Immune System

AIDS-defining illnesses: diagnosis and management

Clinical Overview and When to Suspect AIDS-defining Illnesses

— Pneumocystis jirovecii pneumonia (PJP)

— Esophageal candidiasis, disseminated/extrapulmonary candidiasis

— CMV retinitis, colitis, esophagitis

— Toxoplasma encephalitis

— Cryptococcal meningitis (extrapulmonary)

— Mycobacterium avium complex (MAC) disseminated

— TB (pulmonary or extrapulmonary)

— Progressive multifocal leukoencephalopathy (JC virus)

— Kaposi sarcoma, primary CNS lymphoma, non-Hodgkin lymphoma, invasive cervical cancer

— HIV wasting syndrome, HIV encephalopathy

— Chronic (>1 mo) cryptosporidiosis, isosporiasis

— Recurrent bacterial pneumonia (≥2 in 12 mo), recurrent Salmonella bacteremia

— Known HIV with CD4 trending down or off ART/non-adherent

— Newly diagnosed HIV presenting with constitutional symptoms, oral thrush, weight loss

— Unusual or "opportunistic-looking" infection in any patient with risk factors (MSM, IVDU, prior STI, sex worker contact, incarceration history, partner with HIV)

— Atypical presentations: subacute headache, dyspnea on exertion with clear CXR, dysphagia with thrush, painless violaceous skin lesions, retinal "pizza pie" findings

— <500: candidiasis, TB, Kaposi, zoster

— <200: PJP, toxo

— <100: cryptococcus, esophageal candidiasis

— <50: MAC, CMV, CNS lymphoma

Definition: AIDS is HIV infection plus either CD4 <200 cells/µL (or CD4% <14%) or an AIDS-defining condition regardless of CD4 count

Core AIDS-defining illnesses (CDC Category C) to memorize:

When to suspect on Step 3:

CD4-based risk thresholds (memorize cold):

Step 3 management: Any new opportunistic infection mandates HIV testing if status unknown, CD4 count, viral load, and full OI screen (toxo IgG, CMV IgG, hepatitis B/C, syphilis, latent TB) — order all at the initial visit, not piecemeal

Board pearl: A CD4 count above the typical threshold does not rule out an OI; nadir CD4 and rate of decline matter — a patient just restarted on ART may still be vulnerable until immune reconstitution

Presentation Patterns and Key History

— ART adherence (gaps, pharmacy refills, pill counts), most recent CD4 and viral load

— Prior OIs and prophylaxis history (TMP-SMX, azithromycin)

— Travel (endemic mycoses: histo, cocci, penicilliosis/talaromyces), pets (toxo, bartonella), TB exposure, incarceration

— Sexual practices, partner notification status

— Substance use, housing instability (TB risk, adherence barrier)

— Vaccination history (pneumococcal, HBV, HPV, influenza, COVID, Tdap)

PJP: subacute (2–4 wk) progressive dyspnea on exertion, dry cough, low-grade fever, profound exercise desaturation; often the AIDS-defining diagnosis at HIV presentation

Cryptococcal meningitis: indolent 2–4 week headache, fever, nausea, subtle personality change; classic absence of meningismus in advanced AIDS

Toxoplasma encephalitis: focal neuro deficits, headache, fever, seizures over days–weeks; usually CD4 <100 and toxo IgG positive

CMV retinitis: painless floaters, scotomata, visual field loss; CD4 <50; emergent ophthalmology

CMV colitis/esophagitis: bloody diarrhea, abdominal pain or odynophagia with deep linear ulcers

Esophageal candidiasis: odynophagia + oral thrush in patient with AIDS — treat empirically, EGD only if no response

MAC: fevers, drenching night sweats, weight loss, diarrhea, elevated alk phos, anemia; CD4 <50

PML: subacute focal deficits (hemiparesis, aphasia, ataxia, visual field cuts) without fever evolving over weeks

Kaposi sarcoma: painless violaceous patches/plaques on skin, palate, GI tract; HHV-8

Primary CNS lymphoma: subacute focal deficits + single ring-enhancing lesion; EBV-driven

Cryptosporidiosis: chronic watery non-bloody diarrhea, weight loss

Key history elements to elicit:

Key distinction: Toxoplasma vs CNS lymphoma — toxo gives multiple ring-enhancing lesions with positive toxo IgG and responds to empiric pyrimethamine-sulfadiazine in 10–14 days; CNS lymphoma is typically single, EBV PCR positive in CSF, and hot on thallium SPECT/PET

Board pearl: A patient with AIDS and headache > 1 week needs LP after head imaging even if afebrile and exam non-focal — cryptococcus hides in plain sight

Physical Exam Findings (and Functional/Performance Assessment)

— Oral thrush (pseudomembranous candidiasis) → marker of advancing immunosuppression

— Oral hairy leukoplakia on lateral tongue (EBV) — does not scrape off

— Aphthous-appearing palatal lesions: Kaposi sarcoma (violaceous), HSV, CMV

— Fundoscopy: fluffy yellow-white retinal infiltrates with hemorrhage ("pizza pie") = CMV retinitis; cotton-wool spots alone = HIV retinopathy (benign)

— Cryptococcal papilledema from elevated ICP

— Focal deficits → toxo, PML, CNS lymphoma, stroke

— Cognitive slowing, psychomotor retardation → HIV-associated neurocognitive disorder (HAND)

— Cranial nerve palsies → cryptococcus, TB meningitis, lymphomatous meningitis

— Peripheral neuropathy → HIV itself or d-drugs (rare now)

General: cachexia, temporal wasting, low BMI (HIV wasting if >10% loss); fevers; tachypnea on exertion is a tell for PJP

HEENT:

Lymph nodes: persistent generalized lymphadenopathy is common; asymmetric, hard, fixed nodes suggest lymphoma, TB, or KS

