# CD4 Count and Opportunistic Infections

> What CD4 count thresholds predict which opportunistic infections?

The CD4 cutoffs at 200, 100 and 50 that tell you which opportunistic infection a question stem is describing, and which drug prevents it.

CD4 below 200 cells/mm³ predicts Pneumocystis jirovecii pneumonia; below 100 adds Toxoplasma encephalitis, cryptococcal meningitis and Candida esophagitis; below 50 adds disseminated Mycobacterium avium complex, CMV retinitis and CNS lymphoma. Between 200 and 500, expect thrush, zoster and bacterial pneumonia. Tuberculosis and Kaposi sarcoma occur at any count.

## What CD4 count thresholds predict which opportunistic infections?

CD4 count predicts which organism a patient with HIV presents with, and stems hinge on three cutoffs: **200, 100 and 50 cells/mm³**. Between 200 and 500, infections still look ordinary -- bacterial pneumonia, zoster, thrush.

Below **200**, *Pneumocystis jirovecii* pneumonia becomes the defining risk. Below **100**, parasites, yeasts and reactivating viruses arrive: *Toxoplasma gondii* encephalitis, *Cryptococcus neoformans* meningitis, *Candida* esophagitis, chronic *Cryptosporidium* diarrhea and PML. Below **50**, surveillance is gone -- disseminated *Mycobacterium avium* complex, CMV retinitis, primary CNS lymphoma.

**Tuberculosis and Kaposi sarcoma occur at any CD4 count**, so a normal number never excludes them; only the presentation shifts. Anchor every stem to this ladder in [Infectious Disease](/topics/infectious-disease).

## The CD4 threshold table worth memorizing

Thirteen infections cover nearly every opportunistic-infection question, with threshold, prophylaxis and treatment.

| CD4 threshold | Infection | Classic presentation | Prophylaxis | Treatment |
| --- | --- | --- | --- | --- |
| Any count | Tuberculosis | Cough, night sweats; miliary if low | Isoniazid + pyridoxine (latent TB) | RIPE |
| Any count | Kaposi sarcoma (HHV-8) | Violaceous skin/palatal plaques | None | ART; chemotherapy if visceral |
| <500 | Oral candidiasis (thrush) | White plaques that scrape off | None | Clotrimazole troches |
| <200 | *Pneumocystis jirovecii* pneumonia | Dry cough, hypoxia, diffuse infiltrates, ↑ LDH | TMP-SMX | TMP-SMX; steroids if PaO2 <70 mmHg |
| <150 | Disseminated histoplasmosis | Fever, hepatosplenomegaly, pancytopenia; intracellular yeast | Itraconazole if hyperendemic | Amphotericin B, then itraconazole |
| <100 | *Toxoplasma* encephalitis | Ring-enhancing basal ganglia lesions | TMP-SMX if Toxoplasma IgG positive | Pyrimethamine + sulfadiazine + leucovorin |
| <100 | Cryptococcal meningitis | Headache, ↑ opening pressure, CSF antigen positive | None | Amphotericin B + flucytosine, then fluconazole |
| <100 | *Candida* esophagitis | Odynophagia with thrush; linear ulcers | None | Fluconazole |
| <100 | Cryptosporidiosis | Chronic watery diarrhea; acid-fast oocysts | None | ART; nitazoxanide adjunct |
| <200 (usually <100) | Progressive multifocal leukoencephalopathy | Progressive deficits, non-enhancing white matter | None | ART alone; no antiviral |
| <50 | Disseminated *Mycobacterium avium* complex | Fever, weight loss, anemia, ↑ alk phos | Azithromycin weekly | Clarithromycin + ethambutol |
| <50 | CMV retinitis | Painless ↓ vision, floaters, "pizza-pie" retina | None | Valganciclovir |
| <50 | Primary CNS lymphoma (EBV) | Solitary periventricular mass | None | ART + methotrexate or radiation |

## What makes an HIV infection AIDS

AIDS is diagnosed when the CD4 count falls below **200 cells/mm³**, the **CD4 percentage falls below 14%**, or any AIDS-defining condition appears regardless of count.

