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Foundational Sciences · Microbiology
HIV & AIDS-Defining Opportunistic Infections
A CD4-count-driven tour of the AIDS-defining opportunistic infections the boards test, pairing each organism's identifying stain/morphology with its disease, classic vignette buzzword, and first-line treatment. Everything is anchored to the 200/100/50 threshold staircase and the CNS ring-enhancing-lesion differential.
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The CD4 Count Is Your Roadmap
HIV is a retrovirus that infects and depletes CD4+ helper T cells, crippling cell-mediated immunity. Because cell-mediated immunity is what contains intracellular pathogens, fungi, and protozoa, those are precisely the organisms that reactivate or invade as the CD4 count falls. The absolute CD4 count predicts which opportunistic infection to expect, and the boards exploit this relentlessly: they hand you a CD4 number plus a buzzword and ask for the organism, the stain, or the drug.
Learn the staircase — each threshold (200 → 100 → 50) unlocks a predictable set of AIDS-defining infections. Two board reflexes to bank now: (1) any AIDS-defining illness in an HIV+ patient = clinical AIDS, regardless of the CD4 number (AIDS is defined as CD4 <200 or an AIDS-defining condition), and (2) starting ART restores CD4 and lets you stop prophylaxis once the count is durably above threshold.
CD4 Thresholds — Must Know
- CD4 < 500: oral thrush (Candida), oral hairy leukoplakia (EBV, non-scrapable, lateral tongue), Kaposi sarcoma (HHV-8), reactivation TB
- CD4 < 200: *Pneumocystis jirovecii* pneumonia (PCP); start TMP-SMX prophylaxis here; also PML (JC virus); disseminated histoplasmosis in endemic areas (Ohio/Mississippi River valleys)
- CD4 < 100: *Toxoplasma* encephalitis, *Cryptococcus* meningitis, Candida esophagitis (AIDS-defining)
- CD4 < 50: the "basement two M's" — disseminated MAC and cMV (retinitis/colitis/esophagitis); also primary CNS lymphoma (EBV)
- ↑ (1,3)-β-D-glucan: PCP, Candida, Histoplasma, Aspergillus — NOT Cryptococcus or Mucor
- ↑ LDH + diffuse bilateral interstitial infiltrates + hypoxia → think PCP
Organism → Key Feature → Disease → Treatment
| Organism | Key lab / morphology clue | Disease in AIDS | First-line treatment |
|---|---|---|---|
| *Pneumocystis jirovecii* (fungus) | Cup/disc-shaped cysts on methenamine silver (GMS); "crushed ping-pong balls"; cannot culture; ↑LDH, ↑β-D-glucan | Diffuse interstitial pneumonia (PCP), dry cough, hypoxia, ground-glass | TMP-SMX; add steroids if PaO₂ <70 or A–a gradient ≥35 |
| *Toxoplasma gondii* (protozoan) | Positive IgG serology; multiple ring-enhancing lesions (basal ganglia) | Toxoplasmic encephalitis | Pyrimethamine + sulfadiazine + leucovorin |
| *Cryptococcus neoformans* (encapsulated yeast) | India ink halo; CrAg latex agglutination; narrow-based budding; mucicarmine-red capsule | Meningoencephalitis (↑ ICP) | Amphotericin B + flucytosine, then fluconazole |
| *Mycobacterium avium* complex (AFB) | Acid-fast bacilli; foamy macrophages; ↑ALP | Disseminated MAC — fever, wasting, diarrhea, hepatosplenomegaly | Macrolide (azithro/clarithro) + ethambutol ± rifabutin |
| *Cytomegalovirus* (herpesvirus) | Owl's-eye intranuclear inclusions | Retinitis ("pizza-pie" fundus), colitis, esophagitis (linear ulcers) | Ganciclovir / valganciclovir; foscarnet if resistant |
| *Candida albicans* (yeast) | Germ-tube +, pseudohyphae; scrapable white plaques | Thrush; esophagitis (odynophagia) = AIDS-defining | Fluconazole (systemic for esophagitis) |
| *JC virus* (polyomavirus) | Nonenhancing white-matter lesions, no mass effect; CSF PCR | Progressive multifocal leukoencephalopathy (PML) | No antiviral — ART / immune reconstitution |
| *Cryptosporidium* (protozoan) | Acid-fast oocysts in stool | Chronic watery, non-bloody diarrhea | ART; nitazoxanide (adjunct) |
| *Histoplasma capsulatum* (dimorphic fungus) | Intracellular yeast in macrophages; urine/serum antigen; Ohio/Mississippi valley, bat/bird droppings | Disseminated histoplasmosis | Amphotericin B, then itraconazole |
Buzzword Vignettes (Part 1)
- "CD4 90, subacute headache and fever; CSF opening pressure markedly elevated; India ink shows budding yeast with a clear halo" → *Cryptococcus neoformans* meningitis → amphotericin B + flucytosine, then fluconazole; serial LPs to manage raised ICP.