Pulmonary: PJP often has a near-normal exam with hypoxia disproportionate to findings; A–a gradient elevated; bacterial pneumonia has focal crackles; TB may show apical findings

Cardiac: pericardial effusion (TB, KS, lymphoma) — pulsus paradoxus; HIV cardiomyopathy

Abdomen: hepatosplenomegaly (MAC, disseminated histo, lymphoma); RUQ tenderness from cholangiopathy (cryptosporidium, microsporidia, CMV)

Skin: violaceous non-blanching plaques (KS), umbilicated papules (molluscum, cryptococcus, histo, talaromyces), eosinophilic folliculitis, severe seborrheic dermatitis, refractory psoriasis flare

Neuro:

Functional/performance: Karnofsky or ECOG score guides prognosis and chemo eligibility for AIDS-related lymphoma/KS

Step 3 management: At every AIDS-related encounter document weight, oral exam, fundoscopic screen (or refer if CD4 <50), and brief cognitive screen — these drive screening decisions and prophylaxis intensification

Board pearl: Hypoxia after a few steps in clinic ("ambulatory pulse ox drop ≥5%") in an HIV patient is essentially PJP until proven otherwise — get an ABG and CXR before they leave the room

Diagnostic Workup — Initial Labs, Imaging, and Bedside Tests

— HIV antigen/antibody combo (if status unknown) → confirmatory differentiation assay → HIV RNA viral load

— CD4 count and CD4%, HIV viral load

— CBC with diff (cytopenias from HIV, MAC, lymphoma, drugs), CMP (LFTs, Cr), LDH (elevated in PJP, lymphoma), beta-2 microglobulin

— Lactate, glucose if septic

— Blood cultures ×2, mycobacterial blood cultures if CD4 <50 (MAC)

— RPR/treponemal test, hepatitis A/B/C serologies, GC/CT NAAT (3-site if applicable), trichomonas

— Toxoplasma IgG, CMV IgG, cryptococcal serum antigen (CrAg) if CD4 <100, latent TB testing (IGRA preferred)

— G6PD before dapsone/primaquine

— HLA-B*5701 before abacavir

— Pregnancy test in women

— CXR: PJP shows bilateral perihilar interstitial/ground-glass infiltrates, can be normal early

— Pulse ox + ABG: calculate A–a gradient — drives adjunctive steroids

— Serum 1,3-β-D-glucan elevated in PJP (sensitive, not specific)

— Serum LDH elevated in PJP

— Induced sputum or BAL for PJP DFA/PCR, AFB ×3, bacterial cultures, fungal stain

Universal initial bundle for any patient with suspected AIDS-defining illness:

Pulmonary workup (suspected PJP/TB/bacterial PNA):

Neuro workup: Head CT or MRI before LP in AIDS; MRI brain with contrast preferred

Diarrhea workup: stool studies including modified acid-fast for cryptosporidium, cyclospora, isospora, microsporidia stain, C. difficile, GI multiplex PCR; if persistent → colonoscopy with biopsy for CMV

Visual symptoms: same-day dilated fundoscopy by ophthalmology

CCS pearl: On the CCS case, order CD4, HIV viral load, CBC, CMP, LDH, blood cultures, CXR, ABG, and serum CrAg simultaneously on initial screen — sequential ordering wastes virtual clock time and tanks efficiency scoring

Board pearl: A negative serum cryptococcal antigen essentially excludes cryptococcal disease (sensitivity >95%) — a cheap, high-yield screen in any AIDS patient with headache or CD4 <100

Diagnostic Workup — Advanced and Confirmatory Studies

— Induced sputum DFA (sensitivity 50–90%) → if negative and suspicion high, bronchoalveolar lavage with silver/Giemsa/DFA/PCR (sensitivity >95%)

— Quantitative PCR distinguishes colonization from infection

— LP with opening pressure (always measure — drives therapeutic LPs)

— CSF: India ink, CSF cryptococcal antigen (highly sensitive/specific), fungal culture, cell count, protein, glucose

— Repeat LPs to keep OP <20 cm H₂O — single most important survival driver

— MRI: multiple ring-enhancing lesions at gray–white junction and basal ganglia

— Toxoplasma IgG (negative IgG makes toxo very unlikely)

— Empiric trial of pyrimethamine-sulfadiazine + leucovorin × 10–14 days; clinical/radiographic improvement confirms

— Brain biopsy reserved for non-responders or atypical features

— MRI: usually solitary periventricular lesion, may be ring-enhancing

— CSF EBV PCR positive, cytology, flow cytometry

— Thallium SPECT or FDG-PET: hot in lymphoma, cold in toxo

— Stereotactic biopsy is definitive

— MRI: subcortical white matter lesions, non-enhancing, no mass effect, asymmetric

— CSF JC virus PCR

— Retinitis: clinical diagnosis by dilated fundoscopy

— Colitis/esophagitis: endoscopy with biopsy showing intranuclear "owl's eye" inclusions

— Serum CMV PCR supportive but not diagnostic of end-organ disease

PJP confirmation:

Cryptococcal meningitis:

Toxoplasma encephalitis:

CNS lymphoma:

PML:

CMV:

MAC: mycobacterial blood cultures (gold standard) or bone marrow/liver biopsy with AFB

TB: sputum AFB ×3, NAAT (Xpert MTB/RIF), culture; respiratory isolation until ruled out

Kaposi sarcoma: biopsy showing spindle cells, HHV-8 staining

Esophageal candidiasis: empirical fluconazole; EGD if no improvement in 3–5 days to rule out CMV/HSV ulcers

Key distinction: PML lesions do not enhance and lack mass effect — this differentiates from toxo and lymphoma at the imaging level alone

Board pearl: Always check opening pressure in suspected cryptococcal meningitis — failing to manage elevated ICP is the most common missed step on exam questions

Risk Stratification and First-Line Management Logic

— PJP severity by ABG: PaO₂ <70 mmHg or A–a gradient ≥35 = moderate-severe → add adjunctive corticosteroids

