⁴ The pathogenesis is not fully understood but is thought to relate to changes in the immune response directed against local antigen. ⁵ Two different pathogenic mechanisms might explain its occurrence. A paradoxical reaction to antigens of microbiologically inactive organisms that occurs despite specific potent, appropriate therapy, or an inflammatory reaction that unmasks a smouldering but active infection even when there is no obvious specific trigger. ^6,7 The symptoms during this clinical syndrome can be prolonged and severe. ⁶ Treatment is often with nonsteroidal anti-inflammatory drugs or corticosteroids. The use of corticosteroids may carry a risk in HIV-infected individuals. ⁷ Cessation of ART is generally not recommended.

The diagnosis of IRS in this patient is suggested by the appearance of new manifestations or the worsening of previous features related to histoplasmosis after an initial improvement with antifungal therapy. Immune reconstitution syndrome was documented by an undetectable viral load at day 30 and exacerbation of the infection despite appropriate antifungal therapy with defervescence on recommencing intravenous amphotericin B therapy and then continuing with itraconazole treatment.

Tuberculoid granulomas including giant cells and necrosis surrounding intracellular yeasts are classically observed in immunocompetent patients with histoplasmosis ⁸ but not in severely immunocompromised HIV-infected patients with disseminated histoplasmosis.^9,10 The conversion from histiocytic infiltrates before HAART to well-formed epithelioid and giant cell granulomas after HAART compatible with the restoration of T-cell-dependent macrophage activation has been reported in tuberculosis-associated IRS. ¹ A similar immune process may occur with histoplamosis-associated IRS.

The timing, clinical manifestations, and favorable outcome without the modification of ART suggest that the clinical manifestations were probably linked to immunological changes associated with response to HAART. Histoplasmosis is an additional opportunistic pathogen to be considered as part of the differential diagnosis of hepatosplenomegaly in HIV-infected individuals and may induce IRS in HIV-infected patients following the initiation of HAART.