Immune System

Immune reconstitution inflammatory syndrome

Clinical Overview and When to Suspect IRIS

— HIV patient started on ART within the last 4–8 weeks who now presents with new or worsening symptoms despite rising CD4 and falling viral load

— Baseline CD4 <100 cells/µL, especially <50

— Recent or active OI: TB, MAC, cryptococcal meningitis, PJP, CMV retinitis, PML, KS, hepatitis B/C

— High pre-ART HIV viral load (>100,000 copies/mL)

— Short interval between OI treatment initiation and ART start

— Mycobacterial: TB-IRIS and MAC-IRIS (most common worldwide)

— Cryptococcal IRIS (highest mortality—CNS pressure)

— PML-IRIS (JC virus, can be fatal)

— CMV, VZV, HSV, HBV/HCV flares

— Kaposi sarcoma IRIS (paradoxical lesion enlargement)

Board pearl: IRIS is not ART failure—viral load is falling. The clinical worsening reflects immune success, not drug toxicity or resistance. Do not stop ART reflexively.

Definition: Immune reconstitution inflammatory syndrome (IRIS) is a paradoxical clinical deterioration that occurs after restoration of pathogen-specific immunity, most commonly in HIV patients starting antiretroviral therapy (ART), but also after stopping immunosuppression, post-transplant, or postpartum.

Core mechanism: As CD4 count rises and HIV viral load falls, the recovering immune system mounts an exaggerated inflammatory response against either a previously diagnosed opportunistic infection (paradoxical IRIS) or a subclinical/unrecognized pathogen (unmasking IRIS).

When to suspect on Step 3:

Most common culprits (memorize):

Timeline: Median onset 2–8 weeks after ART start; cryptococcal and TB-IRIS can occur up to 6 months later.

Non-HIV settings: post-solid organ transplant tapering, natalizumab/fingolimod withdrawal (PML-IRIS in MS), neutrophil recovery after chemotherapy, postpartum immune rebound, anti-TNF discontinuation.

Presentation Patterns and Key History

— TB-IRIS: Recurrent fevers, expanding lymphadenopathy (often suppurative), worsening pulmonary infiltrates, new pleural/pericardial effusions, CNS tuberculomas, or paradoxical worsening of meningitis

— Cryptococcal IRIS: Recurrent headache, rising intracranial pressure, vision changes, lymphadenitis, or pulmonary nodules—culture often sterile because pathogen is already killed

— MAC-IRIS: Fevers, focal lymphadenitis (cervical, mesenteric), abdominal pain, weight loss

— PML-IRIS: Worsening focal neurologic deficits, new contrast enhancement on MRI of prior PML lesions

— CMV-IRIS: Immune recovery uveitis/vitritis with floaters and decreased vision in patients with prior CMV retinitis

— HBV-IRIS: Transaminase flare, can mimic acute hepatitis

— KS-IRIS: Sudden enlargement, edema, and inflammation of existing KS lesions

— Exact date ART started and regimen

— Pre-ART CD4 nadir and viral load

— Any OI diagnosed before or shortly after ART

— Adherence to OI therapy and ART

— Timing of new symptoms relative to ART

— Recent CD4/VL trends (should show improvement)

Step 3 management: Always ask "When did ART start, and what was the CD4 nadir?" A pre-ART CD4 <50 with ART started within the prior 2 months in a deteriorating patient is IRIS until proven otherwise. Document viral load trajectory—falling VL supports IRIS over treatment failure or drug resistance.

General clue: New or worsening inflammatory symptoms in an HIV patient 2–8 weeks after ART initiation, with documented immunologic recovery (rising CD4, falling viral load by ≥1 log).

Paradoxical IRIS: Worsening of an OI that was already diagnosed and being treated (e.g., TB lymphadenitis enlarges despite appropriate RIPE therapy).

Unmasking IRIS: New presentation of a previously subclinical infection (e.g., florid cryptococcal meningitis appearing 3 weeks after ART).

Pathogen-specific presentations:

Key history points to extract:

Physical Exam Findings and Inflammatory Assessment

— Fever is the most common finding (often relapsing/remitting)

— Tachycardia proportional to inflammation

— Hypotension is uncommon unless adrenal IRIS (TB adrenalitis flare) or sepsis from secondary infection

— Hypoxia in pulmonary TB/PJP-IRIS or pulmonary KS-IRIS

— Suppurative lymphadenitis with overlying erythema and fluctuance—classic for TB- or MAC-IRIS

— Asymmetric, tender, rapidly enlarging cervical/supraclavicular/axillary/mesenteric nodes

— May develop sinus tracts and fistulization

— Meningismus, photophobia, papilledema, cranial nerve palsies (cryptococcal-IRIS, TB meningitis-IRIS)

— Focal deficits, ataxia, cognitive decline (PML-IRIS, tuberculoma)

— Fundoscopy: immune recovery uveitis/vitritis in CMV retinitis history—look for vitreous haze, cystoid macular edema

— Sudden expansion of violaceous KS plaques with surrounding edema

— New zoster (dermatomal vesicles), folliculitis, eosinophilic folliculitis flare

— Genital/perianal HSV reactivation

— Check for sepsis criteria—IRIS can mimic and coexist with sepsis

— Assess volume status; cryptococcal/TB meningitis-IRIS patients may need CSF pressure measurement

— Quantify functional decline vs. pre-ART baseline

Key distinction: Suppurative lymphadenitis in a recently-started ART patient = TB-IRIS until proven otherwise, even if AFB smears are negative—the immune response has often already sterilized the node, but inflammation persists.

