Opportunistic Infections in HIV

• Toxoplasma gondii: reactivation of tissue cysts acquired years earlier; requires prior seropositivity, so a Toxoplasma IgG-negative patient with ring-enhancing lesions argues strongly against toxoplasmosis.
• CMV: reactivation of latent infection in a seropositive host; end-organ disease (retinitis, colitis, esophagitis) at profound CD4 depletion.
• Mycobacterium tuberculosis: reactivation can occur at any CD4 count, which is why the CDC/NIH/IDSA opportunistic infection guidelines advise latent TB testing at HIV diagnosis regardless of CD4.
• JC virus (progressive multifocal leukoencephalopathy) and VZV/HSV similarly reactivate.

Modifiable risk factors examiners plant

• ART non-adherence or interruption: the dominant modifiable driver; virologic failure precedes CD4 decline.
• Missed or refused chemoprophylaxis: no TMP-SMX below the PCP threshold.
• Missed vaccinations: pneumococcal, influenza, hepatitis B per ACIP.
• Behavioral/exposure factors: smoking, injection drug use, untreated water, undercooked meat and cat-litter exposure, unstable housing, alcohol use disorder.
• Concomitant corticosteroids or chemotherapy.

Non-modifiable risk factors

• Low CD4 nadir and high viral load; late presentation with AIDS-defining illness at diagnosis.
• Prior serostatus (Toxo IgG+, CMV IgG+, positive IGRA).
• Geographic residence/travel in fungal-endemic regions; country of origin for TB.
• Older age and prior OI history.

• CD4+ T-cell depletion and impaired cellular immunity: HIV specifically targets CD4+ T cells, macrophages, and dendritic cells, progressively destroying adaptive immunity while innate immunity remains relatively intact. When CD4 counts fall below 200 cells/μL, cell-mediated immunity becomes severely compromised, allowing intracellular pathogens (MAC, CMV, toxoplasmosis, tuberculosis) to disseminate unchecked.

• Dysregulation of immune response: Loss of CD4+ helper T cells impairs production of interferon-gamma (IFN-γ) and IL-2, critical cytokines for macrophage activation and Th1 responses. This creates an environment favoring fungal infections (PCP, cryptococcal disease, histoplasmosis) and protozoal infections (cryptosporidiosis) that require robust cell-mediated immunity.

• Quantitative and qualitative immunoglobulin defects: B-cell dysfunction results in reduced antibody responses and poor opsonization, increasing susceptibility to encapsulated bacteria and allowing reactivation of latent viral infections (CMV, toxoplasmosis, TB).

• Breakdown of mucosal barriers: Oral and esophageal candidiasis reflect both local CD4 depletion and disrupted epithelial integrity, serving as markers of significant immunosuppression (typically CD4 <200).

• Impaired pathogen clearance from latency: Reactivation of latent pathogens (TB, toxoplasmosis, CMV) occurs when CD4 counts fall below specific thresholds, as the body can no longer maintain immune control of dormant infection.

Bacterial OIs

• Recurrent bacterial infections (sinusitis, otitis media, pneumonia) typically with encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae); present with fever, productive cough, or focal respiratory findings
• Mycobacterium avium complex (MAC) presents with fever, night sweats, weight loss, abdominal pain, and chronic diarrhea; occurs when CD4 <50

Fungal OIs

• Pneumocystis jirovecii pneumonia (PCP): Progressive dyspnea, non-productive cough, fever, and chest tightness over weeks; elevated LDH (>400) is characteristic; occurs at CD4 <200
• Cryptococcal meningitis: Subacute fever, headache, and meningeal signs (though meningismus may be subtle); "cryptococcal antigen-positive but culture-negative CSF" is a classic presentation at CD4 <100
• Oral/esophageal candidiasis: White plaques on tongue/palate (thrush), painful swallowing, or dysphagia; indicates CD4 <200
• Histoplasmosis (endemic areas): Fever, hepatosplenomegaly, lymphadenopathy, can mimic lymphoma; CD4 <50

