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Bone Wizardry — Microbiology

The CD4 Ladder

As the immune system collapses, bugs show up in a predictable order. Know the CD4 thresholds, know the bugs, know the prophylaxis. This is one of the most testable topics on boards.

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Before We Start
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An HIV+ patient walks in. You check the labs. The CD4 count tells you exactly which bugs to worry about. Let's see if you already know the ladder.

Quick — at what CD4 count do you start PCP prophylaxis with TMP-SMX?
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The CD4 Slider — Watch the Bugs Appear
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Drag the slider down. As the CD4 count drops, new opportunistic infections light up at their threshold. This is the ladder boards loves to test.

CD4: 500
RELATIVELY SAFE
Oral Candidiasis
Thrush. White plaques on tongue/palate. Scrapes off.
Kaposi Sarcoma
HHV-8. Violaceous skin lesions. Spindle cells on bx.
Pneumocystis (PCP)
Bilateral ground-glass. Dry cough. LDH elevated.
Histoplasma
Ohio/Mississippi river valleys. Macrophages with yeast.
Coccidioides
Southwest US. Spherules with endospores.
Toxoplasma
Multiple ring-enhancing brain lesions. Cat feces.
Cryptosporidium
Chronic watery diarrhea. Acid-fast oocysts.
Cryptococcus
Meningitis. India ink. Latex agglutination.
MAC
Disseminated. High fever, weight loss, diarrhea.
CMV Retinitis
"Pizza pie" fundoscopy. Can cause blindness.
CNS Lymphoma
EBV-driven. Single periventricular ring-enhancing lesion.
🔑 CD4 levels drop like a countdown: 500 → 200 → 100 → 50. "Five-two-one-DONE." At 50, everything's invited to the party.
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CD4 < 500 — The Early Signs
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These show up first. The immune system is weakening but not destroyed yet.

💬 Oral candidiasis (thrush) — white plaques on the tongue and buccal mucosa that scrape off to reveal a red base. Caused by Candida albicansNormal oral flora that overgrows when T-cell immunity drops. It's a dimorphic fungus — yeast at 37°C (in body), mold at 25°C. The yeast form with pseudohyphae is what you see on KOH prep.. Often the first sign of HIV progression.
💜 Kaposi sarcoma — caused by HHV-8Human herpesvirus 8 (also called KSHV). It infects endothelial cells and drives abnormal vascular proliferation. Most common in HIV+ men who have sex with men. The virus is necessary — no HHV-8 = no Kaposi.. Violaceous (purple-red) skin nodules. Biopsy shows spindle cells with slit-like vascular spaces. Can involve skin, GI, lungs.
An HIV+ patient with a CD4 of 420 comes in with white plaques on their tongue. The plaques scrape off. What's the diagnosis?
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CD4 < 200 — AIDS-Defining Territory
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CD4 below 200 = AIDS by definition. This is where the big three fungi hit.

🌫 Pneumocystis jirovecii (PCP) — the #1 AIDS-defining illness. Presents with gradual-onset dry cough, dyspnea on exertion, and fever. CXR shows bilateral ground-glass opacities. LDH is elevated (board pearl!).

Diagnosis: Methenamine silver stainGMS (Grocott's methenamine silver) stains the cyst walls of Pneumocystis black against a green background. The cysts look like crushed ping-pong balls. Bronchoalveolar lavage (BAL) is the specimen of choice — sputum induction is less sensitive. on BAL. Treatment: TMP-SMX (high dose). If PaO2 < 70, add steroids (prednisone) to prevent inflammatory lung damage.

Histoplasma capsulatum — Ohio/Mississippi River valleys. Think bird and bat droppings. Disseminates in HIV+ patients: fever, hepatosplenomegaly, pancytopenia. See macrophages packed with small yeastHisto is a tiny intracellular yeast (2-4 µm) — small enough to live INSIDE macrophages. This is the classic "tiny yeast within macrophages" on biopsy. Compare to Crypto which is larger and has a thick capsule visible on India ink..

Coccidioides immitis — Southwestern US (Arizona, California deserts). Spherules with endosporesThe pathognomonic finding. In tissue, Coccidioides forms large spherules (20-60 µm) filled with endospores. When the spherule ruptures, endospores scatter and each forms a new spherule. It's an arthroconidial dimorphic fungus. on biopsy. Can disseminate to bones, skin, meninges in immunocompromised.

BOARD TRAP: PCP Ground-Glass vs Bacterial Pneumonia
PCP = bilateral, diffuse, ground-glass opacities (hazy, like looking through frosted glass). Bacterial pneumonia = lobar consolidation (dense white-out of one lobe). If the CXR is bilateral and hazy with elevated LDH in an HIV+ patient — think PCP, not bacteria.
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CD4 < 100 — The Brain and Gut Get Hit
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Below 100, bugs start crossing the blood-brain barrier and colonizing the GI tract for good.