AIDS-defining conditions include *Pneumocystis* pneumonia, esophageal candidiasis, disseminated MAC, CMV disease, extrapulmonary cryptococcosis, cerebral toxoplasmosis, PML, Kaposi sarcoma, CNS lymphoma, invasive cervical cancer, tuberculosis and HIV wasting.

Staging never reverses: treatment that restores the count above 200 stops the prophylaxis, not the label. The percentage criterion matters because absolute counts swing with illness.

## How HIV is diagnosed, and why viral load tracks treatment

Screening begins with a **fourth-generation antigen/antibody immunoassay**, detecting **p24 antigen** plus HIV-1 and HIV-2 antibodies two to three weeks after exposure. A reactive screen goes to an **HIV-1/HIV-2 antibody differentiation immunoassay**, which identifies the type; a negative or indeterminate result triggers an **HIV-1 nucleic acid test**. Western blot is gone.

Acute HIV has a signature: reactive screen, negative differentiation assay, positive nucleic acid test with high viral load. Infants under 18 months carry maternal IgG and need nucleic acid testing.

**Viral load, not CD4 count, measures whether therapy is working.** Suppression follows within weeks; CD4 recovery lags months. Detectable virus means resistance or non-adherence, where regimen choice matters -- see [HIV antiretroviral drugs](/blog/hiv-antiretroviral-drugs-usmle).

## Telling toxoplasmosis, CNS lymphoma and PML apart

Three CNS processes dominate advanced HIV; imaging plus CSF separates them.

| Feature | *Toxoplasma* encephalitis | Primary CNS lymphoma | PML |
| --- | --- | --- | --- |
| Lesions | Multiple, basal ganglia and grey-white junction | Usually solitary, periventricular | Multiple, subcortical white matter |
| Enhancement | Ring-enhancing with edema | Weak ring or homogeneous; crosses corpus callosum | Non-enhancing |
| Mass effect | Present | Present | Absent |
| CSF and serology | Toxoplasma IgG positive | EBV DNA positive in CSF | JC virus PCR positive in CSF |
| Next step | Empiric therapy, reimage at 2 weeks | Biopsy, then chemotherapy or radiation | Start ART; supportive care |

Multiple ring-enhancing lesions under 100 justify empiric anti-toxoplasma therapy; **failure to shrink at repeat imaging in two weeks** triggers biopsy. Cryptococcus causes meningitis, not mass lesions -- see the [meningitis differential](/blog/meningitis-bacterial-viral-fungal-usmle).

## When to stop prophylaxis, and why IRIS is not treatment failure

Prophylaxis stops once therapy holds the count above threshold. Discontinue *Pneumocystis* and toxoplasmosis prophylaxis after three months above 200 on suppressive therapy, restarting if the count falls back. Stop MAC prophylaxis and CMV or cryptococcal maintenance after three suppressed months above 100.

**Immune reconstitution inflammatory syndrome (IRIS)** is paradoxical worsening weeks after therapy starts, worst at very low baseline counts; tuberculosis, MAC, cryptococcal meningitis and CMV are the classic triggers. Continue therapy, treat the unmasked organism, add steroids if severe. In cryptococcal meningitis, defer therapy until after antifungal induction.

## If you only remember one thing

Five numbers carry most of the exam value.

> **Exam-day cheat sheet**
> 1. Under 200 -> *Pneumocystis*. TMP-SMX prevents and treats it.
> 2. Under 100 -> Toxoplasma, Cryptococcus, *Candida* esophagitis, PML.
> 3. Under 50 -> MAC, CMV retinitis, CNS lymphoma.
> 4. AIDS = CD4 <200, CD4% <14%, or any AIDS-defining condition.
> 5. Viral load grades the drugs; CD4 grades the immune system.

