Opportunistic Infections in HIV for USMLE Step 1 & 2 CK

Learn high-yield opportunistic infections in HIV by CD4 count, with key pathogens, imaging clues, prophylaxis, and treatment for USMLE Step 1 and Step 2 CK.

Why Opportunistic Infections in HIV Matter for Step Exams

On USMLE Step 1 and Step 2 CK, opportunistic infections in HIV are classic, high-yield territory. Questions often anchor around **CD4⁺ T-cell thresholds**, characteristic **clinical and radiologic findings**, and decisions about **when to start or stop prophylaxis and treatment**.

For respiratory and systemic infections in advanced HIV, you must be able to:

• Match **specific pathogens** to **CD4 count ranges**.
• Recognize **imaging patterns** (e.g., ground-glass opacities, ring-enhancing brain lesions, retinal findings).
• Choose appropriate **diagnostic tests**, **first-line therapies**, and **prophylaxis regimens**.

Mastering these patterns will help you quickly decode Step-style vignettes and avoid common pitfalls on both **USMLE Step 1** and **USMLE Step 2 CK**.

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Pathophysiology: CD4 Decline and Predictable Infections

As **CD4⁺ T-cell counts decline** in untreated HIV infection, **T-cell–mediated immunity** becomes progressively impaired. This immunologic decline leads to a **predictable sequence of opportunistic infections**, which serve as clinical milestones and guide prophylaxis decisions.

CD4 Thresholds and Key Opportunistic Infections

| CD4 count (cells/µL) | Common opportunistic infections | |----------------------|----------------------------------| | > 500 | Usually none; bacterial pneumonia and tuberculosis may still occur | | 200–500 | Reactivation of *Mycobacterium tuberculosis*, herpes zoster, oral thrush (*Candida*) | | < 200 | *Pneumocystis jirovecii* pneumonia (PJP) | | < 100 | *Toxoplasma gondii* encephalitis, disseminated *Mycobacterium avium* complex (MAC) | | < 50 | Cytomegalovirus (CMV) retinitis, disseminated MAC, other severe infections |

**Step 1 focus:**

• Memorize these **CD4 thresholds** and associated pathogens.
• Link them to **impaired T-cell–mediated immunity** and to classic **radiologic or histologic findings**.

**Step 2 CK focus:**

• Expect vignettes emphasizing **symptoms, imaging, and labs**.
• Know **when to initiate or discontinue prophylaxis** and how to manage acute infections alongside **antiretroviral therapy (ART)**.

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Clinical Presentation of Major Opportunistic Infections

Pneumocystis jirovecii Pneumonia (PJP)

• **CD4 level:** < 200 cells/µL
• **Epidemiology:** Most common opportunistic pneumonia in advanced HIV.
• **Symptoms:**
• Subacute **dry cough**
• **Progressive dyspnea**
• **Low-grade fever**
• **Exam/Imaging:**
• **Bilateral diffuse interstitial** or **ground-glass opacities** on chest CT or X-ray

**Step 1 pearls:**

• Recognize **silver stain** appearance of **“cup-shaped” cysts**.
• Classify *P. jirovecii* as a **yeast-like fungus**.

**Step 2 CK pearls:**

• Identify **hypoxemia disproportionate to imaging findings**.
• Understand that **early TMP-SMX and adjunctive steroids** improve survival.

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Toxoplasma gondii Encephalitis

• **CD4 level:** < 100 cells/µL
• **Pathogenesis:** Reactivation of **latent infection** acquired from **undercooked meat** or **cat feces exposure**.
• **Clinical features:**
• **Headache**
• **Confusion**
• **Seizures**
• **Focal neurologic deficits**
• **Imaging:**
• **Multiple ring-enhancing lesions** with surrounding **edema** on MRI or CT

**Step 1 pearls:**

• Differentiate **Toxoplasma lesions** from **CNS lymphoma**:
• Toxoplasma: usually **multiple** lesions.
• CNS lymphoma: usually **solitary**, **EBV-positive**.
• Recall **folate antagonist mechanisms** and **leucovorin rescue**.

**Step 2 CK pearls:**

• In patients with **multiple ring-enhancing brain lesions** and **CD4 < 100**, start **empiric anti-Toxoplasma therapy** before biopsy.
• **Clinical improvement within 1–2 weeks** supports the diagnosis.

