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Core Principle of HIV/AIDS and Immunocompromised Hosts
HIV targets CD4+ T cells through CD4 receptor binding and CCR5/CXCR4 coreceptor engagement, progressively depleting cell-mediated immunity.
AIDS is defined as CD4+ count <200 cells/μL or presence of an AIDS-defining illness regardless of CD4+ count.
The hallmark is opportunistic infections that occur in predictable patterns based on CD4+ count thresholds — each level of immunosuppression opens the door to specific pathogens.
Understanding CD4+ count correlations allows prediction of which infections to expect and when prophylaxis is indicated.
Board pearl: The CD4+ count is the single best predictor of opportunistic infection risk in HIV patients.
HIV Virology and Replication Cycle
HIV is an enveloped retrovirus with two copies of positive-sense RNA genome, reverse transcriptase, protease, and integrase enzymes.
Attachment: gp120 binds CD4 receptor → conformational change → gp41-mediated fusion with host membrane.
Reverse transcription occurs in cytoplasm: viral RNA → DNA via reverse transcriptase (error-prone, leading to high mutation rate).
Integration: viral DNA integrates into host chromosome via integrase enzyme → permanent infection of that cell lineage.
New virions bud from host cell membrane, acquiring envelope proteins.
Board pearl: Each enzyme in the replication cycle is a drug target — fusion inhibitors, reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors.
Acute HIV Syndrome
Occurs 2–4 weeks after initial infection in 40–90% of patients, lasting 1–2 weeks.
Presents as mononucleosis-like syndrome: fever, lymphadenopathy, pharyngitis, rash (maculopapular, involving palms/soles), myalgias.
During this phase: extremely high viral load (>1 million copies/mL), highly infectious, but antibody tests often negative (window period).
Diagnosis requires HIV RNA PCR or p24 antigen testing — antibodies haven't developed yet.
CD4+ count transiently drops then partially recovers; viral load drops to set point after immune response develops.
Board pearl: Patient with mono-like illness + rash on palms/soles + recent high-risk exposure = acute HIV until proven otherwise.
HIV Testing and Diagnosis
Fourth-generation combination immunoassay detects both HIV antibodies and p24 antigen — positive as early as 2–3 weeks post-exposure.
If screening test positive → HIV-1/HIV-2 antibody differentiation immunoassay to confirm and distinguish types.
If differentiation assay negative or indeterminate → HIV RNA PCR to catch acute infection in window period.
False positives can occur with autoimmune disease, recent influenza vaccination, or pregnancy — always confirm positive screens.
CD4+ count and HIV viral load are used for monitoring, not diagnosis.
Board pearl: In acute HIV syndrome with negative antibody test, order HIV RNA PCR — can detect infection as early as 10 days post-exposure.
CD4+ Count Thresholds and Opportunistic Infections
CD4+ >500: mostly normal infections, though increased risk of tuberculosis, bacterial pneumonia, herpes zoster.
CD4+ 200–500: oral thrush (Candida), hairy leukoplakia (EBV), Kaposi sarcoma, lymphoma.
CD4+ <200: Pneumocystis jirovecii pneumonia (PCP), esophageal candidiasis, HIV wasting syndrome.
CD4+ <100: Toxoplasma gondii encephalitis, cryptococcal meningitis, HIV-associated dementia.
CD4+ <50: Mycobacterium avium complex (MAC), CMV retinitis, CNS lymphoma.
Board pearl: Know the CD4+ thresholds — if given CD4+ count of 45, immediately think MAC and CMV; if CD4+ is 180, think PCP.
Pneumocystis jirovecii Pneumonia (PCP)
Most common opportunistic infection in AIDS; occurs when CD4+ <200 cells/μL.
Presents with subacute dyspnea, dry cough, fever; exam shows tachypnea with minimal lung findings.
CXR: bilateral interstitial infiltrates (ground-glass opacities on CT); can be normal early.
Diagnosis: induced sputum or BAL showing cysts/trophozoites on silver stain or direct fluorescent antibody.
Labs: elevated LDH (nonspecific but supportive), hypoxemia with increased A-a gradient.
Board pearl: HIV patient with CD4+ <200, progressive dyspnea, bilateral infiltrates, and elevated LDH = PCP until proven otherwise.
Toxoplasma gondii Encephalitis
Reactivation of latent infection when CD4+ <100; most common cause of focal brain lesions in AIDS.
Presents with headache, confusion, fever, focal neurologic deficits, seizures.
CT/MRI: multiple ring-enhancing lesions with predilection for basal ganglia; often with surrounding edema.
Diagnosis presumptive based on imaging + positive Toxoplasma IgG (indicates prior exposure capable of reactivating).