## How this is tested on the exam

**CD4 of 30, painless vision loss, floaters, fluffy retinal infiltrates.** Answer: CMV retinitis; give valganciclovir.

**CD4 of 80, headache for a week, several ring-enhancing basal ganglia lesions.** Answer: cerebral toxoplasmosis; pyrimethamine, sulfadiazine and leucovorin, then reimage.

**Baseline CD4 of 20, fever and enlarging nodes two weeks after therapy starts.** Answer: IRIS; continue therapy, treat the unmasked infection.

## Common wrong-answer traps

**Trap: stopping antiretroviral therapy when the patient worsens.** Early deterioration is usually IRIS, not drug failure -- continue and treat the organism.

**Trap: assuming a normal CD4 count excludes serious disease.** Tuberculosis and Kaposi sarcoma appear at any count, and acute HIV presents as mononucleosis with a negative antibody test.

**Trap: judging the regimen by the CD4 count.** Viral load defines success; a slowly recovering count with undetectable virus is expected.

## Sources

- [CDC -- HIV](https://www.cdc.gov/hiv/)
- [IDSA practice guidelines](https://www.idsociety.org/practice-guideline/practice-guidelines/)
- [USMLE Step 2 CK content outline](https://www.usmle.org/step-exams/step-2-ck)

HIV questions reward one reflex: read the CD4 count first. [Practice HIV/AIDS questions on StepGenie](https://dashboard.stepgenie.app/sign-up) and drill the thresholds, prophylaxis and CNS lesion split.

## Frequently asked questions

### At what CD4 count do you start Pneumocystis prophylaxis?

Start Pneumocystis prophylaxis when the CD4 count falls below 200 cells/mm³, and also when the CD4 percentage is below 14% or the patient has oropharyngeal candidiasis or another AIDS-defining illness. TMP-SMX is first line and conveniently covers toxoplasmosis as well; dapsone, atovaquone or aerosolized pentamidine substitute when sulfa is not tolerated. Stop once antiretroviral therapy holds the count above 200 for more than three months.

### How do you distinguish cerebral toxoplasmosis from primary CNS lymphoma?

Toxoplasmosis produces multiple ring-enhancing lesions in the basal ganglia and at the grey-white junction in a patient with positive Toxoplasma IgG, while primary CNS lymphoma is usually a single periventricular mass with EBV DNA detectable in the cerebrospinal fluid. Because the imaging overlaps, treat empirically for toxoplasmosis and repeat imaging after two weeks; lesions that fail to shrink are the indication for brain biopsy.

### Can a patient have AIDS with a CD4 count above 200?

Yes. AIDS is defined by a CD4 count below 200 cells/mm³, a CD4 percentage below 14%, or any AIDS-defining condition regardless of the count. Kaposi sarcoma, tuberculosis and invasive cervical cancer can appear at higher counts and still establish the diagnosis. The classification also never reverses: once a patient meets criteria, treatment that restores the count does not undo the diagnosis.

### What is immune reconstitution inflammatory syndrome in HIV?

IRIS is paradoxical clinical worsening in the weeks after antiretroviral therapy begins, caused by a recovering immune system mounting inflammation against organisms it previously ignored. Risk is highest when the starting CD4 count is very low and the viral load very high, and tuberculosis, Mycobacterium avium complex, cryptococcal meningitis and CMV are the classic triggers. Continue antiretroviral therapy, treat the unmasked infection, and add corticosteroids in severe cases.

### Which test detects HIV before antibodies appear?

HIV-1 nucleic acid testing detects viral RNA earliest, within roughly two weeks of exposure, and the p24 antigen measured by the fourth-generation immunoassay turns positive shortly after; antibodies take three to four weeks. Acute HIV therefore shows a reactive fourth-generation screen, a negative HIV-1/HIV-2 antibody differentiation assay, and a positive nucleic acid test with a very high viral load.

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