— Cryptococcal meningitis: OP, mental status, CSF fungal burden predict mortality

— Toxo: GCS, midline shift, herniation risk

— Step 1: Stabilize (oxygen, fluids, anticonvulsants, ICP management)

— Step 2: Obtain diagnostic specimens before empirical therapy when feasible (but do not delay treatment for critically ill)

— Step 3: Start OI-directed therapy

— Step 4: Start/continue OI prophylaxis for other organisms by CD4 stratum

— Step 5: Initiate or resume ART — timing matters

— Most OIs: start ART within 2 weeks of OI treatment initiation (improves survival)

— Cryptococcal meningitis and TB meningitis: delay ART 4–6 weeks to reduce paradoxical IRIS-associated mortality

— Pulmonary TB with CD4 <50: start ART within 2 weeks; CD4 ≥50: within 8 weeks

— CD4 <200 or oropharyngeal candidiasis → TMP-SMX for PJP

— CD4 <100 + positive toxo IgG → TMP-SMX covers toxo too

— CD4 <50 → consider azithromycin for MAC only if not started on effective ART (current guideline downgrade)

— Latent TB (positive IGRA) → INH + B6 ×9 mo or rifapentine-INH × 3 mo (avoid with PI/INSTI interactions)

Severity assessment drives empiric therapy choices:

General management framework in any newly diagnosed AIDS patient with an OI:

ART timing with acute OI:

Prophylaxis thresholds to recall:

Stop prophylaxis when CD4 >200 for ≥3 months on ART (PJP, toxo)

Step 3 management: For a hospitalized AIDS patient with new OI, the order set should include — OI-directed therapy, OI prophylaxis for organisms below their CD4 threshold, social work/case management for ART access (Ryan White program), partner notification (state-dependent), vaccination review at discharge

Board pearl: The single most important intervention for long-term survival in AIDS is effective ART with virologic suppression — every encounter should reassess adherence and barriers, not just the OI in front of you

Pharmacotherapy — First-Line Regimens by AIDS-defining Illness

— First-line: TMP-SMX 15–20 mg/kg/day IV or PO divided q6–8h × 21 days

— Adjunctive prednisone if PaO₂ <70 or A–a ≥35: 40 mg BID ×5d, 40 mg daily ×5d, 20 mg daily ×11d — start within 72 h

— Alternatives: clindamycin + primaquine (check G6PD), atovaquone (mild only), IV pentamidine (toxic — pancreatitis, hypoglycemia, nephrotoxicity)

— Sulfa allergy with severe disease: desensitize or use clinda-primaquine

— Induction: liposomal amphotericin B + flucytosine × ≥2 weeks

— Consolidation: fluconazole 800 mg daily × 8 wks

— Maintenance: fluconazole 200 mg daily until CD4 >100 for ≥3 mo and suppressed VL ≥3 mo

— Therapeutic LPs for OP >25 cm H₂O — drain to normal pressure or 50% reduction

— Pyrimethamine + sulfadiazine + leucovorin × ≥6 weeks → suppressive doses until CD4 >200 ×6 mo

— Alternative: TMP-SMX or pyrimethamine + clindamycin

— Add dexamethasone only for significant edema/mass effect

— Sight-threatening (zone 1): intravitreal ganciclovir/foscarnet + oral valganciclovir

— Peripheral: oral valganciclovir 900 mg BID ×21 d → 900 mg daily maintenance

PJP:

Cryptococcal meningitis:

Toxoplasma encephalitis:

CMV retinitis:

MAC: clarithromycin (or azithromycin) + ethambutol ± rifabutin; continue ≥12 mo and until CD4 >100 ×6 mo on ART

Esophageal candidiasis: fluconazole 100–400 mg/day × 14–21 d; echinocandin if azole-resistant

TB-HIV: standard RIPE; rifabutin replaces rifampin if on PI-based ART

Kaposi sarcoma: ART alone for limited disease; liposomal doxorubicin for visceral/extensive

CNS lymphoma: high-dose methotrexate-based regimen + ART; whole-brain RT if not chemo candidate

ART backbone for treatment-naïve: bictegravir/TAF/FTC or dolutegravir + TAF/FTC (or TDF/FTC); choose based on renal function, pregnancy, drug interactions

Board pearl: Adjunctive steroids in PJP must be started early (<72 h) — they reduce mortality only when given before respiratory failure progresses

Procedures and Expanded Pharmacology Notes

— Indication: opening pressure >25 cm H₂O or symptomatic ICP

— Remove CSF to reduce OP by 50% or to ≤20 cm H₂O

— Repeat daily until OP normalizes; consider lumbar drain or VP shunt if refractory

— Rifampin induces CYP3A4 → drops PI and some INSTI levels → use rifabutin with PIs; dolutegravir dose-doubled with rifampin

— Pyrimethamine + TMP-SMX → bone marrow suppression; always add leucovorin

— TDF + nephrotoxins (amphotericin, foscarnet) → switch to TAF or alternative

— Valganciclovir + zidovudine → severe neutropenia

— Clarithromycin + many ART agents → QTc; azithromycin preferred for MAC with ART

— Atovaquone absorption requires fatty meal

— Primaquine, dapsone, sulfonamides → check G6PD

— Paradoxical worsening of treated OI after ART start (typically 2–8 wks)

— Most severe with cryptococcal and TB meningitis — basis for delaying ART

— Management: continue ART and OI therapy; add corticosteroids for severe inflammatory symptoms; do not stop ART unless life-threatening

Therapeutic LPs in cryptococcal meningitis:

Bronchoscopy with BAL: gold standard for PJP when induced sputum negative; also samples for TB, fungi, bacterial cultures, malignancy

Intravitreal injections (ganciclovir/foscarnet): sight-threatening CMV retinitis; ophthalmology-driven

