# Clinical Cases: DNA Viruses

## Case 1: Herpes Simplex Encephalitis

### Presentation
A 52-year-old woman is brought to the emergency department by her husband because of 3 days of fever, headache, and progressive confusion. Today she had a generalized seizure at home. Her husband reports she has been behaving strangely, with difficulty finding words and personality changes. She has no history of immunocompromise. On examination, temperature is 39.2°C, she is disoriented to time and place, and has difficulty naming common objects. MRI brain shows T2 hyperintensity and swelling involving the left temporal lobe and insular cortex. CSF analysis shows 85 WBC/μL (90% lymphocytes), protein 78 mg/dL, glucose 55 mg/dL (serum glucose 100 mg/dL).

### Clinical Image
![MRI showing temporal lobe involvement in HSV encephalitis](image_01.png)
*MRI brain demonstrating T2/FLAIR hyperintensity involving the temporal lobe and insular cortex, characteristic of herpes simplex encephalitis.*

**Image Source**: Lecture image - HSV encephalitis imaging

### Questions

1. **What is the most likely diagnosis and causative agent?**

2. **Why does this infection characteristically involve the temporal lobes?**

3. **What is the most important diagnostic test, and how quickly should treatment begin?**

4. **What is the prognosis, and what factors affect outcome?**

### Answers

1. **Diagnosis and causative agent**: This is **herpes simplex encephalitis (HSE)**, most commonly caused by **HSV-1** (over 90% of adult cases). HSE is the most common cause of sporadic fatal encephalitis in the United States. The presentation with fever, altered mental status, seizures, focal neurologic deficits (especially aphasia), and characteristic temporal lobe involvement on imaging is classic.

2. **Temporal lobe predilection**: The temporal lobe predilection is thought to relate to the virus's route of entry into the CNS. HSV-1 may access the brain via:
   - **Olfactory nerve** from the nasal mucosa to the olfactory bulb and then to the medial temporal lobe
   - **Trigeminal nerve** (site of latency) with retrograde spread along meningeal branches to the temporal lobe

   The **limbic system** (which includes the temporal lobes, insula, and cingulate gyrus) is characteristically affected, explaining the personality changes, memory disturbances, and psychiatric symptoms often seen.

3. **Diagnostic test and treatment timing**: **CSF PCR for HSV DNA** is the gold standard for diagnosis, with sensitivity >95% and specificity >99%. Results are typically available within hours to a day.

   **However, treatment with IV acyclovir (10 mg/kg every 8 hours) must begin IMMEDIATELY** upon clinical suspicion - do not wait for PCR results. HSE has a mortality rate of 70% if untreated, reduced to approximately 20-30% with prompt acyclovir. Every hour of delay increases the risk of death and permanent neurologic damage. Treatment duration is typically 14-21 days.

4. **Prognosis and prognostic factors**: Even with treatment, mortality is 20-30%, and significant neurologic sequelae occur in up to 50% of survivors, including:
   - Memory impairment (especially anterograde memory from hippocampal damage)
   - Personality changes
   - Epilepsy
   - Aphasia

   **Factors affecting outcome**:
   - Time to treatment initiation (most critical factor)
   - Age (worse outcomes in very young and elderly)
   - Level of consciousness at presentation
   - Extent of brain involvement on imaging

---

## Case 2: Infectious Mononucleosis with Complications

### Presentation
A 17-year-old high school student presents with 2 weeks of fatigue, sore throat, and fever. He was seen at an urgent care clinic a week ago and was prescribed amoxicillin for strep throat despite a negative rapid strep test. Two days later, he developed a widespread maculopapular rash. Examination reveals temperature 38.5°C, posterior cervical and axillary lymphadenopathy, pharyngeal erythema with tonsillar enlargement and exudates, a diffuse maculopapular rash, and a palpable spleen tip. Laboratory studies show WBC 14,000/μL with 60% lymphocytes (many atypical), AST 145 U/L, and ALT 168 U/L.

### Clinical Image
![Atypical lymphocytes on peripheral smear](image_02.png)
*Peripheral blood smear demonstrating atypical lymphocytes (reactive CD8+ T cells) with abundant blue cytoplasm, irregular nuclei, and cytoplasm molding around surrounding red blood cells, characteristic of infectious mononucleosis.*

**Image Source**: Lecture image - EBV laboratory findings

### Questions

1. **What is the diagnosis, and what caused the rash?**

2. **What is the origin of the atypical lymphocytes seen on peripheral blood smear?**

3. **What are the potential complications, and why is this patient's physical activity being restricted?**

4. **How would you confirm the diagnosis serologically?**

### Answers

1. **Diagnosis and rash etiology**: This is **infectious mononucleosis** caused by **Epstein-Barr virus (EBV)**. The rash developed after administration of **ampicillin/amoxicillin**, which occurs in up to 90% of patients with infectious mononucleosis who receive these antibiotics. The mechanism is not a true allergy but rather an interaction between the viral infection and the drug, possibly related to altered drug metabolism or immune activation. This does not preclude future use of aminopenicillins.