🧠 Toxoplasma gondii — multiple ring-enhancing brain lesions on MRI. Presents with headache, confusion, focal neurological deficits, seizures. Source: reactivation of latent infection (cat feces, undercooked meat).
🦠 Cryptococcus neoformans — meningitis. Subacute headache, fever, neck stiffness. Diagnosis: India ink stain of CSF (see the halo!), latex agglutination for capsular antigen (most sensitive), or cryptococcal antigen (CrAg)CrAg is the most sensitive and specific test for Cryptococcal meningitis. It detects the polysaccharide capsular antigen in CSF or serum. Latex agglutination was the old method — lateral flow assays (LFA) are now preferred. Opening pressure is often very elevated (>25 cm H2O) — serial lumbar punctures are therapeutic..
💩 Cryptosporidium — chronic, profuse, watery diarrhea that won't stop. Acid-fast oocysts on stool exam. No great treatment — the real cure is immune reconstitutionThe only reliable treatment for Cryptosporidium in AIDS is getting the CD4 count back up with ART. Nitazoxanide has limited efficacy. The diarrhea can cause massive volume loss — supportive care while ART kicks in. with ART.
🔑 At CD4 < 100, three C's crash the party: Cryptococcus (brain), Cryptosporidium (gut), and the Cat parasite (Toxo, also brain). "The C's come for you under a hundred."

The Big Boards Battle: Ring-Enhancing Lesions

Toxoplasmosis
VS
CNS Lymphoma
CD4
< 100
Lesions
MULTIPLE ring-enhancing
Location
Basal ganglia, corticomedullary junction
Serology
Toxo IgG positive
First step
Empiric TMP-SMX → repeat imaging in 2 weeks
Responds?
Yes → confirms Toxo
CD4
< 50 (usually)
Lesions
SINGLE, periventricular
Location
Periventricular white matter
Serology
EBV+ in CSF (PCR)
First step
If no response to Toxo tx → biopsy
Responds?
No → biopsy shows B-cell lymphoma
BOARD TRAP: Multiple vs Single Ring-Enhancing Lesions
This is a classic boards question. Multiple ring-enhancing lesions in an HIV+ patient = Toxo until proven otherwise. Single periventricular lesion = think CNS lymphoma (EBV-driven). The management algorithm: try empiric Toxo treatment first. If it doesn't improve in 2 weeks → biopsy for lymphoma.
HIV+ patient, CD4 = 65. MRI shows a SINGLE ring-enhancing lesion near the ventricles. Toxo IgG is negative. What's the most likely diagnosis?
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CD4 < 50 — The Bottom of the Ladder
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Below 50, the immune system is essentially gone. The last bugs to arrive are the most devastating.

🦠 Mycobacterium avium complex (MAC) — disseminated disease. High fevers, drenching night sweats, weight loss, chronic diarrhea. Labs show anemia and massively elevated alkaline phosphataseMAC infiltrates the liver and bone marrow, causing an elevated alk phos out of proportion to other LFTs. It also causes pancytopenia from marrow infiltration. Blood cultures on special mycobacterial media are diagnostic — takes 1-2 weeks to grow..
👁 CMV retinitis — the classic fundoscopic finding: "pizza pie" appearance (hemorrhages = ketchup, exudates = cheese). Also described as "cottage cheese and ketchup." Painless vision loss. Can cause blindness if untreated. Treatment: ganciclovir or valganciclovir.
🧠 Primary CNS lymphoma — EBV-driven B-cell lymphoma. Single periventricular ring-enhancing lesion on MRI. EBV PCR positive in CSF. Only appears when immunity is completely wrecked. Distinguished from Toxo by being single, periventricular, and Toxo-IgG negative.

CMV can also cause esophagitis (linear, deep ulcers — vs Candida's white plaques, vs HSV's shallow round ulcers) and colitis (bloody diarrhea, biopsy shows intranuclear "owl eye" inclusions).

An HIV+ patient with CD4 = 30 reports painless, progressive vision loss in the left eye. Fundoscopy shows hemorrhages and white/yellow exudates described as "ketchup and cheese." What's the diagnosis and treatment?
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Prophylaxis — When to Start What
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Boards loves prophylaxis thresholds. Three drugs, three numbers. That's it.

