Decoupling of Clinical and Laboratory Paradigms: Diagnostic Challenges in Atypical Cytomegalovirus Neurological Immune Reconstitution Inflammatory Syndrome Complicated by Secondary Hemophagocytic Lymphohistiocytosis.

The clinical management of patients with advanced human immunodeficiency virus (HIV) infection initiating combination antiretroviral therapy (cART) may be complicated by immune reconstitution inflammatory syndrome (IRIS), a paradoxical inflammatory response capable of unmasking previously subclinical opportunistic infections. Although classical manifestations of IRIS are well recognized, atypical presentations involving the central nervous system (CNS) and associated hyperinflammatory syndromes such as secondary hemophagocytic lymphohistiocytosis (sHLH) remain diagnostically challenging and may contribute to delayed treatment. We report the case of a 36-year-old man with advanced HIV infection (CD4+ T-lymphocyte count of 22.94 cells/µL) who developed persistent fever and neurological symptoms two weeks after initiating cART. Brain magnetic resonance imaging showed no structural abnormalities, and cerebrospinal fluid (CSF) cytochemical analysis was unremarkable. However, a multiplex polymerase chain reaction syndromic panel performed on CSF detected cytomegalovirus (CMV), supporting the diagnosis of unmasking CMV-associated neurological IRIS. During hospitalization, the patient developed a severe systemic inflammatory syndrome characterized by probable secondary hemophagocytic lymphohistiocytosis, stage 3 acute kidney injury, severe cholestatic hepatopathy, and hematologic abnormalities. Targeted antiviral therapy with valganciclovir was initiated promptly, accompanied by a short course of intravenous dexamethasone to control the hyperinflammatory response. The patient experienced progressive clinical improvement with complete recovery of neurological function, normalization of renal function, and marked resolution of hepatic and hematologic abnormalities. This case highlights the diagnostic value of multiplex molecular testing in patients with suspected neuro-IRIS when conventional neuroimaging and CSF studies are non-diagnostic. It also underscores the importance of early recognition and timely combined antiviral and immunomodulatory therapy in severe inflammatory presentations associated with advanced HIV infection.