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Mycobacterium avium Complex (MAC)

• **CD4 level:** < 100 cells/µL (disseminated disease)
• **Source:** Environmental exposure; **non-tuberculous mycobacterium**.
• **Symptoms:**
• **Fever**
• **Weight loss**
• **Diarrhea**
• **Anemia**
• **Elevated alkaline phosphatase**

**Step 1 pearls:**

• Recognize MAC as an **acid-fast**, **non-tuberculous mycobacterium** from **environmental sources**.

**Step 2 CK pearls:**

• Systemic symptoms plus **markedly elevated alkaline phosphatase** in AIDS strongly suggest **disseminated MAC**.

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Cytomegalovirus (CMV) Retinitis

• **CD4 level:** < 50 cells/µL
• **Pathogenesis:** Reactivation of **latent CMV infection**.
• **Symptoms:**
• **Floaters**
• **Blurred vision**
• **Scotomata** (visual field defects)
• Possible **retinal detachment**
• **Fundoscopy:**
• **Fluffy yellow-white retinal infiltrates with hemorrhages**
• Classic **“pizza pie” appearance**

**Step 1 pearls:**

• Identify CMV’s **“owl’s-eye” intranuclear inclusions**.
• Classify CMV as a **DNA virus**.
• Differentiate from **HSV retinitis**, which typically causes **peripheral necrosis**.

**Step 2 CK pearls:**

• Sudden **vision changes** in an AIDS patient with **CD4 < 50** require **urgent ophthalmologic evaluation**.
• Early antiviral therapy plus ART supports **vision preservation** and long-term recovery.

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Other Notable Opportunistic Pathogens

These organisms are also high-yield in advanced HIV and can appear in both Step 1 and Step 2 CK vignettes.

| Pathogen | Key findings | CD4 threshold (cells/µL) | |---------------------------|------------------------------------------------------------------------------|--------------------------| | *Bartonella henselae* | **Bacillary angiomatosis**—vascular skin lesions resembling Kaposi sarcoma; **Warthin-Starry stain positive** | < 100 | | *Histoplasma capsulatum* | **Disseminated disease** with **hepatosplenomegaly**; **oval yeasts within macrophages** (silver stain) | < 150 | | *Cryptococcus neoformans* | **Meningitis** diagnosed via **India ink** or **cryptococcal antigen test** | < 100 |

**Step 1 pearls:**

• Recognize classic stains:
• **Warthin-Starry** for *Bartonella*.
• **Silver stain** for *Histoplasma*.
• **India ink** for *Cryptococcus*.
• Understand each organism’s **morphology** and **environmental reservoir** (as described in your primary resources).

**Step 2 CK pearls:**

• Differentiate **vascular skin lesions** of **Bartonella (bacillary angiomatosis)** from **Kaposi sarcoma**.
• Emphasize **empiric therapy** and **diagnostic confirmation strategies** for disseminated fungal infections.

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Diagnostic Approach: Labs, Imaging, and Key Tests

On USMLE Step 1 and Step 2 CK, you will often be asked to choose the **best next diagnostic test** or interpret a **classic imaging or stain**.

PJP

• **Imaging:**
• Chest X-ray or CT: **bilateral diffuse interstitial** or **ground-glass opacities**.
• **Definitive diagnosis:**
• **Direct fluorescent antibody (DFA) staining** or **PCR** from **induced sputum** or **bronchoalveolar lavage (BAL)**.

Toxoplasma gondii Encephalitis

• **Imaging:**
• MRI or CT: **multiple ring-enhancing lesions** with **surrounding edema**.
• **Laboratory:**
• **Positive serum IgG** supports **reactivation**.
• **Definitive diagnosis:**
• **Brain biopsy** if diagnosis remains uncertain after empiric therapy.

Mycobacterium avium Complex

• **Laboratory clues:**
• **Anemia**
• **Elevated alkaline phosphatase**
• **Definitive diagnosis:**
• **Blood cultures** or **bone marrow biopsy** showing **acid-fast bacilli**.

