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This is a clinician-written, evidence-based summary aligned to the USMLE Step 2 CK Content Outline. It is intended for medical students preparing for USMLE Step 2 CK. Management reflects current ACC/AHA, USPSTF, and APA guidelines. Always cross-reference with UpToDate, institutional protocols, and clinical judgment.
The Bottom Line
- CD4 <200: PCP risk; give TMP-SMX prophylaxis and treat PCP with TMP-SMX plus corticosteroids if PaO2 <70 or A-a gradient >=35
- CD4 <100 + Toxoplasma IgG positive: toxoplasmosis prophylaxis with TMP-SMX; ring-enhancing brain lesions are treated empirically with pyrimethamine-sulfadiazine-leucovorin or TMP-SMX
- CD4 <50: CMV retinitis and disseminated MAC risk; ART is the main MAC prevention, azithromycin prophylaxis only if ART cannot be started promptly
- Cryptococcal meningitis: amphotericin B plus flucytosine induction, then fluconazole; delay ART several weeks to reduce fatal IRIS risk
- Do not treat a positive cryptococcal antigen or CNS lesion as routine HIV alone — advanced AIDS with neurologic symptoms needs urgent targeted evaluation
Overview
Opportunistic infections in HIV occur because progressive CD4 T-cell depletion impairs cell-mediated immunity. The specific infection strongly correlates with CD4 count: PCP below 200, toxoplasmosis below 100, and CMV retinitis or disseminated MAC below 50. ART is the most important intervention, but acute OI treatment, prophylaxis, and ART timing vary by pathogen. Step 2 CK questions often test CD4 thresholds, classic presentations, and when to add adjunctive corticosteroids or delay ART.
Epidemiology
In the ART era, opportunistic infections are most common in patients with undiagnosed HIV, poor access to care, medication nonadherence, drug resistance, or interrupted therapy. PCP remains one of the most common AIDS-defining illnesses in the United States. CMV retinitis and disseminated MAC are now less common but remain high-yield in patients with CD4 counts below 50 cells/mm3.
Clinical Features
Symptoms
PCP: subacute fever, progressive dyspnea, nonproductive cough, pleuritic chest discomfort, exertional hypoxemia
Toxoplasmosis: headache, fever, confusion, seizures, or focal neurologic deficits in CD4 <100
CMV retinitis: floaters, scotoma, blurry vision, or painless vision loss in CD4 <50
Disseminated MAC: prolonged fever, night sweats, weight loss, abdominal pain, diarrhea, anemia in CD4 <50
Cryptococcal meningitis: headache, fever, nausea, photophobia, altered mental status; meningismus may be absent
Esophageal candidiasis: odynophagia or dysphagia in advanced HIV
Signs
PCP may have a normal lung exam despite severe hypoxemia
Toxoplasmosis: focal deficits, cranial nerve palsies, papilledema, or seizures
CMV retinitis: fluffy white retinal lesions with hemorrhage, classically "pizza pie" appearance
Cryptococcosis: elevated intracranial pressure, papilledema, cranial nerve palsies
MAC: hepatosplenomegaly, lymphadenopathy, pallor from anemia
Investigations
First-line
CD4 count and HIV viral loadFrames the differential and prophylaxis needs; CD4 thresholds are heavily tested
Chest X-ray and pulse oximetry / ABG for suspected PCPCXR may show bilateral diffuse interstitial infiltrates or be normal; ABG identifies severe disease requiring steroids
Toxoplasma IgGPositive IgG supports reactivation risk; negative IgG makes toxoplasmosis less likely
Dilated ophthalmologic exam for suspected CMV retinitisDiagnosis is usually clinical by experienced retinal examination; do not wait for blood CMV PCR if vision threatened
Second-line
