Diagnosis and Management of Cryptococcal Relapse

Abstract

Despite improvements in the antifungal regimens and the roll out of antiretroviral therapy (ART) in sub-Saharan Africa, mortality due to cryptococcal meningitis remains high. Relapse of an initially successfully treated infection contributes to this mortality and is often a clinical dilemma in differentiating between paradoxical immune reconstitution inflammatory syndrome (IRIS) and culture-positive relapse or treatment failure. Herein, we present a clinical case scenario and review the case definitions, differential diagnosis, and management of relapse with an emphasis on the current diagnostic and management strategies. We also highlight the challenges of resistance testing and management of refractory relapse cases. The risk of relapse is influenced by: 1) the choice of induction therapy, with higher mortality risk with fluconazole monotherapy which can select for resistance; 2) non-adherence to or lack of secondary prophylaxis; 3) failure of linkage-to-care or retention-in-care of HIV ART programs.

Keywords: Cryptococcal meningitis; Cryptococcus; Drug resistance; HIV; Relapse.

Figure 1. Differential Diagnosis for Symptomatic Relapse of Cryptococcal Meningitis

Differential diagnosis for persons presenting with recurrent symptoms of cryptococcal meningitis. Pathologic mechanisms that can lead to symptomatic relapse of cryptococcal meningitis include microbiologic relapse, persistent infection, immune reconstitution inflammatory syndrome (IRIS), or unrelated causes that can mimic cryptococcal meningitis. Potential causes of each pathologic mechanism are listed and discussed further in the text.

Figure 2

Head CT of patient with CM relapse. Contrast-enhanced head CT of patient following his second hospitalization. Multiple round, sharply marginated, rim-enhancing lesions are apparent.

Figure 3a

The photograph shows the gross appearance of the brain within the cranial cavity following sawing of the skull cap. There is a scanty purulent exudate seen in the subarachnoid space (black arrow). The surface vessels are congested and the brain is visibly swollen showing signs of increased intracranial pressure.

Figure 3b

The photograph shows coronal sections of the cerebral hemispheres. Note the focus of necrosis (purple arrow) with surrounding hyperemia and oedema (blue outline). The histopathological examination of the brain showed mixed aetiology meningoencephalitis (acute bacterial infection and Cryptococcus yeast forms). A focal area in the parenchymal corresponding with a cryptococcoma showed surrounding gliosis and hemorrhage. The yeast forms stained positive with PAS stain. The ZN stain was negative.