Opportunistic Infections in Advanced HIV: Presentation & Treatment

Overview: the CD4 count as a map

Thresholds. The CD4 count predicts which opportunists can emerge. Tuberculosis and bacterial pneumonia occur at any count, and oral thrush signals a CD4 falling toward the Pneumocystis range.

Principles. Classic syndromes are treated empirically while confirmatory tests run. Each treated infection is followed by maintenance therapy (secondary prophylaxis) until ART restores the CD4 count. ART itself is started early, usually within 2 weeks, because immune recovery is what ultimately controls these pathogens.

Pneumocystis pneumonia

Organism. Pneumocystis jirovecii is a fungus that cannot be cultured. Its membrane contains cholesterol rather than ergosterol, so azoles and amphotericin are useless against it.

Presentation. Weeks of progressive exertional dyspnea, dry cough, and low-grade fever, often with thrush, at CD4 <200. The lung exam may be normal, but saturation falls sharply with ambulation. LDH is elevated (sensitive, not specific). The chest film shows bilateral perihilar interstitial or ground-glass opacities; if it is normal, CT reveals patchy ground-glass. Subpleural cysts can rupture, so a spontaneous pneumothorax in AIDS should prompt a search for PJP. Pleural effusion or bulky adenopathy points elsewhere (TB, Kaposi sarcoma, lymphoma).

Diagnosis. Induced sputum with methenamine silver or immunofluorescent stain (or PCR) comes first; if negative, bronchoscopy with BAL (sensitivity >90%). An elevated serum β-D-glucan supports the diagnosis. Never delay treatment: organisms stay detectable for days to weeks after therapy begins.

Treatment. High-dose TMP-SMX (15–20 mg/kg/day of trimethoprim, IV or oral) for 21 days. Add prednisone within 72 hours when room-air PaO2 is <70 mmHg or the A–a gradient is ≥35 mmHg: 40 mg twice daily on days 1–5, 40 mg daily on days 6–10, then 20 mg daily through day 21. Steroids blunt the inflammatory surge from dying organisms and reduce respiratory failure and death. TMP-SMX toxicity includes rash, cytopenias, transaminitis, hyperkalemia (trimethoprim blocks the collecting-duct sodium channel, like amiloride), and a creatinine rise from blocked tubular secretion.

• Primaquine + clindamycin: mild to severe disease; screen G6PD first because primaquine causes oxidant hemolysis and methemoglobinemia.
• Atovaquone: mild disease only; absorption requires a fatty meal.
• IV pentamidine: severe disease; hypoglycemia followed by diabetes, pancreatitis, nephrotoxicity, hypotension, and QT prolongation.

Dapsone alone and aerosolized pentamidine are prophylactic options, not treatment for active pneumonia.

Focal brain lesions: toxoplasmosis, lymphoma, and PML

Toxoplasmosis. Latent cysts (acquired from undercooked meat or cat feces) reactivate in Toxoplasma IgG-positive patients with CD4 <100, producing fever, headache, confusion, seizures, and focal deficits. MRI, more sensitive than CT, shows multiple ring-enhancing lesions with edema at the gray-white junction and basal ganglia. A negative IgG makes toxoplasmosis unlikely.

Empiric therapy. Pyrimethamine + sulfadiazine + leucovorin for at least 6 weeks, then lower-dose maintenance; with sulfa allergy, pyrimethamine + clindamycin + leucovorin, and TMP-SMX is another option. Leucovorin (folinic acid) is already reduced, so it bypasses pyrimethamine's DHFR block and protects the marrow; folic acid does not. Steroids are reserved for mass effect. Clinical and MRI improvement is expected within about 2 weeks; without it, stereotactic brain biopsy is next.

Primary CNS lymphoma. An EBV-driven diffuse large B-cell lymphoma at CD4 <50, typically a single, irregularly enhancing periventricular mass, often in a Toxoplasma IgG-negative patient. CSF EBV DNA PCR and a hot thallium SPECT or hypermetabolic PET (toxoplasmosis is cold) support it; brain biopsy confirms. Avoid steroids before biopsy when possible, because they can shrink lymphoma and make the biopsy nondiagnostic. Treatment is ART plus high-dose methotrexate-based therapy.