Vital signs:

Lymphatic exam (high yield):

Pulmonary: New crackles, dullness (effusion), bronchial breath sounds; chest exam often disproportionate to pre-ART baseline.

Neurologic (critical to document):

Abdominal: Hepatosplenomegaly, RUQ tenderness (HBV-IRIS hepatitis flare), mesenteric adenitis tenderness.

Skin/mucosa:

Hemodynamic and inflammatory severity assessment:

Diagnostic Workup — Initial Labs, Imaging, and Microbiology

— CD4 count—should be higher than pre-ART nadir

— HIV viral load—should be decreasing by ≥1 log₁₀ or undetectable

— Without these, the diagnosis is not IRIS

— CBC with diff (leukocytosis or new eosinophilia)

— CMP (LFT elevation in HBV/HCV-IRIS, hyponatremia in adrenal TB-IRIS)

— CRP and ESR—usually markedly elevated

— LDH (PJP, lymphoma differential)

— Procalcitonin can help distinguish bacterial superinfection

— TB: Sputum AFB smear, culture, NAAT (Xpert MTB/RIF), CXR, lymph node FNA/biopsy with AFB stain and culture; biopsy often shows granulomas with few or no organisms

— Cryptococcus: Serum and CSF cryptococcal antigen (CrAg), CSF opening pressure (often elevated), India ink, fungal culture

— MAC: Blood mycobacterial cultures, lymph node biopsy/culture

— CMV: CMV PCR, dilated ophthalmologic exam

— PJP: Beta-D-glucan, induced sputum/BAL PCR

— Hepatitis: HBV DNA, HCV RNA, hepatitis serologies

— PML: CSF JC virus PCR

— CXR/CT chest: New mediastinal/hilar adenopathy, cavities, effusions, miliary pattern, "tree-in-bud"

— CT abdomen/pelvis: Mesenteric adenitis, splenic lesions, hepatic abscesses

— MRI brain with contrast: Tuberculomas, expanding PML lesions with new enhancement, cryptococcomas, immune recovery vitritis

CCS pearl: Order CD4, HIV VL, CRP, blood cultures (bacterial + AFB + fungal), CXR, and pathogen-specific testing in parallel on day 1. Do not delay LP if neurologic signs present—measure and document opening pressure.

Confirm immune reconstitution (mandatory):

General inflammatory labs:

Pathogen-directed workup:

Imaging:

Lumbar puncture indications: Headache, fever, altered mentation, or focal neuro deficits—measure opening pressure, send cell count, glucose, protein, CrAg, AFB, fungal/bacterial cultures, JCV PCR.

Diagnostic Workup — Advanced and Confirmatory Studies

— Excisional or core lymph node biopsy when adenopathy is the dominant finding—send for histopathology, AFB/fungal stains, mycobacterial culture, and NAAT

— Histology typically shows well-formed granulomas (reflecting immune recovery) often with few or no organisms, distinguishing IRIS from active uncontrolled infection

— Biopsy also rules out lymphoma, KS, Castleman disease

— Serial LPs to manage elevated ICP (drain to opening pressure <20 cm H₂O or by 50%)

— CSF cultures are often sterile in IRIS (organism already killed) but inflammation persists

— Distinguishes IRIS from cryptococcal relapse (positive culture, rising titer)

— Confirmed HIV with ART initiation

— Decline in viral load ≥1 log or rising CD4

— Clinical deterioration consistent with inflammatory process

— Exclusion of treatment failure, drug resistance, nonadherence, drug reaction, and new infection

Board pearl: IRIS is a diagnosis of exclusion. Always rule out (1) treatment failure of the OI, (2) drug-resistant organism, (3) new/superimposed infection, (4) drug toxicity (e.g., abacavir hypersensitivity, IRIS-mimicking DRESS), and (5) malignancy before committing to the IRIS label.

Tissue diagnosis is often required:

Bronchoscopy with BAL: Indicated for unclear pulmonary infiltrates—send AFB, fungal, PJP PCR, CMV, bacterial cultures, cytology.

Repeat lumbar puncture in cryptococcal-IRIS:

Ophthalmology consult: Slit-lamp and dilated fundoscopy in any patient with prior CMV retinitis on ART—identifies immune recovery uveitis, cystoid macular edema, epiretinal membrane.

Drug susceptibility: In TB-IRIS, always reconfirm rifampin/INH susceptibility—rule out drug-resistant TB as a cause of clinical worsening before attributing to IRIS.

Therapeutic drug monitoring: Especially when rifamycins interact with PIs/INSTIs—subtherapeutic TB drug levels mimic IRIS.

HIV resistance testing: If viral load is not suppressing as expected, send genotype before assuming IRIS.