EGD/colonoscopy with biopsy: diagnose CMV (owl's eye inclusions on H&E, IHC), Kaposi, lymphoma; for refractory esophageal symptoms despite empiric fluconazole

Stereotactic brain biopsy: when toxo trial fails or imaging favors lymphoma/PML

Indwelling pleural drainage: TB or KS effusions (avoid pleurodesis in KS as chemotherapy may regress effusion)

Drug interaction landmines to know cold:

IRIS (immune reconstitution inflammatory syndrome):

CCS pearl: When ordering amphotericin, simultaneously order pre-hydration with normal saline 500 mL, electrolyte repletion (K, Mg), and daily creatinine/electrolytes — these are graded as appropriate supportive orders

Board pearl: A patient on ART for 4 weeks who develops worsening lymphadenopathy or pulmonary infiltrates is more likely experiencing IRIS than treatment failure — biopsy/culture if unclear, but keep ART going

Special Populations — Elderly and Renal/Hepatic Impairment

— Accelerated comorbidities: CVD, CKD, osteoporosis, frailty, cognitive impairment occur 5–10 years earlier than HIV-negative peers

— Polypharmacy: review for drug–drug interactions (statins, warfarin, PPIs, antifungals, ART)

— Annual screening: lipids, A1c, DEXA at 50 (men with HIV) or earlier, colorectal cancer, anal Pap in MSM, cervical Pap (more frequent than general population)

— Vaccinations: pneumococcal (PCV20 or PCV15→PPSV23), zoster (RZV ≥18 yrs with HIV per ACIP), hepatitis B, HPV through age 45, influenza, COVID, Tdap

— Cognitive screening: distinguish HAND from Alzheimer's; check viral load suppression — uncontrolled HIV worsens HAND

— Avoid TDF if CrCl <60; use TAF (safer renal/bone profile) or alternative

— Dose-adjust TMP-SMX, valganciclovir, fluconazole, acyclovir by CrCl

— Avoid amphotericin deoxycholate in CKD — use liposomal amphotericin

— Watch tenofovir for Fanconi syndrome (proteinuria, glycosuria, hypophosphatemia)

— HIVAN (collapsing FSGS, more common in patients of African descent) — ACE inhibitor + ART; nephrology referral

— HIV/HCV coinfection: treat HCV with DAAs after checking ART interactions (avoid sofosbuvir-velpatasvir with efavirenz issues; sofosbuvir/velpatasvir generally compatible with INSTI regimens)

— HIV/HBV coinfection: always include TDF or TAF + FTC/3TC in ART — covers both viruses; never use 3TC monotherapy (resistance)

— Stopping HBV-active ART → risk of fulminant HBV flare; counsel and monitor

— Avoid nevirapine if CD4 high or hepatic dysfunction (hepatotoxicity)

Older adults with HIV (≥50 years now >50% of US PLWH):

Renal impairment:

Hepatic impairment:

Step 3 management: For an HIV patient with eGFR 45, change TDF→TAF, switch TMP-SMX prophylaxis dose to single-strength daily or three times weekly, and confirm no other nephrotoxins; recheck renal function in 2–4 weeks

Board pearl: HBV/HIV coinfection mandates that both components of ART (the NRTI backbone) be HBV-active — discontinuing tenofovir without alternative HBV coverage triggers severe hepatitis flares

Special Populations — Pregnancy, Pediatrics, and Marginalized Groups

— Universal HIV screening at first prenatal visit and rescreening third trimester in high-prevalence areas

— Goal: undetectable viral load by delivery — virtually eliminates perinatal transmission

— Preferred ART: dolutegravir + TAF/FTC (dolutegravir now preferred throughout pregnancy after updated safety data showed no significant NTD increase) or bictegravir/TAF/FTC, or raltegravir-based

— Avoid efavirenz only in first trimester historically — current guidelines allow

— Mode of delivery: vaginal delivery acceptable if VL <1000 near delivery; scheduled C-section at 38 weeks if VL ≥1000 or unknown

— IV zidovudine intrapartum if VL >1000 or unknown

— Neonate: ART prophylaxis (ZDV alone if low-risk, combination if high-risk), HIV DNA/RNA PCR at birth, 2–4 wks, 4 mo (antibody tests unreliable until 18 mo)

— No breastfeeding in US (formula recommended); in resource-limited settings, breastfeed with maternal ART

— OI prophylaxis: TMP-SMX safe in pregnancy (folate supplement); avoid in immediate peripartum if possible due to kernicterus risk in neonate

— Diagnose with HIV DNA/RNA PCR, not antibody, before 18 months

— Start ART in all HIV-infected infants regardless of CD4

— PJP prophylaxis 4–6 weeks to 1 year in all HIV-exposed infants until HIV excluded

— Confidentiality concerns affect adherence

— Hormone therapy interactions: integrase inhibitors generally compatible with estradiol/spironolactone; counsel and monitor

— Linkage to care critical; same-day ART start ("rapid start") improves engagement

— Ryan White, ADAP, 340B programs cover medications regardless of insurance

Pregnancy:

Pediatrics:

Adolescents/transgender patients:

Incarcerated/unhoused populations:

Step 3 management: Pregnant patient newly diagnosed with HIV at 28 weeks — start dolutegravir/TAF/FTC same day, obtain CD4/VL/resistance testing, screen for OIs and STIs, schedule weekly VL trending, plan IV ZDV during labor if VL not <1000 by 36 weeks, arrange neonatology consult

Board pearl: Perinatal transmission risk is <1% if maternal VL <50 at delivery — the single most powerful preventive intervention is virologic suppression, not delivery mode

Complications and Adverse Outcomes

— PJP: respiratory failure requiring mechanical ventilation, pneumothorax (esp. with pentamidine nebs), persistent diffusion impairment

— Cryptococcal meningitis: elevated ICP → herniation, vision/hearing loss, hydrocephalus, paradoxical IRIS, relapse if maintenance stopped prematurely

