owl eye inclusion

**Description:** CMV-infected cells become markedly enlarged (cytomegaly). They contain a single, large, basophilic or purple intranuclear inclusion surrounded by a clear halo, which gives the "owl's eye" look. Smaller basophilic cytoplasmic inclusions may also be present. The inclusions are seen on H&E, and CMV immunohistochemistry confirms the diagnosis.

**Pathophysiology:** CMV is a dsDNA enveloped herpesvirus (HHV-5). It replicates in the nucleus, and the inclusion represents viral assembly and replication material, with margination of chromatin forming the halo. The virus establishes latency in monocytes/macrophages and CD34+ progenitor cells. It is spread through saliva, urine, sexual contact, transplacental transfer, breast milk, blood transfusion and organ transplant.

**Clinical associations:** - **Immunocompromised patients** (AIDS with CD4 <50, transplant recipients): CMV retinitis ("pizza pie" or "cottage cheese and ketchup" fundus), colitis (GI ulcers with bloody diarrhea), esophagitis (linear ulcers), pneumonitis, and encephalitis or polyradiculopathy. - **Congenital CMV:** the most common congenital infection. Findings include periventricular calcifications, microcephaly, chorioretinitis, sensorineural hearing loss, hepatosplenomegaly and petechial "blueberry muffin" rash. It is a leading infectious cause of sensorineural hearing loss. - **Immunocompetent hosts:** mononucleosis-like illness that is heterophile (Monospot) negative.

**Diagnosis:** Histology (owl's eye inclusions) shows tissue-invasive disease. Other tests are PCR for CMV DNA and the pp65 antigenemia assay. Serology (IgG) reflects past exposure only. In a newborn, urine or saliva PCR within the first 2-3 weeks of life diagnoses congenital CMV.

**Treatment:** Ganciclovir (IV) or valganciclovir (PO) are first line. Foscarnet is used for ganciclovir-resistant CMV, and cidofovir is another option. Ganciclovir's main toxicity is bone marrow suppression (neutropenia). Foscarnet causes nephrotoxicity and electrolyte disturbances (hypocalcemia, hypomagnesemia). Ganciclovir needs phosphorylation by viral UL97 kinase, so resistance arises from UL97 mutations. Foscarnet does not need viral activation.

**High-yield differentials of viral inclusions:** - **Owl's eye:** CMV. - **Cowdry A (intranuclear, eosinophilic) and multinucleated giant cells with ground-glass nuclei (Tzanck smear):** HSV and VZV. - **Negri bodies (cytoplasmic eosinophilic inclusions in Purkinje cells and hippocampal neurons):** rabies. - **Guarnieri bodies:** smallpox/vaccinia. - **Molluscum bodies (Henderson-Paterson):** molluscum contagiosum. - **Intranuclear "smudge cells":** adenovirus. - **Reed-Sternberg cells with owl-eye appearance:** Hodgkin lymphoma. Don't confuse this with CMV. The "owl's eyes" there are binucleate RS cells with prominent eosinophilic nucleoli.

**Board tip:** An AIDS or transplant patient with odynophagia or bloody diarrhea and biopsy showing large intranuclear inclusions with a halo is CMV. Treat with ganciclovir.