Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy

Abstract

HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4(+) count was 117 and the HIV viral load >10(4); imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4(+) was 300 and HIV viral load <10(3), but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8(+) lymphocytes; CD4(+) lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8(+)/CD4(+) T cells, with massive infiltration of the cerebral parenchyma by CD8(+) cytotoxic T lymphocytes in the absence of sufficient CD4(+) response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART.

Central nervous system immune reconstitution inflammatory syndrome (IRIS) after hematopoietic SCT

“…Such lesions have been described in cases of IRIS, 2,3 although in many other CNS-IRIS cases, the MRI findings have shown intensive gadolinium enhancement. 2,8,9 The CNS symptoms of our patient emerged 8 months after complete cessation of immunosuppressive treatment (and half a year after the recovery of blood CD4 cells), a timing compatible with the onset of IRIS. Moreover, several antiepileptics were administered, including phenytoin, carbamazepine and sodium valproate and, owing to drug interactions, the trough level of antifungal voriconazole was found to be low (o0.5 mg/l).…”

Soft tissue abscess and lymphadenitis due to Mycobacterium avium Complex as an expression of immune reconstitution inflammatory syndrome after a second scheme of highly active antiretroviral therapy

“…For example, in a case published by VENDRELY et al 19 about a patient who presented a progressive multifocal leucoencephalopathy as a manifestation of IRIS or in other patients with cryptococosis-associated IRIS 13 .…”

CNS–Immune Reconstitution Inflammatory Syndrome in the Setting of HIV Infection, Part 1: Overview and Discussion of Progressive Multifocal Leukoencephalopathy–Immune Reconstitution Inflammatory Syndrome and Cryptococcal–Immune Reconstitution Inflammatory Syndrome

“…These figures are notable because while some PML-IRIS cases are mild and resolve with continued HAART, other cases may lead to significant morbidity and even mortality because of a severe inflammatory response characterized histopathologically by a marked influx of CD8ϩ T-cell lymphocytes and macrophages in the areas of demyelination and inflammatory reaction. 6,15,37,[48][49][50][51][52][53][54][55][56][57][58][59][60][61] In fact, in 2 cases, PML-IRIS proved fatal after only 2 weeks of HAART. 6 Presumably, the vast outnumbering of CD8ϩ T-cell lymphocytes compared with CD4ϩ T-cell lymphocytes may produce an uncontrolled inflammatory response that could prove fatal.…”

“…8,15 While some of these risk factors are still being debated, such as age and sex, 8 and while criteria are still being expanded and further defined 2,17 and the pathogenesis of IRIS remains not wellunderstood (with some investigators suggesting that there may even be different mechanisms for different pathogens), 7,18,28 there is general acceptance that IRIS can be diagnosed in an HIVinfected individual when there is evidence that the patient's immune system is reconstituting (higher CD4 counts and decreasing HIV-1 RNA levels), yet the patient is paradoxically worsening with the development of new symptoms that cannot be explained by drug toxicity, OI, medical noncompliance, or allergic reactions. 6,16,19 IRIS then is often a diagnosis of exclusion. 8 Diagnosis, however, can be supported by the detection of atypical imaging and laboratory findings, such as new imaging patterns and laboratory tests that might not show viable organisms.…”