— Toxo: status epilepticus, herniation, residual focal deficits, hydrocephalus

— CMV retinitis: blindness, retinal detachment (occurs in 30–50% — refer ophtho even after treatment), immune recovery uveitis with ART

— CMV colitis: perforation, hemorrhage, stricture

— MAC: profound anemia, wasting, biliary obstruction

— TB: meningitis, miliary spread, MDR/XDR resistance, hepatotoxicity from RIPE

— PML: progressive irreversible deficits, death within months without ART; IRIS-PML can cause acute worsening

— Kaposi: visceral hemorrhage, lymphedema, pulmonary KS with respiratory failure

— CNS lymphoma: poor prognosis, median survival months without effective ART + chemo

— TMP-SMX: rash (often non-allergic if no systemic symptoms — can continue), Stevens-Johnson, hyperkalemia, marrow suppression, hepatitis, AKI

— Amphotericin: nephrotoxicity, hypokalemia, hypomagnesemia, infusion reactions

— Flucytosine: marrow suppression — check levels

— Pyrimethamine: cytopenias (always with leucovorin)

— ART class-specific: weight gain (INSTIs, TAF), renal/bone (TDF), lipoatrophy (older NRTIs), neuropsychiatric (efavirenz), hypersensitivity (abacavir → HLA-B*5701 screen), hyperbilirubinemia (atazanavir)

— IRIS in any OI

— Accelerated atherosclerosis, MI; statin threshold lower — REPRIEVE trial supports pitavastatin in PLWH age 40–75 with low-moderate CV risk

— Non-AIDS malignancies (lung, anal, hepatocellular, Hodgkin)

— Osteoporosis, frailty, HAND, CKD

OI-specific complications:

Treatment-related:

Long-term HIV complications (even with viral suppression):

Board pearl: The REPRIEVE trial showed pitavastatin reduces MACE by ~35% in PLWH with low-to-moderate ASCVD risk — primary prevention statin therapy has a lower threshold in HIV

When to Escalate Care — ICU, Consults, and Inpatient Triage

— PJP with PaO₂ <60 on supplemental O₂, RR >30, need for HFNC/NIV/intubation

— Cryptococcal or TB meningitis with depressed mental status, seizures, OP >40, hydrocephalus

— Toxoplasma with status epilepticus, herniation

— Sepsis from any source (bacterial pneumonia, MAC bacteremia, Salmonella)

— Massive hemoptysis (TB, KS), upper GI bleed from KS, CMV

— IRIS with respiratory or CNS compromise

— Infectious disease: any new OI or treatment failure, complex drug interactions, ART initiation in OI setting

— Ophthalmology: same-day for any visual symptom with CD4 <100

— Neurology/neurosurgery: focal deficits, elevated ICP, biopsy decisions

— Pulmonology: BAL for non-diagnostic sputum; refractory PJP

— Hematology/oncology: AIDS-defining malignancies

— Gastroenterology: chronic diarrhea workup, suspected CMV colitis, KS surveillance

— Dermatology: KS, atypical skin lesions, severe drug reactions

— Social work/case management: ART access, housing, partner notification, adherence support

— Psychiatry: depression/substance use — major drivers of nonadherence

— Hypoxia or hemodynamic instability

— Inability to tolerate PO therapy

— Suspected meningitis pending LP

— Severe diarrhea with dehydration or weight loss

— New focal neuro deficits

— Suspected TB requiring respiratory isolation in negative-pressure room

— Need for IV induction therapy (amphotericin, IV ganciclovir, IV pentamidine)

ICU criteria in AIDS patients:

Specialty consults:

Admission criteria:

Discharge readiness: stable vitals, oral therapy tolerated, follow-up arranged within 1–2 weeks, ART started or continued, prophylaxis prescribed, vaccines updated

CCS pearl: For any HIV patient presenting with cough and fever, place on respiratory isolation immediately while ruling out TB — this order is graded; lifting isolation requires 3 negative AFB sputums or negative NAAT

Step 3 management: Transfer to ICU for AIDS patient with PJP needing >6 L O₂, or worsening A–a gradient despite 48 h of TMP-SMX + steroids — early intubation improves outcomes versus crash intubation

Key Differentials — Same-Category (Other Opportunistic and HIV-Related) Causes

— PJP: bilateral perihilar interstitial, normal CD4 unusual, β-D-glucan high, LDH high, exercise desaturation

— Bacterial PNA (Strep pneumo, H. flu): lobar, acute onset, often recurrent — defines AIDS if ≥2 episodes/year

— TB: upper lobe cavitary if CD4 >200; atypical lower lobe/diffuse if CD4 <200; must rule out before steroids

— MAC pulmonary: less common as isolated pulmonary disease in AIDS (more disseminated)

— Endemic fungi: histoplasmosis (Ohio/Mississippi valleys — disseminated with pancytopenia, ulcers), coccidioidomycosis (Southwest), talaromycosis (Southeast Asia — umbilicated skin lesions)

— Cryptococcal pneumonia: nodules; check serum CrAg

— Kaposi sarcoma pulmonary: nodules with "flame-shaped" perihilar opacities, pleural effusions, gallium-negative/thallium-positive

— Lymphoma: nodes, masses

— Toxoplasmosis: multiple ring-enhancing, basal ganglia, IgG+, responds to empiric therapy

— Primary CNS lymphoma: solitary, periventricular, EBV PCR+, hot on PET

— PML: non-enhancing white matter, no mass effect, JCV PCR+

— Cryptococcoma: rare, gelatinous pseudocysts

— Tuberculoma: ring-enhancing, often basal meningitis

— HIV encephalopathy: diffuse atrophy, white matter changes, no focal lesion

Pulmonary infiltrates in AIDS — differentiating:

CNS lesions in AIDS — differentiating:

Chronic diarrhea: cryptosporidium, microsporidia, isospora, cyclospora, CMV colitis, MAC, C. difficile, KS, lymphoma, HIV enteropathy, ART-related (PI, ddI historically)

Cytopenias: HIV itself, MAC, parvovirus B19 (pure red cell aplasia), drug-induced (ZDV, TMP-SMX, ganciclovir), lymphoma marrow involvement

Skin lesions: KS, bacillary angiomatosis (Bartonella — treat with doxycycline or erythromycin), molluscum, disseminated cryptococcus, histoplasmosis (umbilicated), syphilis

Key distinction: Bacillary angiomatosis can look identical to Kaposi sarcoma — biopsy with Warthin-Starry stain identifies Bartonella, and treatment is antibiotics not chemotherapy. Always biopsy "KS-like" lesions in low-resource or atypical settings

Key Differentials — Other-Category Causes

— Solid organ transplant on calcineurin inhibitors → PJP, CMV, fungal infections

— Hematologic malignancies (CLL, lymphoma) and stem cell transplant

— High-dose chronic corticosteroids (≥20 mg prednisone equivalent ×4 wks)

— Biologics: anti-TNF (TB reactivation), rituximab (PML, PJP), JAK inhibitors (HSV, zoster)

— Primary immunodeficiency (CVID, hyper-IgM) presenting in adulthood

— PJP-like pneumonitis: viral pneumonia (COVID-19, influenza, RSV), hypersensitivity pneumonitis, drug-induced pneumonitis, DAH, lymphoid interstitial pneumonia (LIP — more in pediatric HIV)

— Cryptococcal meningitis mimics: TB meningitis, neurosyphilis, lymphomatous meningitis, sarcoid CNS, fungal meningitis from other species

— Toxoplasmosis CNS mimics: brain abscess (bacterial), tuberculoma, lymphoma, metastatic cancer

— PML mimics: HIV leukoencephalopathy, ischemic strokes, MS (rare in HIV)

— CMV retinitis mimics: HIV retinopathy (cotton wool spots only, asymptomatic), syphilitic uveitis, ARN (HSV/VZV — rapidly progressive), toxoplasma retinochoroiditis

— MAC mimics: TB, lymphoma, disseminated histoplasmosis — all present with fever, night sweats, hepatosplenomegaly, cytopenias

— Chronic HIV diarrhea mimics: IBD, microscopic colitis, celiac, lactose intolerance, ART-related, C. difficile

— Wasting syndrome: hyperthyroidism, malignancy, depression, malabsorption, MAC, chronic infection

Non-HIV immunocompromise mimicking AIDS-defining illness:

Conditions that mimic specific OIs:

Headache in HIV patient: tension/migraine, sinusitis, medication overuse, cryptococcal meningitis, TB meningitis, neurosyphilis, toxo, lymphoma, IRIS, idiopathic intracranial hypertension

Step 3 management: HIV patient on chronic corticosteroids for an autoimmune condition develops dyspnea — workup must address PJP risk even if CD4 >200, because steroids alone confer susceptibility; add PJP prophylaxis (TMP-SMX SS daily) when prednisone ≥20 mg/d for ≥4 weeks

Board pearl: A "stroke-like" picture in HIV with subacute progression over weeks and no enhancement on MRI is PML until proven otherwise — JC virus PCR on CSF is the test that resolves the differential

Secondary Prevention, Discharge Medications, and Long-Term Plan

— PJP: TMP-SMX DS daily → discontinue when CD4 >200 ×3 mo on ART

— Toxoplasmosis: pyrimethamine + sulfadiazine + leucovorin (suppressive doses) → discontinue when CD4 >200 ×6 mo

— Cryptococcus: fluconazole 200 mg daily → discontinue when CD4 >100 ×3 mo + VL suppressed ≥3 mo + asymptomatic

— CMV retinitis: valganciclovir 900 mg daily → discontinue when CD4 >100 ×3–6 mo + treated lesions inactive (ophtho confirms)

— MAC: clarithromycin/azithromycin + ethambutol ≥12 mo total → discontinue when CD4 >100 ×6 mo on ART

— Histoplasmosis: itraconazole ≥12 mo → discontinue when CD4 >150 ×6 mo on ART, negative blood/urine antigens

— Goal: VL <50 indefinitely

— Single-tablet regimens improve adherence: bictegravir/TAF/FTC; dolutegravir/3TC (2-drug, if no HBV and no resistance); doravirine combos

— Resistance testing if VL >500 on therapy

— Long-acting injectable cabotegravir + rilpivirine IM every 1–2 months for virologically suppressed patients with adherence challenges

— Statin per REPRIEVE if age 40–75 with HIV

— Aspirin per standard ASCVD risk (no longer routine primary prevention)

— BP, lipid, A1c, weight monitoring every 3–6 mo

— Cancer screening: cervical Pap annually then per guidelines, anal cytology in MSM/transgender women, lung CT if eligible, mammography, colonoscopy

— Vaccines: PCV20 or PCV15→PPSV23, HBV (if non-immune), HAV, HPV (through 26, consider through 45), influenza, COVID, Tdap, recombinant zoster vaccine (RZV) for adults ≥18 with HIV, meningococcal if asplenic/MSM in outbreaks, mpox

— Avoid live vaccines (MMR, varicella) if CD4 <200

OI secondary prophylaxis (chronic suppressive/maintenance therapy) until immune reconstitution:

Primary prophylaxis discontinuation mirrors above thresholds

ART maintenance:

Comprehensive secondary prevention:

CCS pearl: On discharge for an AIDS patient with treated OI, the order set must include: ART (or continue), OI maintenance therapy, primary prophylaxis for other organisms, statin per REPRIEVE, vaccines due, PCP follow-up in 1–2 weeks, ID follow-up in 2–4 weeks, lab orders (CD4, VL, CMP, CBC) at 4 weeks