CMV Retinitis

• **Clinical exam:**
• **Fundoscopy** showing **fluffy yellow-white retinal infiltrates with hemorrhages** ("pizza pie" retina).
• **Histology (Step 1):**
• **“Owl’s-eye” intranuclear inclusions** in CMV-infected cells.

Other Pathogens

• *Bartonella henselae*:
• **Warthin-Starry stain** positive in bacillary angiomatosis lesions.
• *Histoplasma capsulatum*:
• **Oval yeasts within macrophages** on **silver stain**.
• *Cryptococcus neoformans*:
• **India ink** or **cryptococcal antigen test** for meningitis.

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Management & Prevention: Treatment and Prophylaxis by CD4 Count

A major Step 2 CK theme is knowing **when to start prophylaxis**, **what to use**, and **when to stop** after immune recovery on ART.

PJP: Treatment and Prophylaxis

• **Treatment:**
• **Trimethoprim-sulfamethoxazole (TMP-SMX)**.
• Add **corticosteroids** if:
• **PaO₂ < 70 mmHg** or
• **A–a gradient ≥ 35 mmHg**.
• **Prophylaxis:**
• Start **TMP-SMX** when:
• **CD4 < 200 cells/µL**, or
• Presence of **oropharyngeal candidiasis**.
• **Duration (Step 2 CK):**
• Continue prophylaxis until **CD4 > 200** for **≥ 3 months** on ART.

Toxoplasma gondii Encephalitis

• **Treatment:**
• **Pyrimethamine + sulfadiazine + leucovorin**.
• **Prophylaxis:**
• **TMP-SMX** when:
• **CD4 < 100** and
• **Positive Toxoplasma IgG**.
• **Step 2 CK strategy:**
• In a patient with **CD4 < 100** and **multiple ring-enhancing lesions**, start **empiric therapy** before biopsy.

Mycobacterium avium Complex

• **Treatment:**
• **Macrolide** (azithromycin or clarithromycin) + **ethambutol** ± **rifabutin**.
• **Prophylaxis:**
• **Azithromycin weekly** when **CD4 < 50** until immune recovery.
• **Stopping prophylaxis (Step 1/2 concept):**
• Prophylaxis is discontinued after **immune reconstitution on ART**.

CMV Retinitis

• **Treatment:**
• **Valganciclovir** or **IV ganciclovir**.
• **Intravitreal therapy** for severe disease.
• **Prophylaxis:**
• **Not routinely recommended**.
• Focus on **maintaining ART** for immune recovery.

Other Pathogens

• *Bartonella henselae*, *Histoplasma capsulatum*, and *Cryptococcus neoformans*:
• Emphasis on **recognizing the infection** and initiating **appropriate empiric therapy**, then confirming with **stains/antigen tests**.

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High-Yield Differentials & Pitfalls

USMLE questions often test your ability to distinguish between **similar-appearing conditions** and avoid common traps.

CNS Lesions in Advanced HIV

| Feature | Toxoplasma encephalitis | Primary CNS lymphoma | |---------------------------|--------------------------------------------------|--------------------------------------| | CD4 threshold | < 100 | Very low CD4 (advanced AIDS) | | Number of lesions | **Multiple** ring-enhancing lesions | Usually **solitary** lesion | | Association | Reactivation of latent *Toxoplasma* (IgG+) | **EBV-positive** tumor | | Initial management (Step 2 CK) | **Empiric anti-Toxoplasma therapy** first | Often biopsy if no response to therapy |

**Pitfall:** Jumping to brain biopsy before a trial of **empiric anti-Toxoplasma therapy** in a classic presentation.

Vascular Skin Lesions in HIV

• **Bacillary angiomatosis (Bartonella henselae):**
• Vascular skin lesions **resembling Kaposi sarcoma**.
• **Warthin-Starry stain positive**.
• **Kaposi sarcoma:**
• Also vascular lesions, but not Warthin-Starry positive.

**Pitfall:** Failing to order appropriate stains and misclassifying **Bartonella** lesions as Kaposi sarcoma.

Respiratory Symptoms in Advanced HIV

• **PJP:**
• **Subacute dry cough**, **progressive dyspnea**, **low-grade fever**.
• **Diffuse interstitial/ground-glass opacities**.
• **Hypoxemia out of proportion** to imaging.
• **Bacterial pneumonia or TB (> 500–200 range):**
• Often more **focal** infiltrates.