Differential: CNS lymphoma (usually solitary lesion, EBV PCR positive in CSF).
Board pearl: Multiple ring-enhancing brain lesions in AIDS patient = empiric treatment for toxoplasmosis; if no response in 2–3 weeks, consider brain biopsy for lymphoma.
Cryptococcal Meningitis
Occurs when CD4+ <100; caused by Cryptococcus neoformans (encapsulated yeast).
Presents insidiously with headache, fever, altered mental status; classic meningeal signs often absent in AIDS.
CSF: elevated opening pressure (very important), low glucose, elevated protein, lymphocytic pleocytosis.
Diagnosis: India ink stain (50–70% sensitive), cryptococcal antigen (>95% sensitive), fungal culture.
Complications: increased intracranial pressure requiring serial LPs, immune reconstitution inflammatory syndrome (IRIS) after starting ART.
Board pearl: AIDS patient with headache and CD4+ <100 → always check serum cryptococcal antigen; if positive, do LP even without meningeal signs.
Mycobacterium avium Complex (MAC)
Disseminated infection occurring when CD4+ <50; caused by M. avium or M. intracellulare.
Presents with fever, night sweats, weight loss, abdominal pain, diarrhea, hepatosplenomegaly.
Labs: anemia, elevated alkaline phosphatase, elevated LDH.
Diagnosis: blood culture for AFB (takes weeks), or tissue biopsy showing acid-fast organisms.
Often concurrent with other opportunistic infections given severe immunosuppression.
Board pearl: AIDS patient with CD4+ <50, fever, weight loss, diarrhea, and elevated alk phos = suspect disseminated MAC.
CMV Disease Spectrum
Occurs when CD4+ <50; can affect multiple organs with different presentations.
CMV retinitis: most common; pizza pie retina (hemorrhage and exudate), vision loss, floaters; diagnosis by fundoscopy.
CMV esophagitis: odynophagia, linear ulcerations on endoscopy (vs. Candida with white plaques, HSV with round ulcers).
CMV colitis: bloody diarrhea, abdominal pain, colonic ulcerations with intranuclear inclusions.
CMV encephalitis: rapidly progressive confusion, lethargy; periventricular enhancement on MRI.
Board pearl: Owl's eye intranuclear inclusions are pathognomonic for CMV; retinitis is most common manifestation in AIDS.
HIV-Associated Malignancies
Kaposi sarcoma: HHV-8 associated; purple papules/plaques on skin/mucosa; can involve GI tract and lungs; occurs at any CD4+ count.
Non-Hodgkin lymphoma: especially primary CNS lymphoma (EBV-associated, CD4+ <50); solitary ring-enhancing brain lesion.
Cervical cancer: HPV-associated; AIDS-defining illness in women; importance of cervical cancer screening.
Anal cancer: HPV-associated; increased risk in MSM; screening with anal cytology in high-risk populations.
Primary effusion lymphoma: HHV-8 and EBV associated; malignant pleural/pericardial/peritoneal effusions.
Board pearl: Solitary brain lesion in AIDS + EBV PCR positive in CSF = primary CNS lymphoma.
Tuberculosis in HIV
Can occur at any CD4+ count but risk increases with immunosuppression; presentation varies by CD4+ level.
High CD4+: typical reactivation TB with upper lobe cavitary disease.
Low CD4+: atypical presentations — middle/lower lobe infiltrates, miliary pattern, extrapulmonary disease, minimal cavitation.
Extrapulmonary sites: lymph nodes, pleura, pericardium, meninges, bone marrow.
Diagnosis challenging: sputum AFB smears often negative; may need tissue biopsy.
Board pearl: HIV patient with fever, weight loss, and lymphadenopathy at any CD4+ count → rule out TB before attributing to HIV alone.
Prophylaxis Based on CD4+ Count
CD4+ <200 or CD4% <14%: TMP-SMX for PCP prophylaxis (also covers Toxoplasma if IgG positive).
CD4+ <100 with positive Toxoplasma IgG: TMP-SMX (if not already on it) or alternative if sulfa allergy.
CD4+ <50: azithromycin for MAC prophylaxis.
All HIV patients: annual influenza vaccine, pneumococcal vaccine, hepatitis A/B vaccines if susceptible.
Prophylaxis can be discontinued when CD4+ rises above threshold for >3 months on ART.
Board pearl: TMP-SMX for PCP prophylaxis also provides protection against Toxoplasma and several bacterial infections.
Immune Reconstitution Inflammatory Syndrome (IRIS)
Paradoxical worsening of pre-existing infection after starting ART due to recovering immune response.