Progressive multifocal leukoencephalopathy. JC polyomavirus reactivates and destroys oligodendrocytes, causing weeks of progressive hemiparesis, aphasia, visual field loss, ataxia, and cognitive decline without fever or headache. MRI shows asymmetric T2/FLAIR subcortical white-matter lesions without enhancement or mass effect; CSF JC virus PCR confirms. No antiviral works (cidofovir failed), so ART is the treatment. PML also follows natalizumab and rituximab, and PML-IRIS after ART can make lesions enhance.

Cryptococcal meningitis

Presentation. Cryptococcus neoformans, an encapsulated yeast from soil contaminated by pigeon droppings, is inhaled and seeds the meninges at CD4 <100. Headache, fever, and malaise build over 1–2 weeks, often without neck stiffness. Confusion, cranial nerve palsies, papilledema, and vision loss reflect raised intracranial pressure; umbilicated skin papules can mark dissemination.

Diagnosis. Serum cryptococcal antigen (CrAg) is a sensitive screen, and a positive result mandates LP. CSF shows a high opening pressure (often >25 cm H2O), few lymphocytes, low glucose, high protein, and a positive CrAg (>95% sensitive); India ink shows encapsulated budding yeast but misses some cases.

Intracranial pressure. Raised pressure drives much of the early mortality. With opening pressure ≥25 cm H2O and symptoms, remove CSF daily by therapeutic LP until the pressure normalizes; persistent elevation may need a lumbar drain or shunt. Acetazolamide, mannitol, and corticosteroids do not help, and dexamethasone worsened outcomes.

Amphotericin B causes nephrotoxicity, hypokalemia, hypomagnesemia, and infusion reactions; flucytosine causes marrow suppression, worse with renal dysfunction.

CMV, esophagitis, and disseminated MAC

CMV retinitis. At CD4 <50, patients report floaters, scotomata, and painless progressive vision loss, usually in one eye first; untreated disease spreads to the other eye and can detach the retina. Dilated fundoscopy shows fluffy yellow-white perivascular retinal necrosis with hemorrhage. Oral valganciclovir treats peripheral lesions; lesions threatening the fovea or optic disc also get intravitreal ganciclovir. IV ganciclovir and foscarnet are alternatives. Ganciclovir needs the CMV UL97 kinase for activation and causes neutropenia; foscarnet needs no activation but causes nephrotoxicity and low calcium, magnesium, and potassium that can trigger seizures. Acyclovir is weak against CMV because it depends on the HSV/VZV thymidine kinase. CMV can also cause colitis, esophagitis, and encephalitis.

Esophagitis. Candida is the most common cause, especially with thrush, so empiric oral fluconazole for 14–21 days comes first. If odynophagia persists after about 3–5 days, EGD with biopsy distinguishes CMV, HSV, idiopathic aphthous ulcers, and resistant Candida.

Disseminated MAC. At CD4 <50, Mycobacterium avium complex causes fever, night sweats, weight loss, diarrhea, abdominal pain, hepatosplenomegaly, abdominal adenopathy, anemia, and a high alkaline phosphatase. Mycobacterial blood cultures or marrow, liver, or node biopsy make the diagnosis. Treat with clarithromycin (or azithromycin) + ethambutol, ± rifabutin, for at least 12 months; two drugs prevent macrolide resistance. Clarithromycin inhibits and rifabutin induces CYP3A4, so doses need adjustment with protease inhibitors. Ethambutol causes optic neuritis, so monitor visual acuity and red-green color vision. Weekly azithromycin alone is prophylaxis, never treatment.

Starting ART and managing IRIS

Timing. Starting ART within 2 weeks of treatment for most OIs (PJP, toxoplasmosis, CMV, MAC, bacterial infections) reduces AIDS progression and death. Cryptococcal meningitis is the key exception: wait 4–6 weeks. For PML, cryptosporidiosis, microsporidiosis, and Kaposi sarcoma, immune recovery from ART is itself the main therapy.

Immune reconstitution inflammatory syndrome. Usually within the first weeks to months of ART, recovering T cells attack residual antigen. In paradoxical IRIS a treated infection flares; in unmasking IRIS a subclinical one surfaces. Fever, lymphadenitis, enlarging brain lesions, or worsening infiltrates follow. Risk is highest with a low baseline CD4, high viral load, an OI diagnosed shortly before ART, and a brisk virologic response. IRIS is a diagnosis of exclusion: rule out a new infection, drug toxicity, and treatment failure. Continue ART and OI therapy; treat mild cases with NSAIDs and moderate–severe cases with prednisone; interrupt ART only for life-threatening reactions.