**Pitfall:** Overlooking PJP because the chest X-ray seems “mild” compared with the degree of dyspnea.

Visual Changes in Advanced HIV

• **CMV retinitis:**
• **Floaters**, **blurred vision**, **scotomata**.
• **“Pizza pie”** retina: fluffy yellow-white infiltrates with hemorrhages.
• **HSV retinitis:**
• Typically causes **peripheral necrosis**.

**Pitfall:** Not recognizing that **sudden visual changes** with **CD4 < 50** require **urgent ophthalmologic evaluation** and early antiviral therapy.

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Exam Vignette with Stepwise Reasoning

**Vignette:**

A 36-year-old man with untreated HIV presents with 2 weeks of progressive shortness of breath and nonproductive cough. He has had low-grade fevers and increasing fatigue. His CD4 count is 120 cells/µL. On exam, he is tachypneic with an oxygen saturation of 88% on room air. Chest X-ray shows bilateral diffuse interstitial infiltrates. Arterial blood gas reveals a PaO₂ of 65 mmHg. Induced sputum is obtained for diagnostic testing.

**Question:** Which of the following is the most appropriate initial treatment?

A. Azithromycin monotherapy

B. Valganciclovir

C. TMP-SMX plus corticosteroids

D. Pyrimethamine, sulfadiazine, and leucovorin

**Stepwise reasoning:**

• CD4 count **< 200** → high risk for **PJP**.
• Symptoms: **subacute dry cough**, **progressive dyspnea**, **low-grade fever**.
• Imaging: **bilateral diffuse interstitial infiltrates**.
• PaO₂ **< 70 mmHg** (65 mmHg) → meets criteria for **adjunctive corticosteroids**.
• First-line therapy for PJP is **TMP-SMX**.

**Correct answer: C. TMP-SMX plus corticosteroids**

• **Azithromycin** is used for **MAC prophylaxis** when CD4 < 50.
• **Valganciclovir** is used for **CMV retinitis**.
• **Pyrimethamine + sulfadiazine + leucovorin** is used for **Toxoplasma gondii encephalitis**.

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Key Takeaways

• **CD4 thresholds are central**: memorize which infections appear at **> 500, 200–500, < 200, < 100, and < 50** cells/µL.
• **PJP (CD4 < 200):** subacute dry cough, dyspnea, ground-glass opacities; diagnose with **DFA or PCR** from induced sputum/BAL; treat with **TMP-SMX ± steroids**.
• **Toxoplasma encephalitis (CD4 < 100):** multiple **ring-enhancing lesions**; treat with **pyrimethamine + sulfadiazine + leucovorin**; start **empiric therapy** before biopsy.
• **MAC (CD4 < 100, < 50 for prophylaxis):** fever, weight loss, diarrhea, anemia, **elevated alkaline phosphatase**; treat with **macrolide + ethambutol ± rifabutin**; prophylax with **weekly azithromycin** when CD4 < 50.
• **CMV retinitis (CD4 < 50):** floaters, blurred vision, **“pizza pie”** retina; treat with **valganciclovir or IV ganciclovir**, plus intravitreal therapy if severe.
• **Stains and morphology are Step 1 gold:** silver stain for **PJP and Histoplasma**, **Warthin-Starry** for *Bartonella*, **India ink** for *Cryptococcus*, **owl’s-eye inclusions** for CMV.
• **Prophylaxis decisions and ART timing** are Step 2 CK priorities: know when to **start** and **stop** prophylaxis based on **CD4 recovery**.

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Keep Learning

To solidify these concepts for **USMLE Step 1** and **Step 2 CK**, actively quiz yourself on:

• Matching **CD4 counts to pathogens**.
• Recognizing **imaging and stain patterns**.
• Choosing **prophylaxis and treatment** based on CD4 level and clinical presentation.

You can continue building your clinical reasoning skills and pattern recognition across other high-yield topics by exploring more resources on our core concepts at /core-concepts and integrating them into your regular question practice at /build. Repeated exposure to these opportunistic infection patterns will make HIV vignettes some of the most straightforward points on your exam.