Follow-Up, Monitoring Parameters, and Counseling

— Baseline: CD4, VL, resistance genotype, CMP, CBC, lipids, A1c, hepatitis serologies, HLA-B*5701 (if abacavir), urinalysis, pregnancy test

— 2–4 weeks after ART start: VL, CMP (especially renal if TDF), tolerance check

— Every 3 months until suppressed: VL, CD4

— Once suppressed >2 years with stable CD4 >300: VL every 6 months, CD4 annually (or stop monitoring CD4 if >500 sustained)

— Lipids, A1c, renal function every 6–12 months

— Bone density at 50 (men) or postmenopausal women, earlier with risk factors

— PJP: clinical improvement by day 4–7; if worsening, consider TB, IRIS, bacterial superinfection, drug failure, ARDS

— Cryptococcal meningitis: repeat LP at 2 weeks for CSF culture sterility before switching to consolidation

— CMV retinitis: monthly dilated fundoscopy until inactive, then per ophtho

— TB: monthly sputum smear/culture, LFTs

— Toxo: clinical and MRI improvement at 10–14 days

— U=U (Undetectable = Untransmittable): a suppressed VL means no sexual transmission — powerful adherence and stigma message

— Disclosure: encourage partner notification; in most US states, providers can assist via partner services through health departments

— Safer sex: condoms still protect against other STIs and pregnancy

— PrEP for HIV-negative partners: tenofovir/emtricitabine or long-acting cabotegravir

— PEP: 28-day three-drug ART within 72 h of exposure

— Substance use treatment, mental health support, smoking cessation (huge survival impact)

— Nutrition, exercise, weight (INSTI-related weight gain — counsel and monitor)

— Family planning and reproductive counseling

ART monitoring cadence:

OI-specific monitoring:

Counseling priorities:

Rehab: pulmonary rehab post-severe PJP; cognitive rehab for HAND/PML; physical therapy after prolonged hospitalization

Step 3 management: After hospitalization for first OI, schedule PCP within 1–2 weeks, ID within 4 weeks, repeat CD4/VL at 4 weeks, reinforce adherence at each visit, screen depression with PHQ-9, and confirm prescription pickup via pharmacy or refill data

Board pearl: U=U is now standard counseling — viral suppression to <200 copies/mL eliminates sexual transmission risk; this changes the conversation around relationships, disclosure, and reproduction

Ethical, Legal, and Patient Safety Considerations

— HIV status protected under HIPAA with additional state-specific protections in many states

— Disclosure to family/employers requires explicit patient consent

— Documenting HIV status in shared records: minimize where possible; never disclose in patient portals to unauthorized users

— Most states require providers to counsel patients on disclosure to current/former partners

— Health department-assisted partner services allow anonymous notification

— Some states have specific HIV exposure/transmission criminal statutes — counsel patients on legal landscape, but advocate for evidence-based modernized laws

— Tarasoff-like duties: in some jurisdictions, providers may have duty to warn an identifiable partner at ongoing risk if patient refuses disclosure — know your state law

— HIV testing: most states now use opt-out consent (CDC-recommended) rather than written informed consent — counsel and test unless declined

— ART initiation: discuss benefits, side effects, lifelong commitment, drug interactions, U=U

— Research participation: extra vulnerability protections in marginalized populations

— HIV is reportable to state health departments in all US states

— AIDS-defining conditions (TB, certain STIs) have separate reporting requirements

— Suspected child or elder abuse, intimate partner violence (often co-occurring) — mandatory reporting per state law

— Hospital discharge is the highest-risk transition: ART continuity gaps cause viral rebound and resistance

— Use medication reconciliation and verify outpatient ART supply before discharge

— 340B and Ryan White programs cover medications for uninsured patients — ensure linkage before discharge

— Communicate with outpatient HIV provider; send discharge summary within 48 h

— HAND or CNS OI may impair capacity — assess for each major decision

— Advance directives, surrogate decision-maker designation — especially important in patients without legal next-of-kin recognition (LGBTQ+ patients in states without protective statutes)

Confidentiality:

Partner notification:

Informed consent:

Mandatory reporting:

Transitions of care safety:

Capacity and end-of-life:

Step 3 management: An AIDS patient with PML and progressive cognitive decline still wants to continue full code status — assess capacity for that specific decision, document, involve palliative care early, and revisit goals of care at each hospitalization. Capacity is decision-specific, not global

Board pearl: Same-day ART initiation ("rapid ART") at HIV diagnosis is now recommended — barriers like insurance enrollment should not delay starting therapy; bridge with starter packs and 340B

High-Yield Associations and Rapid-Fire Clinical Facts

— <500: candidiasis, TB, KS, zoster, bacterial PNA, HSV

— <200: PJP, esophageal candidiasis, HIV-associated dementia (early)

— <100: toxoplasmosis, cryptococcus, microsporidia/cryptosporidia chronic, PML

— <50: MAC, CMV, CNS lymphoma, disseminated histoplasmosis

— "Pizza pie" retina → CMV

— "Owl's eye" inclusions on biopsy → CMV

— India ink positive CSF → cryptococcus

— Yeast forms with narrow-based budding, encapsulated → cryptococcus

— Yeast within macrophages in bone marrow → histoplasma

— Acid-fast oocysts in stool → cryptosporidium/cyclospora/isospora

— Multiple ring-enhancing lesions, IgG+ → toxo

— Non-enhancing white matter lesions, JCV PCR+ → PML

— Violaceous plaques, HHV-8 → KS

— Oral hairy leukoplakia → EBV (not premalignant)

— Bacillary angiomatosis → Bartonella henselae/quintana

— TMP-SMX: PJP + toxo + isospora prophylaxis in one

— Fluconazole: cryptococcus consolidation/maintenance, candida

— Liposomal amphotericin + flucytosine: cryptococcus induction

— Pyrimethamine + sulfadiazine + leucovorin: toxo

— Valganciclovir: CMV oral

— Clarithromycin + ethambutol: MAC

— Rifabutin (not rifampin): TB with PI-based ART

— Avoid live vaccines if CD4 <200 (no MMR, varicella, yellow fever)