- "CD4 75, headache and right-sided weakness; MRI shows multiple ring-enhancing lesions in the basal ganglia; Toxoplasma IgG positive" → *Toxoplasma gondii* encephalitis → pyrimethamine + sulfadiazine + leucovorin empirically; biopsy only if no radiographic response.
- "CD4 150, three weeks of dry cough and exertional dyspnea; bilateral ground-glass infiltrates; LDH markedly elevated; PaO₂ 65" → *Pneumocystis jirovecii* → TMP-SMX + corticosteroids (PaO₂ <70 meets the steroid threshold).
- "CD4 30, blurry vision and floaters; fundus shows hemorrhages and fluffy exudates ('pizza pie')" → *Cytomegalovirus* retinitis → valganciclovir (or IV/intravitreal ganciclovir).
CNS Lesions: Nail the Differential
Ring-enhancing brain lesions in AIDS are a board favorite, and three entities separate cleanly:
- Multiple ring-enhancing lesions in the basal ganglia with positive Toxo IgG = toxoplasmic encephalitis — treat empirically and expect radiographic improvement in ~2 weeks.
- A solitary ring-enhancing lesion that fails to respond, with EBV DNA in the CSF and uptake on thallium-201 SPECT / PET, points to primary CNS lymphoma (EBV-driven).
- PML is the contrast case: JC virus causes nonenhancing demyelinating white-matter lesions with no mass effect and no edema plus progressive focal deficits — diagnosed by JC-virus PCR, and reversed only by restoring immunity with ART.
Separately, subacute meningitis with high opening pressure but sparse CSF cells is cryptococcal until proven otherwise — send CrAg and India ink.
Diagnosis & Prophylaxis Pearls
- Stains to memorize: GMS/silver → Pneumocystis (and fungi broadly); India ink → Cryptococcus; acid-fast → MAC and Cryptosporidium oocysts; owl's-eye inclusions → CMV
- Antigen tests: CrAg (Cryptococcus, serum/CSF), urine Histoplasma antigen, serum β-D-glucan (PCP/Candida/Aspergillus)
- Prophylaxis by CD4:
- < 200 → TMP-SMX (PCP; also covers Toxoplasma)
- < 100, Toxo IgG+ → TMP-SMX (Toxoplasma)
- < 50 → azithromycin (MAC)
- Stop prophylaxis once ART raises the CD4 durably above threshold
- Esophagitis DDx: Candida (most common — white plaques, treat empirically with fluconazole) vs CMV (single large/linear deep ulcers, owl's-eye inclusions) vs HSV (multiple small shallow "volcano/punched-out" ulcers)
Buzzword Vignettes (Part 2)
- "CD4 25, weeks of fever, night sweats, weight loss, and diarrhea; hepatosplenomegaly; ↑ alkaline phosphatase; blood culture grows acid-fast bacilli" → disseminated *Mycobacterium avium* complex → azithromycin/clarithromycin + ethambutol.
- "CD4 80, painful swallowing; endoscopy shows white plaques" → *Candida* esophagitis → fluconazole (systemic).
- "CD4 40, watery non-bloody diarrhea for weeks; modified acid-fast stain of stool shows small red oocysts" → *Cryptosporidium* → ART for immune reconstitution ± nitazoxanide.
- "Violaceous vascular skin papules; biopsy shows neutrophils and bacilli on Warthin-Starry silver stain" → *Bartonella henselae* (bacillary angiomatosis) → doxycycline or a macrolide (erythromycin) — distinguish from HHV-8 Kaposi sarcoma, whose spindle-cell lesions contain no organisms.
Classic Memory Hooks
- CD4 staircase — "200, 100, 50":
- 200 = Pneumocystis (and Prophylaxis starts here)
- 100 = Toxo, Cryptococcus, Candida esophagitis
- 50 = the two M's in the basement: MAC and cMV
- One-line buzzword → bug:
- Owl's eye → CMV
- India ink halo → Cryptococcus
- Crushed ping-pong balls / cup-shaped cysts on silver stain → Pneumocystis
- Pizza-pie fundus → CMV retinitis
- Multiple ring-enhancing → Toxoplasma; solitary non-responder → CNS lymphoma (EBV)
- Nonenhancing white matter, no mass effect → PML (JC virus)
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