Diagnostic criteria (French/INSHI for TB-IRIS, similar frameworks for cryptococcal):

Risk Stratification and Management Logic

— Mild: Self-limited fevers, small lymphadenopathy, mild symptoms—continue ART, continue OI treatment, supportive care, NSAIDs

— Moderate: Significant symptoms (e.g., painful suppurative nodes, moderate effusions, hepatitis flare without liver failure)—add corticosteroids, drain abscesses

— Severe/life-threatening: Respiratory failure, CNS involvement with elevated ICP, airway compression, severe hepatitis—high-dose steroids, ICU, do not stop ART unless truly life-threatening

— Worsens long-term outcomes

— Risks viral rebound and drug resistance

— Rarely needed except in life-threatening CNS IRIS unresponsive to steroids

— TB without CNS involvement, CD4 <50: Start ART within 2 weeks of TB therapy (mortality benefit outweighs IRIS risk)

— TB without CNS involvement, CD4 ≥50: Start ART by 8 weeks

— TB meningitis: Delay ART for 4–8 weeks (early ART increases mortality from CNS IRIS)

— Cryptococcal meningitis: Delay ART by 4–6 weeks after starting antifungal therapy (early ART increases mortality)

— PJP, other OIs: Start ART within 2 weeks

— Prednisone 40 mg/day × 2 weeks, then 20 mg × 2 weeks is recommended in high-risk TB-IRIS patients (CD4 <100, starting ART within 30 days of TB therapy)—reduces IRIS incidence by ~30%

Step 3 management: The exam loves the "timing of ART" question. Default: start ART within 2 weeks of OI diagnosis except for TB meningitis and cryptococcal meningitis, where you wait 4–8 weeks.

Severity tiers guide therapy:

Cardinal principle: DO NOT STOP ART in most cases. Stopping ART:

Optimal ART timing to prevent IRIS (key Step 3 concept):

Corticosteroid prophylaxis:

Treat the underlying OI fully—do not switch or discontinue OI therapy reflexively.

Pharmacotherapy — First-Line Regimens

— Prednisone 1–1.5 mg/kg/day (or equivalent IV methylprednisolone) for 1–2 weeks, then taper over 4–12 weeks depending on response

— Indicated for TB-IRIS with airway/CNS compromise, severe lymphadenitis, large effusions

— Cryptococcal-IRIS: Steroids more controversial; use cautiously, ensure antifungal therapy is active and ICP is controlled

— Monitor for steroid complications: hyperglycemia, reactivation of HSV/CMV, strongyloides hyperinfection (screen and treat with ivermectin if from endemic area), osteonecrosis

— TB: RIPE regimen unchanged; ensure rifamycin–ART interactions managed (rifabutin preferred with PIs; dose-adjust dolutegravir to BID with rifampin)

— Cryptococcus: Induction amphotericin B + flucytosine, then fluconazole consolidation/maintenance

— MAC: Clarithromycin or azithromycin + ethambutol ± rifabutin

— CMV: Ganciclovir/valganciclovir; intravitreal injections for sight-threatening uveitis

— PJP: TMP-SMX with adjunctive steroids if PaO₂ <70 or A-a >35

— HBV: Ensure ART regimen includes TDF/TAF + emtricitabine/lamivudine

— Reserved for refractory IRIS unresponsive to steroids (e.g., refractory paradoxical TB-IRIS, neurologic IRIS)

— Use under specialist guidance

— Therapeutic LP for elevated ICP in cryptococcal-IRIS (drain to <20 cm H₂O)

— Aspiration/drainage of suppurative lymph nodes or abscesses

— Pericardiocentesis or thoracentesis for symptomatic effusions

— Intravitreal steroids for cystoid macular edema in CMV immune recovery uveitis

Board pearl: Before starting high-dose steroids in any HIV patient, screen for Strongyloides (serology or empiric ivermectin if from endemic area)—steroids precipitate hyperinfection syndrome with high mortality.

Corticosteroids—cornerstone of moderate-to-severe IRIS:

NSAIDs: First-line for mild IRIS—ibuprofen or naproxen for fevers and lymph node pain.

Continue pathogen-specific therapy:

Anti-TNF therapy (thalidomide, infliximab):

Drainage and procedural therapy:

Procedural and Adjunctive Management

— Measure opening pressure with manometer

— If OP >25 cm H₂O, drain to reduce by 50% or to <20 cm H₂O

— Repeat daily until pressures normalize; consider lumbar drain or VP shunt if persistent

— Acetazolamide and mannitol are NOT effective in cryptococcal ICP—use mechanical drainage

— Needle aspiration for fluctuant suppurative nodes (sends material for culture and decompresses)

— Avoid excision when possible (risk of chronic sinus tracts)

— Repeated aspirations may be needed

— Mediastinal/tracheal compression from TB-IRIS lymphadenopathy may require high-dose steroids, urgent ENT/thoracic consult, occasionally stenting or surgical debulking

— Intravitreal corticosteroids or anti-VEGF for cystoid macular edema in immune recovery uveitis

— Pars plana vitrectomy for severe vitritis

— Supportive; transplant evaluation rarely needed

— Do not discontinue tenofovir-based ART (active against HBV)—stopping can cause severe HBV flare

— Continue ART (or in MS patients, plasmapheresis to remove natalizumab)

— High-dose IV methylprednisolone 1 g/day × 5 days, then taper

— Maraviroc has been used adjunctively (limited evidence)

— Continue ART

— Initiate or intensify chemotherapy (liposomal doxorubicin or paclitaxel) for advanced KS

— Avoid systemic corticosteroids—can accelerate KS progression

CCS pearl: In cryptococcal IRIS with headache and elevated opening pressure, the single most important intervention is serial therapeutic LPs, not antifungals or steroids. Document opening pressure each time. KS-IRIS is the one IRIS where steroids are contraindicated.