Protozoal OIs

• Toxoplasmosis: Focal CNS lesions causing headache, seizures, or focal neurologic deficits; ring-enhancing lesions on MRI; occurs at CD4 <100
• Cryptosporidiosis: Chronic, profuse watery diarrhea with malabsorption; can be life-threatening; CD4 <200

Viral OIs

• Cytomegalovirus (CMV): Retinitis causing floaters and visual field cuts ("cottage cheese and ketchup" hemorrhagic retinitis); esophagitis with painful dysphagia; colitis with bloody diarrhea; CD4 <50
• Herpes simplex virus (HSV): Painful oral ulcers, genital lesions, or severe esophagitis; more frequent and severe with CD4 <50
• Tuberculosis: Can present at any CD4 count but more likely atypical with CD4 <50; pulmonary and extrapulmonary disease common

Important Clinical Pearls

• OI symptoms often develop insidiously with vague constitutional symptoms (fever, weight loss, fatigue)
• Multiple concurrent OIs are common in severely immunocompromised patients
• Some OIs (like TB) can occur at relatively preserved CD4 counts (>200) while others (like MAC) require profound immunosuppression
• Immune reconstitution inflammatory syndrome (IRIS) can occur 2-12 weeks after starting ART as immune function improves

• CD4+ T-cell count: The single most important predictor; guides OI risk stratification and prophylaxis decisions. Count <200 indicates high PCP risk; <100 indicates CMV/toxo risk; <50 indicates MAC risk.

• HIV viral load and ART status: Undetectable viral load with preserved CD4 count indicates low OI risk; helps distinguish between ART-naive patients and those with virological failure.

• PCP Diagnosis: Induced sputum or bronchoalveolar lavage (BAL) with Giemsa or immunofluorescent staining; elevated LDH (>400) and A-a gradient >35 mmHg suggest PCP. PCR is increasingly used due to superior sensitivity.

• CNS OIs (toxoplasmosis, cryptococcal meningitis, TB meningitis): MRI brain with contrast (ring-enhancing lesions suggest toxo; cryptococcal serum/CSF antigen >90% sensitive); CSF analysis with opening pressure, glucose, protein, cell count; India ink stain for cryptococcus.

• MAC diagnosis: Blood cultures with special media (Mycobacterium Growth Indicator Tube); colonoscopy with biopsy may show acid-fast bacilli in lamina propria.

• CMV retinitis: Dilated fundoscopic examination by ophthalmology; characteristic hemorrhagic or granular lesions

• Mycobacterial infections: Sputum smear microscopy, TB culture, GeneXpert MTB/RIF for rapid TB diagnosis; chest imaging often shows atypical findings with CD4 <100.

• Cryptococcal meningitis: Serum and CSF cryptococcal antigen (extremely sensitive even when CSF culture negative); India ink stain

• Histoplasmosis: Antigen detection in urine/serum; blood cultures; tissue biopsy with special stains

Pneumocystis jirovecii Pneumonia (PCP)

• First-line: Trimethoprim-sulfamethoxazole (TMP-SMX) 15-20 mg/kg/day of TMP component divided TID-QID for 21 days; plus corticosteroids (prednisone 40 mg BID for 5 days, then 40 mg daily for 5 days, then 20 mg daily to complete 21 days) if PaO2 <70 mmHg or A-a gradient >35
• Alternatives: Pentamidine IV or dapsone + pyrimethamine for sulfa-allergic patients
• Prophylaxis (when CD4 <200): TMP-SMX DS daily (also covers toxo and some bacteria); pentamidine or dapsone + pyrimethamine are alternatives

Cryptococcal Meningitis

• First-line: Amphotericin B deoxycholate 0.7-1 mg/kg/day IV for 2 weeks, then fluconazole 400 mg daily for 8 weeks (consolidation), then 200 mg daily indefinitely (maintenance)
• Liposomal amphotericin preferred if renal dysfunction
• Flucytosine added if available (synergistic with amphotericin) for