CT or MRI brain with contrastToxoplasmosis usually shows multiple ring-enhancing lesions in basal ganglia or corticomedullary junction; primary CNS lymphoma is key differential
Serum cryptococcal antigen and lumbar punctureOpening pressure, CSF cryptococcal antigen, fungal culture; measure opening pressure every time
AFB blood culturesFor disseminated MAC when CD4 <50 with fever, weight loss, anemia, and high alkaline phosphatase
Specialist
Bronchoscopy with BALIf PCP diagnosis uncertain or patient does not improve; silver stain or PCR detects Pneumocystis
Brain biopsyIf ring-enhancing lesions fail to improve after 10-14 days of empiric toxoplasmosis therapy or if Toxoplasma IgG negative and lymphoma suspected
Management
NIH/CDC/HIVMA/IDSA Guidelines for Opportunistic Infections in Adults and Adolescents With HIV1
PCP
- Treatment: TMP-SMX high dose for 21 days
- Add prednisone if PaO2 <70 mmHg on room air or A-a gradient >=35 mmHg
- Alternatives: clindamycin-primaquine, IV pentamidine, atovaquone for mild disease
- Prophylaxis: TMP-SMX when CD4 <200, oropharyngeal candidiasis, or prior PCP; stop after CD4 >200 for >=3 months on ART
2
Toxoplasma gondii encephalitis
- Empiric treatment for typical ring-enhancing lesions in AIDS: pyrimethamine + sulfadiazine + leucovorin, or TMP-SMX
- Chronic maintenance until immune reconstitution
- Prophylaxis: TMP-SMX if CD4 <100 and Toxoplasma IgG positive
- If no clinical/radiographic improvement by 10-14 days, evaluate for CNS lymphoma or alternative diagnosis
3
CMV disease
- CMV retinitis: valganciclovir PO or IV ganciclovir; urgent ophthalmology, intravitreal therapy if sight-threatening
- CMV colitis/esophagitis: IV ganciclovir then valganciclovir
- Blood CMV PCR alone does not diagnose end-organ disease
4
Disseminated MAC
- Treat with azithromycin or clarithromycin plus ethambutol; add rifabutin in severe disease or high bacterial burden
- Primary prophylaxis with azithromycin is generally not needed if ART is started immediately
- Rule out active MAC before starting prophylaxis in patients with compatible systemic symptoms
5
Cryptococcal meningitis
- Induction: liposomal amphotericin B plus flucytosine, then consolidation/maintenance fluconazole
- Aggressively manage elevated opening pressure with repeated therapeutic lumbar punctures
- Delay ART initiation, commonly 4-6 weeks after starting antifungals in cryptococcal meningitis, to reduce severe CNS IRIS
Complications
- Respiratory failure: Severe PCP can progress to ARDS, especially with delayed therapy
- Permanent vision loss: CMV retinitis can rapidly destroy retina without treatment
- Mass effect and seizures: Toxoplasmosis lesions can cause herniation or focal epilepsy
- Raised intracranial pressure: Cryptococcal meningitis mortality is driven by uncontrolled ICP
- IRIS: Worsening inflammation after ART, particularly with TB, cryptococcus, MAC, CMV, and PCP
USMLE Step 2 CK Exam Tips
- 1CD4 <200 + dry cough + bilateral interstitial infiltrates + high LDH = PCP; treat TMP-SMX, add steroids if PaO2 <70
- 2CD4 <100 + multiple ring-enhancing brain lesions = toxoplasmosis until proven otherwise; empiric therapy before biopsy
- 3Single ring-enhancing lesion or no improvement after toxo therapy = consider primary CNS lymphoma
- 4CD4 <50 + floaters/painless vision loss = CMV retinitis; urgent ophthalmology and valganciclovir/ganciclovir
- 5Cryptococcal meningitis requires opening pressure measurement and repeated LPs; do not just give antifungals
- 6MAC prophylaxis is no longer automatic if effective ART can start immediately
- 7TMP-SMX is a high-yield prophylaxis answer because it prevents both PCP and toxoplasmosis
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