Lumbar puncture for ICP management (cryptococcal and TB meningitis IRIS):

Lymph node management:

Airway management:

Ophthalmologic procedures:

Hepatic IRIS:

PML-IRIS:

Kaposi sarcoma IRIS:

Special Populations — Elderly and Renal/Hepatic Impairment

— Immune recovery is slower and less robust—IRIS incidence may be lower but morbidity higher due to comorbidities

— Higher baseline cardiovascular and renal risk—steroid-induced hyperglycemia, hypertension, fluid retention more problematic

— Polypharmacy increases drug–drug interactions (rifampin with statins, anticoagulants, antihypertensives)

— Bone health: cumulative steroids worsen osteoporosis—add calcium, vitamin D, consider bisphosphonate if prolonged steroid course

— Screen for latent TB and strongyloides before steroids

— Tenofovir disoproxil fumarate (TDF): Avoid if CrCl <50; switch to TAF (safer renal/bone profile)

— Amphotericin B (cryptococcal): Nephrotoxic—use liposomal formulation, monitor creatinine and electrolytes (K⁺, Mg²⁺), aggressive IV fluid pre-hydration

— Flucytosine: Renally cleared—dose adjust by CrCl; monitor for cytopenias

— TMP-SMX: Adjust dose if CrCl <30; monitor potassium and creatinine

— Acyclovir/ganciclovir/valganciclovir: Dose-adjust for CrCl

— Steroids do not require renal dose adjustment but worsen fluid retention

— Rifampin, isoniazid, pyrazinamide all hepatotoxic—monitor LFTs weekly during IRIS therapy; hold if ALT >5× ULN asymptomatic or >3× ULN with symptoms

— HBV-IRIS: Continue TDF/TAF + emtricitabine; avoid abrupt discontinuation

— Voriconazole, fluconazole: Hepatotoxic—dose-adjust in Child-Pugh B/C

— Protease inhibitors: Hepatic metabolism—avoid in decompensated cirrhosis; INSTI-based regimens preferred

— Steroids can unmask or worsen hepatic encephalopathy via catabolic state

Step 3 management: In renal dysfunction with cryptococcal IRIS, switch to liposomal amphotericin B plus flucytosine (dose-adjusted), and pre-hydrate with 1 L normal saline before each amphotericin dose. Replete K⁺ and Mg²⁺ daily.

Elderly HIV patients:

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Postpartum, and Pediatrics

— Pregnancy is a state of relative immunosuppression; postpartum immune rebound can trigger IRIS even without ART changes

— Postpartum flare of TB, leprosy, hepatitis B, and autoimmune disease is a recognized "physiologic IRIS"

— Pregnant HIV patients starting ART face IRIS risk similar to non-pregnant; ART is still indicated to prevent vertical transmission

— Preferred ART in pregnancy: Dolutegravir + TDF/TAF + emtricitabine (DTG safe throughout pregnancy per current WHO/DHHS guidance)

— Corticosteroids: Prednisone is preferred (minimal placental transfer due to 11-β-HSD2); dexamethasone crosses placenta and is reserved for fetal indications

— Avoid efavirenz in first trimester if alternatives available (historical concern, now relaxed)

— TB therapy: RIPE is safe in pregnancy; add pyridoxine 50 mg/day with INH

— Children have more robust immune reconstitution—IRIS incidence higher than adults

— Common manifestations: BCG-IRIS (regional lymphadenitis or disseminated BCG at vaccination site), TB-IRIS, herpes zoster

— BCG-IRIS: Local reaction at vaccine site weeks to months after ART—usually self-limited; abscess drainage if suppurative

— Pediatric ART timing follows similar principles: early ART except in TB and cryptococcal meningitis

— Weight-based dosing of all OI and ART medications—use pediatric ID consult

— IRIS-like syndromes occur with rapid tapering of immunosuppression (e.g., for PTLD, BK virus, PML)

— Balance rejection risk vs. infection control—taper gradually

— PML-IRIS after drug withdrawal—plasmapheresis accelerates removal; high-dose steroids for inflammatory phase

Board pearl: Postpartum women with previously stable TB or hepatitis B can present with paradoxical flares 2–6 weeks after delivery—this is a non-HIV IRIS driven by physiologic immune recovery from pregnancy.

