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10 kg, and low-grade fever of 10-months’ duration. Her past medical history was characterized by repeated malaria episodes and intestinal amoebiasis. On clinical examination, she was pale, with bilateral cervical lymphoadenopathy, hepatomegaly, and a remarkably enlarged spleen (longitudinal diameter 19.5 cm at ultrasonography). Laboratory investigations showed hemoglobin 8.4 g/dL, red blood cells = 2,820 x 103/mm3, white blood cells = 2,520 x 103/mm3 with abnormal differential count (lymphocytes = 50.5%, neutrophils = 22.5%, eosinophils = 14%), and platelets = 120 x 103/mm3. Creatinine was 1.8 mg/dL, and urine analysis revealed nonselective glomerular proteinuria. Total serum gamma globulins were increased (44.2%), with IgG 3,105 mg/dL (normal range, 600–1,350 mg/dL) and IgM 990 mg/dL (normal range, 50–350 mg/dL). Iron pattern, liver enzymes, and chest x-ray were normal. HIV test was offered and accepted, which gave a positive result. Moderate immunodeficiency (T4 lymphocytes = 297 cells/mm3) and high viral load (HIV RNA > 500,000 copies/µL) were demonstrated. Serology for schistosomiasis, leishmaniasis, Parvovirus B19, typhoid fever, Epstein-Barr virus, hepatitis B and C viruses, and cytomegalovirus DNA were performed and gave negative results. Hemoglobin electrophoresis was normal. Stools were examined for parasites, but none could be identified. Malaria parasites were repeatedly searched for in thick films stained with 1% Giemsa, but no parasites were identified in 300 oil-immersion fields by an experienced microscopist. Plasmodium falciparum antibodies were detected by indirect immunofluorescence assay at a titer of 1:2,560. PCR analysis for malarial DNA was performed on blood samples collected on the day of admission: both genus-specific real-time PCR and P. falciparum species-specific nested-PCR were positive. The gene amplified was 18 rRNA. The reaction was performed using the protocol described by Lee and others.4–6 A diagnosis of HMS was made, according to Fakunle’s criteria.2 A single dose of mefloquine (500 mg) was administered, the dose being adjusted for reduced renal function. Three days afterward, fever was cleared and molecular assays for Plasmodia were negative, but hypersplenism and pancytopenia improved more slowly. Two months after mefloquine treatment, spleen size was reduced to 14.8 cm, and the abdominal pain improved accordingly. Total serum IgM normalized, and the IFAT malaria titer showed a 4-fold reduction (1:640).
Anti-retroviral therapy was started with dose adjustment for the renal function using lamivudine 150 mg/day, stavudine 15 mg twice/day, and nevirapine 200 mg/day. A few days later, the patient developed continuous fever up to 38°C, severe anemia (Hb 7.6 g/dL), and high creatinine serum levels (7.6 mg/dL). Anti-retroviral therapy was discontinued, and a renal biopsy performed, which showed HIV-related focal and segmental glomerulosclerosis (HIV-associated nephropathy, HIVAN).
Differential diagnosis of splenomegaly in HIV-infected individuals from the tropical belt is complex and should include several conditions, such as HBV, HCV, EBV, CMV, Leishmania, and Schistosoma infections as well as malignant lymphoproliferative disorders. In our case, all of these conditions were ruled out and the diagnosis of HMS was based on Fakunle’s criteria, which do not differ in HIV-seronegative or HIV-seropositive individuals: major criteria were marked splenomegaly, high antibody levels to P. falciparum, serum IgM at least 2 standard deviations above the mean laboratory value, and clinical and immunologic response to antimalarials.2 Among minor criteria, hypersplenism was present.
Initially, malaria parasites were not detected at microscopic examination because of the low sensitivity of the technique in cases of HMS. Evidence of malarial infection is indirect in many HMS patients, and is based on serological criteria; immunohistochemical demonstration of P. falciparum antigens in liver cells is a very specific but invasive method.7 Direct demonstration of specific malarial DNA in the blood with nested PCR and real-time PCR can provide further evidence for diagnosis of HMS. PCR investigations, even qualitative ones, are highly sensitive assays that have proved useful in diagnosis of persistent malaria infections8,9 and which might be useful confirmatory techniques in industrialized countries in diagnosis of HMS. In HIV-infected individuals, such evidence would prevent misleading diagnoses and use of inappropriate therapies.
To conclude, clinicians should be reminded that malaria can cause splenomegaly, regardless of HIV status, and that they still need to consider malaria in their differential diagnoses in patients with suitable travel histories. Further research is warranted, which ideally should be conducted in countries where both HIV infection and malaria are highly prevalent.
Received August 7, 2006. Accepted for publication April 3, 2007.
* Address correspondence to Alberto Matteelli, Infectious and Tropical Medicine Institute, University of Brescia, Italy, Piazza Spedali Civili 1, 25100 Brescia, Italy. E-mail amatteelli{at}bsnet.it 
Authors’ addresses: G. De Iaco, N. Saleri, M. Gulletta, L. Signorini, A. Matteelli, K. Prestini, and F. Castelli, Infectious and Tropical Medicine Institute, University of Brescia, Italy, Telephone: +39 030 399 5802, Fax: +39 030 303 061, E-mail: amatteelli{at}bsnet.it. F. Perandin, G. Ravizzola, and N. Manca, Department of Laboratory Diagnosis, Section of Microbiology, University of Brescia, Spedali Civili, Italy.
Reprint requests: Alberto Matteelli, Infectious and Tropical Medicine Institute, University of Brescia, Italy, Piazza Spedali Civili 1, 25100 Brescia, Italy. E-mail amatteelli{at}bsnet.it.
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