Typically occurs 2–8 weeks after ART initiation; more common with lower baseline CD4+ counts.
Common scenarios: TB (lymph node enlargement, fever), MAC (lymphadenitis), cryptococcal meningitis (increased ICP), CMV (vitritis), PML.
Diagnosis of exclusion: must rule out drug resistance, new opportunistic infection, drug toxicity.
Management: continue ART, treat underlying infection, anti-inflammatory therapy for severe cases.
Board pearl: Patient worsening 4 weeks after starting ART with inflammatory signs = IRIS; do not stop ART.
HIV in Pregnancy and Vertical Transmission
Without intervention, transmission rate 25–30%; with optimal management, can reduce to <1%.
All pregnant women should be tested for HIV; repeat in third trimester if high risk.
Mother with HIV: ART throughout pregnancy regardless of CD4+ count or viral load.
Intrapartum: IV zidovudine if viral load >1000 copies/mL near delivery.
Delivery mode: C-section if viral load >1000 copies/mL at delivery; vaginal delivery if <1000.
Newborn: 4–6 weeks of zidovudine (add 3TC and nevirapine if high transmission risk).
Board pearl: Breastfeeding contraindicated in resource-rich settings; formula feeding prevents postnatal transmission.
Non-HIV Immunocompromised States
Solid organ transplant: CMV (most common), BK virus nephropathy, PTLD (EBV-related), fungal infections.
Hematopoietic stem cell transplant: timeline-dependent — bacterial (first month), CMV/fungal (1–6 months), VZV/encapsulated bacteria (>6 months).
Chemotherapy: neutropenic fever, Pneumocystis (especially with corticosteroids), HSV/VZV reactivation.
Biologics (TNF inhibitors): tuberculosis reactivation, fungal infections (histoplasmosis, coccidioidomycosis), Listeria.
Splenectomy: encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis), Babesia, severe malaria.
Board pearl: Screen for latent TB before starting TNF inhibitors; prophylactic vaccines before splenectomy.
Primary Immunodeficiencies and Infection Patterns
DiGeorge syndrome: absent T cells → viral and fungal infections, PCP.
X-linked agammaglobulinemia (Bruton): absent B cells → recurrent bacterial infections, enteroviral meningoencephalitis.
Common variable immunodeficiency: low immunoglobulins → bacterial infections, Giardia, autoimmunity.
Severe combined immunodeficiency: absent T and B cells → overwhelming infections in infancy, failure to thrive.
Chronic granulomatous disease: defective NADPH oxidase → catalase-positive organisms (Staphylococcus, Aspergillus, Burkholderia).
Board pearl: Recurrent Neisseria infections → check complement; recurrent S. aureus abscesses → check for CGD.
Approach to Fever in the Immunocompromised Host
Broad differential: typical and atypical bacteria, fungi, viruses, parasites, drug fever, malignancy.
Initial evaluation: cultures from all possible sources, CXR, CBC with differential, comprehensive metabolic panel.
Neutropenic fever: immediate broad-spectrum antibiotics (antipseudomonal β-lactam) within 1 hour.
Persistent fever despite antibiotics: add antifungal coverage after 4–7 days.
Consider unusual pathogens based on specific defect: PCP in T-cell deficiency, Aspergillus in neutropenia.
Board pearl: In neutropenic fever, do not delay antibiotics for diagnostic workup — immediate empiric coverage is life-saving.
Board Question Stem Patterns
HIV patient with dyspnea, bilateral infiltrates, CD4+ 150 → Pneumocystis pneumonia.
Multiple ring-enhancing brain lesions in AIDS → empiric toxoplasmosis treatment.
AIDS patient with CD4+ 45 and fever, diarrhea, elevated alkaline phosphatase → disseminated MAC.
Pizza pie retina in HIV patient → CMV retinitis.
Solitary brain lesion + positive EBV PCR in CSF → primary CNS lymphoma.
Patient on TNF inhibitor with fever and pulmonary nodules → reactivation tuberculosis or histoplasmosis.
Post-transplant patient with hemorrhagic cystitis → BK virus.
Worsening symptoms 4 weeks after starting ART → IRIS.
One-Line Recap
HIV progressively destroys CD4+ T cells creating predictable opportunistic infection patterns by CD4+ count — PCP at <200, Toxoplasma/Cryptococcus at <100, MAC/CMV at <50 — while non-HIV immunocompromised states (transplant, chemotherapy, biologics, primary immunodeficiencies) have distinct infection susceptibilities based on their specific immune defects, all requiring prompt recognition and CD4+-guided prophylaxis or defect-specific precautions to prevent life-threatening infections.
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