Pregnancy and postpartum IRIS:

Pediatric IRIS:

Transplant recipients:

MS patients on natalizumab/fingolimod:

Complications and Adverse Outcomes

— Cryptococcal-IRIS: Mortality up to 20–30%, driven by elevated ICP and CNS inflammation

— PML-IRIS: Mortality 20–50%; survivors often have permanent neurologic deficits

— TB-IRIS: Mortality ~3–5%, higher with CNS involvement

— KS-IRIS: Mortality elevated with visceral or pulmonary KS

— Cerebral edema, herniation from elevated ICP

— Hydrocephalus requiring VP shunt

— Seizures, stroke from vasculitis (TB meningitis-IRIS)

— Permanent vision loss from optic neuritis or papilledema

— Cognitive impairment after PML-IRIS

— ARDS from severe pulmonary TB-IRIS or PJP-IRIS

— Airway compression from mediastinal adenopathy

— Bronchopleural fistula, empyema

— Fulminant hepatitis (HBV-IRIS, drug-induced from TB therapy)

— Acute liver failure requiring transplant evaluation

— Permanent vision loss from CMV immune recovery uveitis with cystoid macular edema, epiretinal membrane, cataract

— Steroid-induced: hyperglycemia, infection (HSV/CMV reactivation, strongyloides hyperinfection, bacterial superinfection), psychosis, osteonecrosis, adrenal insufficiency on withdrawal

— Amphotericin: nephrotoxicity, infusion reactions, electrolyte wasting

— Drug–drug interactions: rifampin reduces levels of PIs, INSTIs, contraceptives, warfarin, statins

— Chronic sinus tracts from TB lymphadenitis

— Constrictive pericarditis from TB pericardial-IRIS

— Pulmonary fibrosis after severe TB-IRIS

— Recurrent IRIS episodes (uncommon but reported)

Key distinction: Worsening symptoms with rising viral load or falling CD4 = treatment failure or new OI, not IRIS. Recheck VL and CD4 before attributing deterioration to IRIS.

Mortality: Overall IRIS mortality ~5%, but varies sharply by pathogen:

CNS complications:

Respiratory complications:

Hepatic complications:

Ophthalmologic:

Iatrogenic complications:

Long-term:

When to Escalate Care — ICU, Consultation, and Inpatient Triage

— Respiratory failure requiring mechanical ventilation (severe pulmonary TB, PJP, or KS IRIS)

— Airway compromise from mediastinal/cervical lymphadenopathy

— Refractory elevated ICP with declining mental status (cryptococcal, TB meningitis IRIS)

— Status epilepticus, stroke, herniation risk

— Hemodynamic instability or sepsis from secondary bacterial infection

— Fulminant hepatitis with encephalopathy or coagulopathy

— Need for IV therapy (amphotericin, ganciclovir, IV steroids)

— Suppurative lymphadenitis requiring drainage

— Symptomatic effusions requiring drainage

— Severe pain or functional decline

— Concern for drug-resistant TB or new OI requiring workup

— Uncertain diagnosis requiring biopsy

— Mild, self-limited fevers

— Stable, small lymphadenopathy

— Asymptomatic LFT bumps

— Compliant patient with reliable follow-up within 1–2 weeks

— Infectious disease: Essentially mandatory—co-manage ART, OI therapy, immunosuppression decisions

— Pulmonology: For bronchoscopy, refractory pulmonary IRIS

— Neurology/neurosurgery: CNS-IRIS, ICP management, VP shunt

— Ophthalmology: CMV retinitis history, vision changes

— Hepatology: HBV-IRIS, severe drug-induced hepatitis

— Surgical/IR: Lymph node drainage, biopsy, abscess drainage

— Pharmacy: ART–OI drug interaction review (rifamycins, azoles, PIs/INSTIs)

— Reconcile every medication—rifampin and azole interactions are commonly missed

— Confirm follow-up CD4, VL, LFTs, and pathogen-specific labs within 2 weeks of discharge

— Provide written instructions on warning signs (worsening headache, vision changes, dyspnea, jaundice)

CCS pearl: In suspected cryptococcal-IRIS with headache, admit and obtain LP with opening pressure measurement before any imaging-driven delay. Time-to-LP correlates with neurologic outcome.

ICU admission indications:

Inpatient admission (non-ICU):

Outpatient management acceptable for:

Specialty consultations:

Transitions of care:

Key Differentials — Same-Category (Infectious/HIV-Related)

— Persistent positive cultures (TB sputum, cryptococcal CSF) despite therapy

— No reduction in pathogen burden

— Distinguished from IRIS by microbiologic persistence, not just clinical worsening

— Always reconfirm susceptibility when TB-IRIS is suspected

— MDR-TB can masquerade as IRIS—repeat NAAT for rifampin resistance

— Fluconazole-resistant Cryptococcus in chronic suppression

— A different OI emerging on ART (e.g., PJP in a TB patient)

— Distinguished by new organism identification, different organ pattern

— Rising viral load, falling CD4, resistance mutations

— Symptoms reflect ongoing immunosuppression, not immune recovery

— Send genotype

— Catheter-related bacteremia, hospital-acquired pneumonia, C. difficile

— Elevated procalcitonin, focal bacterial source, positive bacterial cultures

— End-organ disease (colitis, retinitis, esophagitis, encephalitis)

— CMV PCR and tissue biopsy

— Common with immune recovery—dermatomal vesicles, mucosal ulcers

— Often considered "mild IRIS" but treated as zoster/HSV with antivirals

— Can present with B symptoms, lymphadenopathy, CNS lesions mimicking IRIS

— Excisional biopsy with flow cytometry differentiates

— Fevers, lymphadenopathy, splenomegaly, cytopenias

— Lymph node biopsy with HHV-8 staining

— Sarcoidosis-like reactions can occur with immune recovery (non-caseating granulomas, no organism)

Board pearl: The single most important differential is treatment failure of the OI. If cultures remain positive or pathogen burden is not declining, it is not IRIS—escalate antimicrobial therapy and reassess resistance.