2. **Atypical lymphocytes origin**: The atypical lymphocytes are **reactive CD8+ cytotoxic T cells** responding to EBV-infected B lymphocytes, NOT the infected B cells themselves. EBV infects B cells via the CD21 (complement receptor 2) receptor. The immune system mounts a robust T cell response to control the infection, and these activated T cells have the characteristic morphology with abundant blue cytoplasm, irregular nuclei, and membrane molding around adjacent red blood cells.

3. **Complications and activity restriction**:
   - **Splenomegaly** (50% of cases) with risk of **splenic rupture** - the most serious acute complication. Patients should avoid contact sports for 3-4 weeks minimum (some recommend until spleen returns to normal size on imaging)
   - **Hepatitis** (elevated transaminases in 80-90%; clinical jaundice rare)
   - **Airway obstruction** from tonsillar enlargement (may require corticosteroids)
   - **Hemolytic anemia** from cold agglutinins
   - **Thrombocytopenia**
   - Rare: encephalitis, Guillain-Barré syndrome, myocarditis

4. **Serologic confirmation**:
   - **Heterophile antibody test (Monospot)**: Quick screening test detecting antibodies that agglutinate sheep/horse RBCs; may be falsely negative early in illness or in children <4 years
   - **EBV-specific serologies**:
     - **VCA IgM**: Present during acute infection (confirms acute EBV)
     - **VCA IgG**: Present during acute and remains positive lifelong
     - **EBNA (Epstein-Barr nuclear antigen)**: Appears weeks to months after acute infection; if positive, rules OUT acute infection
     - Pattern of VCA IgM+, VCA IgG+, EBNA- confirms acute infection

---

## Case 3: Cervical Cancer Screening Abnormality

### Presentation
A 28-year-old woman presents to discuss her Pap smear results, which showed HSIL (high-grade squamous intraepithelial lesion). She has no symptoms. She has had three sexual partners and has never received the HPV vaccine. She is a non-smoker. Colposcopy is performed, revealing an acetowhite lesion on the cervix at the 3 o'clock position. Biopsy of this area shows CIN 3 (cervical intraepithelial neoplasia grade 3) with cells demonstrating perinuclear clearing and nuclear atypia consistent with koilocytic changes. HPV testing is positive for HPV type 16.

### Clinical Image
![Koilocytes on cervical biopsy](image_03.png)
*Histopathology of cervical biopsy showing koilocytes - squamous cells with characteristic perinuclear clearing (halo) and nuclear atypia, indicating HPV infection.*

**Image Source**: Lecture image - HPV pathology

### Questions

1. **What is the significance of HPV 16 in this case?**

2. **Explain the molecular mechanism by which HPV causes cellular transformation.**

3. **What are the management options for CIN 3?**

4. **How could this condition have been prevented?**

### Answers

1. **Significance of HPV 16**: HPV 16 is a **high-risk HPV type**, responsible for approximately 50% of cervical cancers and a significant proportion of oropharyngeal, anal, penile, vaginal, and vulvar cancers. High-risk HPV types (16, 18, 31, 33, 45, 52, 58) have oncogenic potential, unlike low-risk types (6, 11) that cause genital warts. CIN 3 is a precancerous lesion with high risk of progression to invasive cervical cancer if left untreated.

2. **Molecular mechanism of HPV oncogenesis**: HPV oncogenesis is driven by two viral oncoproteins:
   - **E6 protein**: Binds and promotes **ubiquitin-mediated degradation of p53**, eliminating the cellular response to DNA damage and preventing apoptosis
   - **E7 protein**: Binds and inactivates **retinoblastoma protein (Rb)**, releasing E2F transcription factors and driving uncontrolled cell cycle progression

   In productive infection, the viral genome remains episomal and expression is regulated. When HPV DNA **integrates** into the host chromosome (typically disrupting the E2 regulatory gene), uncontrolled E6/E7 expression drives cellular transformation. The **koilocyte** (cell with perinuclear clearing) is the cytologic hallmark of HPV infection.

3. **Management of CIN 3**: CIN 3 requires treatment due to significant risk of progression to invasive cancer. Options include:
   - **Excisional procedures** (preferred): LEEP (loop electrosurgical excision procedure) or cold knife conization - provides tissue for histologic assessment
   - **Ablative procedures**: Cryotherapy or laser ablation - destroys tissue without specimen
   - After treatment: Close follow-up with repeat cytology and HPV testing
   - **Hysterectomy** is generally not first-line but may be considered in select cases

4. **Prevention strategies**:
   - **HPV vaccination**: The 9-valent vaccine (Gardasil 9) targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, 58. Vaccination is ideally given at ages 11-12 before sexual debut, with catch-up through age 26 (FDA-approved to age 45). The vaccine could have prevented this case.
   - **Cervical cancer screening**: Regular Pap smears and/or HPV testing beginning at age 21 (cytology) or 25 (with HPV testing options)
   - **Risk reduction**: Limiting sexual partners, consistent condom use (partial protection)
   - This case emphasizes the importance of vaccination before HPV exposure