Opportunistic Infections in HIV/AIDS - Pathology

1. Pathophysiologic Basis

• Reactivation of latent infections that were never eradicated (e.g., CMV, toxoplasmosis, TB, varicella-zoster)
• Environmental opportunists that a competent immune system normally keeps in check (e.g., Pneumocystis, Cryptococcus, Candida)

"Opportunistic infections account for most deaths in untreated patients with AIDS." - Robbins Pathologic Basis of Disease

2. CD4 Count Thresholds and OI Susceptibility

3. Major Opportunistic Infections - Pathology

A. Pneumocystis jirovecii Pneumonia (PCP)

• Most common life-threatening OI in HIV/AIDS; presents in 15-30% of untreated patients
• P. jirovecii is a fungus (ascomycete, subphylum Taphrinomycota), formerly called P. carinii
• Mechanism: reactivation of prior latent infection
• Pathology: interstitial pneumonitis with characteristic foamy, eosinophilic alveolar exudate packed with organisms; diffuse alveolar damage
• Clinical: subacute progressive dyspnea, dry cough, fever; bilateral perihilar infiltrates on CXR ("bat-wing" pattern)
• The acronym PCP (Pneumocystis pneumonia) is retained despite the name change
• Source: Goldman-Cecil Medicine, Washington Manual of Medical Therapeutics

B. Cerebral Toxoplasmosis (Toxoplasma gondii)

• Most common cause of focal brain lesion in HIV patients (CD4 < 100)
• Reactivation of latent encysted bradyzoites acquired from cat feces or undercooked meat
• Pathology: ring-enhancing abscesses (necrotic centers surrounded by inflammatory infiltrate), most commonly in basal ganglia and corticomedullary junction
• Multiple lesions on MRI are characteristic; serology (IgG anti-toxoplasma) is usually positive
• Clinical: headache, focal neurologic deficits, seizures, altered consciousness

C. Cryptococcal Meningitis (Cryptococcus neoformans)

• Most common cause of meningitis in AIDS patients; occurs at CD4 < 100 cells/µL
• Ubiquitous fungus; inhaled into lungs, then disseminates hematogenously to CNS
• Pathology: gelatinous meningitis due to large polysaccharide capsule; India ink stain shows encapsulated yeasts; minimal inflammatory reaction (capsule inhibits phagocytosis)
• "Soap-bubble" lesions (cryptococcomas) may form in basal ganglia
• Diagnosis: cryptococcal antigen (CrAg) in CSF or serum; India ink +ve in ~80%
• Source: Rosen's Emergency Medicine, Frameworks for Internal Medicine, Fitzpatrick's Dermatology

D. Cytomegalovirus (CMV) Disease

• Occurs when CD4 < 50 cells/µL; represents reactivation of latent herpesvirus infection
• CMV retinitis: most common manifestation; "pizza pie" retinal appearance with hemorrhage and necrosis; can cause blindness
• CMV colitis: bloody diarrhea; pathology shows owl-eye intranuclear inclusions in colonic mucosal cells (enlarged cells with basophilic intranuclear and cytoplasmic inclusions)
• Also causes CMV esophagitis (linear ulcers), encephalitis, and pneumonitis
• Source: Robbins Pathologic Basis of Disease, Kanski's Clinical Ophthalmology

E. Mycobacterial Infections

Tuberculosis (M. tuberculosis)

• Susceptibility begins early (CD4 < 500), making TB one of the first OIs to appear
• HIV dramatically increases the risk of reactivation of latent TB and accelerates progression
• Particularly common in sub-Saharan Africa
• Extrapulmonary TB (miliary, lymphadenopathy, CNS) is far more common in HIV

Disseminated MAC (M. avium Complex)

• Occurs at very low CD4 counts (< 50); bacteremia, fever, weight loss, night sweats, diarrhea, hepatosplenomegaly
• Pathology: foamy macrophages packed with AFB-positive organisms in lymph nodes, liver, bone marrow (inadequate granuloma formation due to T-cell loss)