Treatment failure of the underlying OI:

Drug-resistant TB or fungal disease:

New opportunistic infection:

HIV ART failure:

Bacterial superinfection:

CMV reactivation or new CMV disease:

Herpes zoster and HSV reactivation:

Lymphoma (non-Hodgkin, primary CNS, plasmablastic):

Multicentric Castleman disease (HHV-8 driven):

Immune reconstitution inflammatory vs. infectious syndromes:

Key Differentials — Other-Category Causes

— Abacavir hypersensitivity: Fever, rash, GI, respiratory symptoms within 6 weeks of starting; HLA-B*5701 screening prevents

— Nevirapine hypersensitivity: Rash, hepatitis, especially in women with higher CD4

— DRESS syndrome: Fever, eosinophilia, rash, multiorgan involvement 2–8 weeks after drug start—can mimic IRIS exactly

— TB drug-induced hepatitis: Distinguish from HBV-IRIS by drug timing and rechallenge response

— Sulfa-induced hepatitis or rash from TMP-SMX

— HIV-associated lymphomas (DLBCL, Burkitt, primary CNS, plasmablastic)

— Kaposi sarcoma progression (vs. KS-IRIS)

— Anal, cervical, lung cancers

— Hepatocellular carcinoma in HBV/HCV co-infection

— Graves disease (most common autoimmune IRIS, occurs months to years after ART)

— SLE, rheumatoid arthritis, sarcoidosis, Guillain-Barré, polymyositis

— Distinguished by serologic testing and tissue biopsy

— TB adrenalitis flare causing acute Addisonian crisis during IRIS

— Check morning cortisol and ACTH stim

— TB pericarditis with tamponade

— HIV-associated pulmonary hypertension

— Myocarditis (CMV, HIV)

— HIV-associated nephropathy progression

— Drug-induced AKI (TDF, amphotericin)

— IRIS-related interstitial nephritis (rare)

— Lipodystrophy from older ART regimens

— Diabetes from steroids or PIs

— HIV-associated neurocognitive disorder

— Steroid psychosis

— Efavirenz CNS toxicity (vivid dreams, depression)

Key distinction: Onset within 2 weeks of ART start with rash and eosinophilia favors drug hypersensitivity (DRESS, abacavir, nevirapine) over IRIS (typically 2–8 weeks). Always review the medication timeline carefully.

Drug reactions and hypersensitivity:

Malignancy:

Autoimmune phenomena post-ART:

Adrenal insufficiency:

Cardiac/vascular:

Renal:

Endocrine:

Psychiatric and neurologic:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Never stop ART for IRIS unless life-threatening CNS disease unresponsive to steroids

— Reinforce adherence counseling—missed doses risk resistance

— Use INSTI-based regimens (bictegravir/TAF/FTC or dolutegravir-based) for tolerability, low pill burden, high barrier to resistance

— TB: Complete 6 months (9–12 months for CNS, bone, or disseminated TB)

— Cryptococcus: Induction → consolidation (fluconazole 400 mg × 8 weeks) → maintenance (fluconazole 200 mg) until CD4 >100 sustained ≥3 months and VL suppressed ≥3 months

— MAC: ≥12 months and CD4 >100 sustained ≥6 months

— CMV: Maintenance until CD4 >100 ≥3–6 months

— PJP: TMP-SMX prophylaxis until CD4 >200 ≥3 months

— TMP-SMX for PJP and toxoplasmosis if CD4 <200 (or oropharyngeal candidiasis, prior PJP)

— Azithromycin for MAC if CD4 <50 (controversial in ART era; many now omit if VL suppressed)

— Slow taper over 4–12 weeks, monitor for symptom recurrence

— Add calcium 1000 mg + vitamin D 800 IU; consider bisphosphonate if prolonged course

— PJP prophylaxis if prednisone ≥20 mg ≥1 month

— ART must include TDF or TAF + 3TC or FTC long-term

— Monitor HBV DNA, LFTs, AFP/US for HCC surveillance

— Pneumococcal (PCV20 or PCV15 + PPSV23), influenza annually, COVID, HPV, hepatitis A/B, Tdap, shingles (recombinant zoster vaccine—safe in HIV)

— Avoid live vaccines if CD4 <200 (varicella, MMR)

— Anal cytology, cervical cytology, low-dose CT for lung cancer if eligible, colonoscopy per guidelines

Step 3 management: Discharge bundle—ART continued, OI therapy continued, steroid taper plan, PJP prophylaxis, calcium/vitamin D, vaccines reviewed, ID follow-up in 1–2 weeks, repeat CD4/VL in 4 weeks.