— RZV (Shingrix) recommended for all adults ≥18 with HIV (non-live)

— Pneumococcal: PCV20 or PCV15→PPSV23

— Elevated LDH + ground-glass = think PJP

— Elevated alk phos + fever + cytopenias = think MAC or disseminated fungal

— β-D-glucan: + in PJP, candidemia, histo; − in cryptococcus, mucor

CD4 thresholds — memorize cold:

Pathognomonic associations:

Drug pearls:

Vaccine pearls in HIV:

Lab pearls:

Treatment timing: PJP steroids within 72 h; ART within 2 weeks of OI except crypto/TB meningitis (4–6 weeks)

Board pearl: REPRIEVE, U=U, rapid ART start, dolutegravir in pregnancy, RZV for all adults with HIV — these are the recently updated guideline shifts most likely to appear on Step 3

Board Question Stem Patterns

— Answer: TMP-SMX + prednisone (calculate A–a gradient ≥35), check HIV, start ART within 2 weeks

— Answer: Liposomal amphotericin + flucytosine; serial therapeutic LPs; delay ART 4–6 weeks

— Answer: Empiric pyrimethamine + sulfadiazine + leucovorin; reassess in 10–14 days

— Answer: Valganciclovir; intravitreal therapy if sight-threatening; ophthalmology immediately

— Answer: Mycobacterial blood cultures; clarithromycin + ethambutol

— Answer: Empiric fluconazole; EGD only if no improvement in 3–5 days

— Answer: CSF JCV PCR; start/optimize ART; no specific antiviral

— Answer: Start dolutegravir/TAF/FTC immediately; trend VL; IV ZDV if VL >1000 at delivery; scheduled C-section if VL ≥1000

— Discontinuing TDF in HBV-coinfected patient without coverage → fulminant hepatitis

— Starting ART in cryptococcal meningitis at day 7 → high-mortality IRIS

— Missing G6PD before dapsone/primaquine → hemolysis

— Live vaccine with CD4 <200 → vaccine-derived infection

— Rifampin + PI without rifabutin substitution → ART subtherapeutic, virologic failure

PJP stem: "32-year-old man with 3 weeks of progressive dyspnea, dry cough, 10-lb weight loss, oral thrush. RR 26, SpO₂ 88% on room air, drops to 82% after walking. CXR bilateral perihilar infiltrates."

Cryptococcal meningitis stem: "AIDS patient, CD4 30, 2-week headache, low-grade fever, no neck stiffness. LP OP 38 cm H₂O, India ink positive."

Toxoplasmosis stem: "CD4 50, new right hemiparesis, MRI multiple ring-enhancing lesions basal ganglia, toxo IgG positive."

CMV retinitis stem: "CD4 25, floaters and decreased vision, fundoscopy fluffy yellow-white retinal lesions with hemorrhage."

MAC stem: "CD4 30, fevers, night sweats, weight loss, elevated alk phos, anemia, hepatosplenomegaly."

Esophageal candidiasis stem: "AIDS patient with odynophagia and oral thrush."

PML stem: "CD4 80, progressive aphasia and right-sided weakness over 4 weeks, MRI bilateral non-enhancing white matter lesions, no mass effect."

Pregnancy stem: "Newly diagnosed HIV at 28 weeks, VL 80,000."

Pitfall stems:

Step 3 management: When a stem provides multiple positive findings (toxo IgG+, cryptococcal antigen+), treat the clinically dominant syndrome while pursuing definitive diagnosis; don't withhold empiric therapy waiting for biopsy

Board pearl: Step 3 stems often test next step logic — "patient with CD4 30 and headache, head CT shows no mass" → next is LP with OP, India ink, CSF CrAg, not empiric antibiotics alone

One-Line Recap

AIDS-defining illnesses are the syndromes that signal advanced HIV (CD4 <200 or specific opportunistic conditions), demand a CD4-stratified diagnostic and therapeutic approach, and require simultaneous OI-directed therapy, ART initiation/optimization, prophylaxis layering, IRIS awareness, and longitudinal secondary prevention to convert a once-fatal diagnosis into a chronic, manageable disease.

Diagnostic anchor: CD4 count predicts which OIs to consider; <200 think PJP/candida, <100 think toxo/crypto, <50 think CMV/MAC/CNS lymphoma — every workup should layer organism-specific tests on this scaffold (β-D-glucan, serum CrAg, toxo IgG, mycobacterial blood cultures, dilated fundoscopy)

Treatment anchor: TMP-SMX + steroids for PJP if A–a ≥35; liposomal amphotericin + flucytosine + serial LPs for cryptococcus; pyrimethamine-sulfadiazine-leucovorin for toxo; valganciclovir ± intravitreal for CMV; clarithromycin + ethambutol for MAC — start ART within 2 weeks of OI except cryptococcal and TB meningitis (delay 4–6 weeks)

Prevention anchor: TMP-SMX prophylaxis when CD4 <200 (covers PJP and toxo if IgG+); discontinue prophylaxis when CD4 >200 ×3 mo on ART; lifelong ART with goal undetectable VL; statin per REPRIEVE; RZV, PCV20, HBV, HPV, influenza/COVID vaccines; cancer screening intensified; U=U counseling

Step 3 management: Same-day ART start at diagnosis, rapid linkage via Ryan White/340B, partner services and confidentiality protections, transitions-of-care safety with verified ART supply at discharge, follow-up PCP 1–2 weeks and ID 2–4 weeks, repeat CD4/VL at 4 weeks, and lifelong longitudinal care addressing CV risk, cancer screening, mental health, substance use, and adherence — the OI is the acute event; the lifelong work is virologic suppression and whole-person preventive care