Cryptococcemia in primary HIV infection

Opportunistic infections have been reported infrequently in primary HIV infection (PHI). ¹ We report the first case to our knowledge of cryptococcemia in PHI.

A 32-year-old previously well Australian male reported an illness commencing six weeks prior consistent with PHI (fever, sweats and a rash) and single mouth ulcer which resolved without treatment. He reported giving and receiving unprotected oral sex with men, but denied any receptive nor insertive intercourse. HIV antibody was detected by enzyme-linked immunosorbent assay, and HIV viral load was 1.3 × 10⁶ copies/mL. Initial HIV-1 Western blot was indeterminate (gp120 and gp160 bands only) and p24 antigenemia was present. CD4 cell count was 206 × 10⁶ cells/L (16%). HIV-1 Western blot was positive on repeat testing four weeks later (p24, gp120, gp160, p41, p17 and p66 bands). He had no previous HIV testing. Syphilis was also confirmed (TPPA reactive, RPR 1:256), which may have also contributed to the presenting symptoms, and he was treated with benzathine penicillin. Liver function tests were abnormal: alanine transaminase 236 U/L (reference range 7–56), gamma-glutamyl transferase 108 U/L (7–64), albumin 20 g/L (35–55) with normal alkaline phosphatase and bilirubin. Hepatitis B infection was confirmed (HBsAg detected, anti-HBc antibody detected, anti-HBc IgM antibody not detected, HBV viral load 31 × 10⁶ copies/mL [7.50 log₁₀]); abdominal ultrasound and transient elastography (FibroScan®) were suggestive of liver cirrhosis. He was also newly diagnosed with non-insulin dependent diabetes mellitus, and gliclazide was commenced.

Two weeks later, he presented with high fevers, rigors, sweats, shortness of breath and cough. There was no headache, neck stiffness or visual disturbance. Physical examination revealed no abnormalities apart from fever (38.1°C). Investigations demonstrated a white cell count 3.7 × 10⁹/L, platelets 83 × 10⁹/L and CD4+ T-lymphocyte (CD4) cell count 204 × 10⁶/L (14%). Serum cryptococcal antigen (latex agglutination titre 1:8) was detected and Cryptococcus neoformans was isolated from multiple sets of blood cultures. CT scans of the brain, chest, abdomen and pelvis and an MRI of the brain were normal. Cerebral spinal fluid examination revealed normal pressure, microscopy, protein and glucose, no growth on culture and negative cryptococcal antigen.

Liposomal amphotericin B and flucytosine induction therapy were commenced. Transition to maintenance oral fluconazole therapy occurred early at day 12 of induction therapy due to treatment related nephrotoxicity. Antiretroviral therapy was deferred due to concern regarding the risk of immune recovery inflammatory syndrome (IRIS) with cryptococcosis ² and precipitation of hepatic decompensation.

Eight weeks following the diagnosis of cryptococcemia, antiretroviral therapy (tenofovir, emtricitabine plus dolutegravir) was commenced. Four weeks later, HIV viral load was 89 copies/mL, CD4 cell count was 453 × 10⁶/L (24%), white cell and platelet counts normalised, and he remained well. HBV viral load declined to 31,000 copies/mL (4.50 log₁₀) and liver function tests normalised.

Opportunistic infections have been reported infrequently in PHI, often associated with transient but severely reduced CD4 cell counts. In PHI, CD4 cell counts are often modestly reduced, however up to 7% of individuals with symptomatic PHI have CD4 cell counts below 300 cells × 10⁶/L.^3,4 Oral and/or esophageal candidiasis ⁵ has been reported most frequently in PHI, followed by cytomegalovirus (CMV) disease, ⁶ Pneumocystis pneumonia, ⁷ toxoplasmosis, ⁸ cryptosporidiosis ⁹ and tuberculosis. ¹⁰ A recent prospective study from Switzerland suggests that opportunistic diseases in PHI may be more frequent than previously appreciated. Of 290 patients with PHI, 21 had opportunistic diseases, including 13 with candida stomatitis and/or oesophagitis, four with CMV disease and one with multisegmental herpes zoster. ¹

There are no previous reports of cryptococcemia in PHI. In one unusual case, C. neoformans was isolated from a biopsy of an isolated subconjunctival nodule, in an otherwise clinically healthy female sex worker. HIV antibody test was negative at presentation, but was positive one month later, and other details such as CD4 cell counts were not included in the report. ¹¹

Cryptococcemia generally reflects a high burden of yeasts in tissue but it can occur without an apparent secondary site of involvement. ¹² In a study of cryptococcal disease from Brazil in the pre-highly active antiretroviral therapy (HAART) era, blood cultures revealed cryptococcemia in 46 of 49 patients with AIDS. ¹³ In a US study from 1996 to 2010, 47 (44%) of 108 HIV-positive patients had cryptococcemia. ¹⁴ Cryptococcemia is associated with increased mortality.^14–16 Guidelines recommend treating cryptococcemia as for central nervous system disease. ¹⁷

Most cases of HIV-associated cryptococcosis are observed in patients with CD4 cell counts < 100× 10⁶/L. ¹⁸ In our case, the CD4 cell count was 204 × 10⁶/L, and cryptococcemia may represent reactivation of cryptococcal infection in PHI due to a more profound nett state of immunocompromise than this CD4 cell count suggests. Hepatitis B virus co-infection accelerates immunologic progression and negatively impacts HIV outcomes in PHI.^19,20 Diabetes mellitus ²¹ and syphilis ²² may also have exacerbated our patient’s cellular immune deficits.

Our case highlights that clinicians need to be aware of the potential for opportunistic infections, including cryptococcosis, during PHI, in particular if the patient has other risk factors for rapid HIV infection progression.