Continue ART indefinitely:

Continue OI therapy to full course:

OI prophylaxis after IRIS resolves:

Steroid taper:

Hepatitis B co-infection:

Vaccinations once stable:

Cancer screening:

Follow-Up, Monitoring Parameters, and Counseling

— 2 weeks post-discharge: Clinical reassessment, medication reconciliation, side effects, adherence

— 4 weeks: Repeat CD4, HIV VL, CMP, CBC, pathogen-specific labs (HBV DNA, cryptococcal serum CrAg if applicable)

— 3 months and ongoing: CD4, VL every 3–6 months once suppressed; transition to every 6 months when stable >1 year

— TB therapy: monthly sputum (if pulmonary), LFTs every 2–4 weeks during intensive phase

— Steroids: Glucose, blood pressure, weight, mood, infection signs

— Amphotericin (if continued): Daily creatinine, K⁺, Mg²⁺, CBC

— Rifampin-containing regimens: LFTs every 2–4 weeks; review ART dose adjustments (DTG BID with rifampin)

— TDF/TAF: Creatinine, urine protein, phosphate; DEXA if long-term

— INSTIs: Weight, lipids, HbA1c (weight gain risk)

— Any prior CMV retinitis: dilated exam every 3 months until CD4 >100 stable

— Immune recovery uveitis: ophthalmology every 1–3 months until resolved

— Pulmonary rehab after severe TB-IRIS with residual lung disease

— Neuro-rehab after PML-IRIS, TB meningitis-IRIS, or stroke complications

— Physical therapy for deconditioning, neuropathy

— Adherence: Even one missed week risks resistance; use pillboxes, reminder apps, single-tablet regimens

— Disclosure and partner services: Encourage disclosure; PrEP for HIV-negative partners; U=U messaging (undetectable = untransmissible)

— Mental health: Depression and substance use common—screen with PHQ-9, refer

— Reproductive health: Contraception (rifampin reduces OCP efficacy—use IUD, DMPA, or barrier); preconception counseling for ART optimization

— Lifestyle: Smoking cessation (lung cancer, CVD), alcohol moderation (hepatitis), nutrition, exercise

— Warning signs: New fever, headache, vision change, dyspnea, jaundice—return immediately

Board pearl: U=U (undetectable = untransmittable) is a cornerstone counseling point—patients with sustained viral suppression cannot sexually transmit HIV, which improves both individual and public health outcomes.

Visit cadence:

Monitoring parameters by therapy:

Ophthalmologic follow-up:

Rehabilitation:

Counseling topics:

Ethical, Legal, and Patient Safety Considerations

— Patients must understand that paradoxical worsening (IRIS) may occur and is not treatment failure—frame it as a sign of immune recovery

— Discuss alternative timing strategies (early vs. delayed ART) when applicable (e.g., TB meningitis, cryptococcal meningitis)

— Document shared decision-making for steroid prophylaxis in high-risk TB patients

— HIV status is protected health information; disclosure to family or employers requires explicit patient consent

— Partner notification: Most states require providers to either notify partners directly or facilitate through public health—know your state law

— Avoid documenting HIV status on visible portions of discharge paperwork if patient privacy is at risk

— HIV is a reportable condition in all US states (named or coded reporting varies)

— Tuberculosis is reportable nationwide—directly observed therapy (DOT) often state-administered

— Suspected nonadherence in active TB triggers public health intervention to prevent transmission

— Medication reconciliation errors are the leading source of harm—rifampin–ART interactions, azole–QT prolongers, and steroid tapers are commonly mismanaged

— Provide written taper schedules and pharmacy contact for questions

— Ensure 2-week post-discharge follow-up is scheduled before leaving hospital

— Bridge prescriptions (≥30 days) to avoid coverage gaps

— Ryan White HIV/AIDS Program provides ART access for uninsured/underinsured—social work referral on admission

— AIDS Drug Assistance Program (ADAP) for outpatient ART

— Verify formulary coverage before discharge to avoid treatment interruption

— Patients with PML-IRIS or TB meningitis-IRIS may have impaired capacity—formally assess and involve surrogates

— Advance care planning is appropriate in severe IRIS with poor prognosis

— Address structural barriers: housing, food insecurity, substance use, stigma—all reduce ART adherence

Step 3 management: The highest-yield transition-of-care safety item is verifying that rifampin dose-adjustments to ART (e.g., dolutegravir BID) are written correctly on the discharge prescription—missed adjustments cause virologic failure.

Informed consent for ART initiation:

HIV disclosure and confidentiality:

Mandatory reporting:

Transitions of care risks:

Insurance and access:

Capacity and autonomy:

Health equity:

High-Yield Associations and Rapid-Fire Clinical Facts

— Most OIs: ART within 2 weeks

— TB without CNS: 2 weeks if CD4 <50; 8 weeks if CD4 ≥50

— TB meningitis: delay ART 4–8 weeks

— Cryptococcal meningitis: delay ART 4–6 weeks

Board pearl: Two timing rules dominate exam questions: (1) start ART within 2 weeks for most OIs, but (2) delay 4–8 weeks for cryptococcal meningitis and TB meningitis due to CNS IRIS mortality.

IRIS occurs in ~10–25% of HIV patients starting ART, highest in those with CD4 <50 and high pre-ART VL.

Median onset: 2–8 weeks after ART; can be delayed up to 6 months for TB and cryptococcal.

Cryptococcal-IRIS has the highest mortality—driven by elevated ICP.

TB-IRIS is the most common worldwide; manifests as paradoxical lymphadenitis or pulmonary worsening.

PML-IRIS occurs in HIV patients and in MS patients who stop natalizumab—high-dose steroids and plasmapheresis.

Postpartum IRIS: Immune rebound after delivery can flare TB, leprosy, hepatitis, autoimmune disease.

CMV immune recovery uveitis affects patients with prior CMV retinitis—floaters, vision loss, requires ophthalmology.

Hepatitis B flares after ART—never stop TDF/TAF without alternative HBV coverage.