F. Candidiasis

• Oral thrush (oropharyngeal candidiasis) is typically the earliest opportunistic infection, appearing when CD4 falls below 500
• Esophageal candidiasis = AIDS-defining (causes odynophagia)
• Invasive/disseminated candidiasis is uncommon in AIDS unless there is also neutropenia or an indwelling catheter
• Source: Robbins Pathologic Basis of Disease

G. Progressive Multifocal Leukoencephalopathy (PML)

• Caused by reactivation of JC virus (a papovavirus); affects CD4 < 100
• Pathology: demyelinating lesions in white matter, bizarre enlarged astrocytes, oligodendrocytes with viral inclusions (ground-glass intranuclear inclusions)
• Clinical: progressive focal neurologic deficits (hemiplegia, visual loss, cognitive decline), no fever, MRI shows non-enhancing white matter lesions
• Diagnosis: JC virus PCR in CSF

H. Cryptosporidiosis

• Cryptosporidium causes intractable, cholera-like watery diarrhea (up to 5-10 L/day) in AIDS patients
• Pathology: oocysts adhere to enterocyte brush border; villous blunting and crypt hyperplasia; no tissue invasion but secretory diarrhea is profound
• Biliary involvement leads to AIDS cholangiopathy

I. Histoplasmosis and Other Endemic Fungi

• Histoplasma capsulatum: disseminated disease in endemic regions (Ohio/Mississippi River valleys); fever, weight loss, hepatosplenomegaly, pulmonary infiltrates
• Coccidioides immitis: disseminated disease in southwestern US/Mexico (CD4 < 250)
• Pathology: inadequate granuloma formation; organisms found in macrophages

4. Opportunistic Neoplasms (AIDS-Defining Cancers)

Kaposi's Sarcoma (KS)

• Caused by HHV-8 (KSHV) - Kaposi's sarcoma herpesvirus
• Tumor of endothelial cells; driven by cytokines from HIV infection + HHV-8
• Violaceous skin plaques/nodules; also involves lungs, GI tract, lymph nodes
• Classic early manifestation; now uncommon in ART era

Non-Hodgkin Lymphoma (NHL)

• Predominantly aggressive B-cell lymphomas (diffuse large B-cell lymphoma, Burkitt lymphoma)
• Driven by EBV-induced B-cell proliferation in a setting of impaired T-cell immune surveillance
• Primary CNS lymphoma (EBV-driven) causes a single ring-enhancing mass (vs. multiple lesions in toxoplasmosis)
• Hodgkin lymphoma also occurs and is nearly always EBV-positive

HPV-Associated Carcinomas

• Cervical and anal squamous cell carcinomas (HPV-related); rate of progression to carcinoma is accelerated
• Squamous intraepithelial lesion (SIL) is 10x more common in HIV+ women

5. CNS Manifestations

• HIV-associated neurocognitive disorder (HAND) / HIV encephalitis: microglia and macrophage activation; neuronal damage via indirect mechanisms (cytokines, gp41-induced nitric oxide, soluble gp120)
• Vacuolar myelopathy
• Peripheral neuropathies
• Opportunistic CNS infections (toxoplasmosis, cryptococcal meningitis, PML, CMV encephalitis, TB meningitis)
• Source: Robbins Pathologic Basis of Disease, Kaplan & Sadock's Synopsis of Psychiatry

6. Summary Table: AIDS-Defining OIs and Their Pathology

7. Effect of ART on OIs

• Robbins, Cotran & Kumar: Pathologic Basis of Disease (Clinical Features of AIDS, pp. 243-245)
• Janeway's Immunobiology 10e (Section 13-38, pp. 362-367)
• Goldman-Cecil Medicine International Edition (Pneumocystis jirovecii Pneumonia chapter)
• Washington Manual of Medical Therapeutics (Opportunistic Infections)
• Rosen's Emergency Medicine (Central Nervous System Manifestations)
• Frameworks for Internal Medicine (Cryptococcal Meningitis)