CD4 Threshold Prophylaxis Drug What It Covers
< 200 PCP prophylaxis TMP-SMX PCP and Toxo (bonus!)
< 100 Toxo prophylaxis TMP-SMX (same drug!) Already covered if on PCP prophylaxis
< 50 MAC prophylaxis Azithromycin MAC only
ALL patients TB screening PPD or IGRA Latent TB → treat with INH × 9 months
💡 The TMP-SMX two-for-one deal: Start at CD4 < 200 and it covers BOTH PCP and Toxo. You don't need a separate Toxo prophylaxis drug. If they ask "what prophylaxis at CD4 < 100?" and TMP-SMX isn't already started — the answer is still TMP-SMX.
🔑 TMP-SMX is a generous lover — one pill covers two bugs. "Two for one, and it never stops giving." MAC needs its own date: azithromycin at 50.
BOARD TRAP: TB Screening Is Universal
Unlike other prophylaxis, TB screening happens at ANY CD4 count. HIV+ patients with latent TB have a much higher reactivation risk. A positive PPD in HIV is ≥ 5 mm (lower cutoff than the general population's 15 mm). Treat with isoniazid + B6 for 9 months.
An HIV+ patient is newly diagnosed with a CD4 of 180. What prophylaxis should you start RIGHT NOW?
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The Diarrhea Differential — Three Bugs, Three Clues
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HIV+ patient with chronic diarrhea. Boards will make you pick between these three. Each has a signature.

Bug CD4 Stool Finding Key Feature
Cryptosporidium < 100 Acid-fast oocysts Watery, high-volume, chronic. No good drug — ART is the treatment.
Isospora belli < 100 Acid-fast oocysts (larger, oval) Also watery diarrhea. TMP-SMX treats it (unlike Crypto).
MAC < 50 AFB smear + culture Diarrhea + fever + weight loss + high alk phos. Disseminated disease.
💡 Quick rule: Acid-fast oocysts on stool = Cryptosporidium or Isospora. The difference? TMP-SMX works for Isospora but NOT Cryptosporidium. If the question says "patient on TMP-SMX prophylaxis still has diarrhea" — it's Cryptosporidium.
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Transplant Infections — The Timeline
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Different from HIV. In transplant patients, the bug depends on how long since the transplant, not CD4 count.

Month 0-1 (Perioperative)
Nosocomial bacteria (surgical wound, UTI, pneumonia, line infections). Same bugs that hit any post-surgical patient. Also HSV reactivation (cold sores, esophagitis).
Month 1-6 (Peak Immunosuppression)
The opportunists arrive: CMV (the big one — pneumonitis, colitis, retinitis), PCP, Aspergillus (invasive pulmonary aspergillosis, vascular invasion, “halo sign” on CT). This is when prophylaxis matters most.
Month 6+ (Late)
Community-acquired infections (because they're back in the world). Cryptococcus. EBV → PTLD (post-transplant lymphoproliferative disorder — B-cell proliferation driven by EBV, treat by reducing immunosuppression).
BOARD TRAP: CMV in Transplant vs HIV
In transplant, CMV is the #1 opportunistic infection and hits at 1-6 months. In HIV, CMV retinitis appears at CD4 < 50. Different context, same virus, different timing. If the stem says "transplant patient, 2 months post-op, fever" — think CMV.
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Decision Tree — "HIV+ Patient Presents With..."
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Walk through the clinical reasoning. Each step quizzes you before revealing the answer.

HIV+ patient, CD4 = 85, presents with headache, confusion, and fever. CT shows multiple ring-enhancing lesions. What's your top diagnosis?
MULTIPLE ring-enhancing lesions at CD4 < 100 = Toxo until proven otherwise. CNS lymphoma is usually SINGLE and periventricular. Bacterial abscess is possible but much less common in this setting.
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The Cheat Sheet — Everything on One Table
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Your one-stop reference. Scroll sideways on mobile.

CD4 Organism Presentation Diagnosis Prophylaxis
< 500 Candida Oral thrush (scrapes off) Clinical / KOH —
< 500 HHV-8 Kaposi sarcoma (violaceous lesions) Biopsy: spindle cells —
< 200 Pneumocystis Dry cough, ground-glass, ↑LDH Silver stain on BAL TMP-SMX
< 200 Histoplasma Disseminated: fever, hepatosplenomegaly Urine/serum antigen —
< 100 Toxoplasma Multiple ring-enhancing brain lesions Serology + empiric tx TMP-SMX
< 100 Cryptococcus Meningitis (headache, fever) India ink, CrAg, latex agglut. —
< 100 Cryptosporidium Chronic watery diarrhea Acid-fast oocysts on stool ART (immune reconstitution)
< 50 MAC Disseminated: fever, wt loss, ↑alk phos Blood culture (AFB media) Azithromycin
< 50 CMV Retinitis ("pizza pie"), esophagitis, colitis Fundoscopy, PCR, biopsy — (monitor)
< 50 EBV → CNS lymphoma Single periventricular ring lesion EBV PCR in CSF, biopsy —
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Quiz — 4 Patients, 4 Bugs
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4 HIV+ patients just arrived. Their CD4 counts are low and their symptoms are specific. Match the bug to the patient before the attending pimps you on rounds.

Bone Wizardry — Opportunistic Infections — The CD4 Ladder