Steroids reduce TB-IRIS incidence by ~30% when given prophylactically to high-risk patients (Meintjes trial).

Optimal ART timing—memorize:

Cryptococcal ICP management: Serial therapeutic LPs—not mannitol, not acetazolamide.

Strongyloides screening before steroids in patients from endemic areas (Latin America, Southeast Asia, sub-Saharan Africa).

Rifampin + dolutegravir: Double DTG to 50 mg BID. Rifampin + bictegravir/elvitegravir: contraindicated.

U=U: Undetectable viral load = no sexual transmission risk.

Autoimmune IRIS: Graves disease is most common; presents months to years after ART.

KS-IRIS: Avoid steroids; use chemotherapy.

PJP-IRIS: Adjunctive steroids if PaO₂ <70 mmHg or A-a gradient >35.

BCG-IRIS in children: Lymphadenitis at vaccine site weeks after ART—usually self-limiting.

Sarcoidosis-like granulomatous reactions can occur with immune recovery without identifiable pathogen.

Board Question Stem Patterns

— 32-year-old HIV+ man with CD4 30 started on RIPE for pulmonary TB 6 weeks ago, then ART 2 weeks ago. Now presents with high fevers and enlarging, tender, fluctuant cervical lymph nodes. CD4 now 110, VL fell from 500,000 to 1,200.

— Best next step: Lymph node aspiration for culture and decompression; continue ART and TB therapy; add prednisone for severe symptoms. NOT stop ART, NOT switch TB regimen.

— HIV+ patient treated for cryptococcal meningitis 8 weeks ago, now on fluconazole consolidation and recently started ART 3 weeks ago. Returns with severe headache and vomiting. CSF: WBC 200 lymphocytes, CrAg positive, culture negative, opening pressure 38 cm H₂O.

— Best next step: Serial therapeutic lumbar punctures to reduce ICP; continue ART; continue fluconazole. NOT amphotericin restart, NOT mannitol.

— Newly diagnosed HIV patient with CD4 25 and pulmonary TB just started on RIPE. When should ART begin?

— Answer: Within 2 weeks (CD4 <50, no CNS TB).

— Same scenario but TB meningitis: delay ART 4–8 weeks.

— HIV+ patient with prior CMV retinitis, now ART × 5 weeks, CD4 risen from 40 to 150. Presents with floaters and decreased vision. Exam: vitritis, cystoid macular edema.

— Diagnosis: Immune recovery uveitis (CMV-IRIS). Management: Continue ART; intravitreal steroids; ophthalmology.

— HIV/HBV co-infected patient started on TDF/FTC/DTG 6 weeks ago. ALT now 600. HBV DNA decreasing, HIV VL suppressed.

— Diagnosis: HBV-IRIS hepatitis flare. Management: Continue ART; supportive; do NOT stop TDF.

— Patient with cutaneous KS starts ART; lesions become more numerous, edematous, painful. New pulmonary lesions on CT.

— Management: Continue ART; initiate liposomal doxorubicin chemotherapy; AVOID systemic steroids.

— MS patient on natalizumab develops PML; drug stopped. Two months later, worsening neurologic deficits with new contrast-enhancing lesions on MRI.

— Management: Plasmapheresis (if recent natalizumab), high-dose IV methylprednisolone.

Key distinction: The wrong answers always include "stop ART" or "switch ART regimen"—these are correct only in life-threatening CNS IRIS unresponsive to steroids, which is rare.

Stem 1 — Classic TB-IRIS:

Stem 2 — Cryptococcal-IRIS:

Stem 3 — Optimal ART timing:

Stem 4 — Immune recovery uveitis:

Stem 5 — HBV-IRIS:

Stem 6 — KS-IRIS:

Stem 7 — PML-IRIS in MS:

One-Line Recap

IRIS is a paradoxical inflammatory deterioration occurring 2–8 weeks after ART-driven immune recovery, treated by continuing ART and the underlying OI therapy while adding corticosteroids for moderate-to-severe disease.

Board pearl: Three exam-defining facts: (1) falling VL + rising CD4 + clinical worsening = IRIS, (2) delay ART for cryptococcal and TB meningitis, otherwise start within 2 weeks, and (3) serial LPs—not mannitol—are the lifesaving intervention in cryptococcal-IRIS with elevated ICP.

Diagnosis requires: Recent ART start, falling viral load, rising CD4, clinical worsening, AND exclusion of treatment failure, drug resistance, new infection, and drug toxicity.

Timing of ART rule: Start within 2 weeks for most OIs; delay 4–8 weeks for TB meningitis and cryptococcal meningitis to avoid fatal CNS IRIS.

Pathogen-specific pearls: TB-IRIS = suppurative adenitis (steroids help, prophylactic prednisone reduces incidence); Cryptococcal-IRIS = elevated ICP (serial LPs are the cure); CMV-IRIS = immune recovery uveitis (ophthalmology, intravitreal steroids); KS-IRIS = chemotherapy, NO steroids; HBV-IRIS = continue TDF/TAF, supportive care; PML-IRIS = high-dose methylprednisolone.

Never reflexively stop ART—do so only in life-threatening CNS IRIS unresponsive to high-dose steroids; otherwise continue, treat the inflammation, and counsel the patient that worsening symptoms reflect immune success, not failure.