Disease-related complications

• Hypoxemic respiratory failure in PCP: diffuse alveolar damage from organism burden plus inflammatory response; signaled by widening A-a gradient and desaturation with ambulation. An emergency — adjunctive corticosteroids must be given at the same time as TMP-SMX, not after intubation.
• Pneumothorax in PCP: cystic/pneumatocele destruction of alveolar walls; sudden pleuritic pain and unilateral absent breath sounds. Emergency.
• Raised intracranial pressure in cryptococcal meningitis: yeast and polysaccharide capsule obstruct arachnoid granulation CSF outflow. Signaled by headache, vomiting, papilledema, sixth-nerve palsy, or vision loss. Emergency — the CDC/NIH/IDSA OI guidelines call for measuring opening pressure and performing therapeutic/serial lumbar punctures, not mannitol or steroids.
• Mass effect and herniation from toxoplasmosis: expanding ring-enhancing abscesses; declining mental status or new focal deficit. Emergency.
• Retinal detachment and irreversible blindness in CMV retinitis: full-thickness necrotizing retinitis; new floaters or field cut with lesions threatening the macula/optic disc is a sight-threatening emergency.
• Cryptosporidiosis: profuse secretory diarrhea causing hypovolemia, electrolyte loss, and wasting; sclerosing cholangitis is a late complication.

Treatment-related complications

• TMP-SMX: rash progressing to Stevens-Johnson syndrome/TEN (emergency, stop drug), myelosuppression, hyperkalemia (ENaC blockade by trimethoprim), hyponatremia, and a benign creatinine rise from blocked tubular creatinine secretion without true GFR loss.
• Dapsone: hemolysis in G6PD deficiency and methemoglobinemia — check G6PD first; cyanosis with normal PaO2 and a saturation gap is the tell.
• Pentamidine: pancreatitis, QT prolongation, and biphasic glycemia (hypoglycemia then insulin-dependent diabetes) from beta-cell toxicity.
• Amphotericin B: dose-dependent nephrotoxicity with renal potassium and magnesium wasting; infusion reactions. Flucytosine: marrow suppression.
• Pyrimethamine: dihydrofolate reductase inhibition — always co-administer leucovorin.
• Ganciclovir: neutropenia; foscarnet: nephrotoxicity and hypocalcemia causing seizures.
• IRIS: paradoxical inflammatory worsening weeks after ART start; most dangerous with cryptococcal and TB meningitis.

• CD4 thresholds are the backbone of every stem: <200 → PCP, esophageal candidiasis; <100 → toxoplasmosis, cryptococcal meningitis; <50 → CMV end-organ disease, disseminated MAC. Read the CD4 before the symptoms.
• PCP buzzwords: exertional desaturation, diffuse bilateral perihilar interstitial infiltrates, normal or near-normal auscultation, elevated LDH, and elevated serum beta-D-glucan. Best next step when PaO2 is low or the A-a gradient is wide: start TMP-SMX plus corticosteroids immediately — do not wait for BAL.
• The toxoplasmosis vs. CNS lymphoma discriminator: multiple ring-enhancing lesions in the basal ganglia with positive Toxoplasma IgG → treat empirically and repeat imaging in about 2 weeks. A solitary periventricular lesion, negative Toxo IgG, or EBV DNA in CSF points to primary CNS lymphoma. PML is the distractor: non-enhancing white-matter lesions without mass effect, JC virus PCR, no fever.
• Cryptococcal meningitis: the exam tests management of pressure, not the drug — measure the opening pressure and drain CSF with serial LPs. Serum cryptococcal antigen is the fastest screen; India ink is the classic but less sensitive answer.
• CMV retinitis is a clinical diagnosis made by dilated fundoscopy ("pizza pie"/cottage cheese and ketchup retina). Do not order serum CMV PCR or a vitreous biopsy as the next step; call ophthalmology.
• Prophylaxis pearl: TMP-SMX below CD4 200 covers both PCP and (at CD4 <100 with positive Toxo IgG) toxoplasmosis. Per the CDC/NIH/IDSA OI guidelines, routine primary MAC prophylaxis is no longer recommended for patients starting effective ART — azithromycin at CD4 <50 is now a common wrong answer.
• ART timing: DHHS guidelines favor starting ART within about 2 weeks of most OIs, but cryptococcal and TB meningitis are the exceptions — early ART worsens IRIS mortality, so treat the infection first.
• Never treat MAC with a macrolide alone — monotherapy breeds resistance; use a macrolide plus ethambutol.