Respiratory

Sarcoidosis: pulmonary and extrapulmonary manifestations

Clinical Overview and When to Suspect Sarcoidosis

— Peak incidence ages 25–45, second smaller peak in women >50

— In the US, African American patients have ~3× higher incidence and more severe, chronic, multiorgan disease

— Northern European (Scandinavian) ancestry also overrepresented

— Slight female predominance; nonsmokers paradoxically more affected

— Young to middle-aged adult with bilateral hilar lymphadenopathy on chest imaging, often incidental

— Dry cough, dyspnea, fatigue lasting weeks to months without clear infection

— Constitutional symptoms (low-grade fever, weight loss, night sweats) with normal infectious workup

— Extrapulmonary clue: erythema nodosum, anterior uveitis, parotid swelling, peripheral facial nerve palsy, asymptomatic hypercalcemia, unexplained AV block in a young patient

Board pearl: A young Black woman with incidental bilateral hilar lymphadenopathy + asymptomatic hypercalcemia on routine labs is the canonical Step 3 stem — don't biopsy reflexively if she meets Löfgren-like criteria; observe and confirm with serial imaging if asymptomatic.

Sarcoidosis is a multisystem granulomatous disease characterized by noncaseating granulomas in affected organs, with the lung involved in >90% of patients

Epidemiology shapes pretest probability:

When to suspect on Step 3:

Löfgren syndrome: acute presentation with fever, bilateral hilar adenopathy, erythema nodosum, migratory polyarthralgia (often ankles) — high spontaneous remission rate (>80%), often diagnosed clinically without biopsy

Heerfordt syndrome: uveitis + parotitis + facial nerve palsy + fever

Diagnosis is one of compatible clinical/radiographic picture + noncaseating granulomas + exclusion of mimics (TB, fungal, berylliosis, lymphoma)

Course is highly variable: ~60% remit spontaneously within 2–5 years; ~30% have chronic progressive disease; mortality 1–5%, mostly from advanced pulmonary fibrosis, cardiac involvement, or neurosarcoidosis

Presentation Patterns and Key History

— Erythema nodosum — tender red nodules on shins, acute and self-limited, favorable prognosis

— Lupus pernio — violaceous indurated plaques on nose/cheeks/ears, chronic disease marker, often with upper airway and bone involvement

— Scar sarcoidosis: infiltration of old tattoos or scars (high-yield buzz)

— Conduction disease (AV block in young adult — red flag)

— Ventricular arrhythmias, sudden cardiac death

— Cardiomyopathy with patchy LGE on MRI

— Cranial nerve VII palsy (most common, often bilateral)

— Aseptic meningitis, hypothalamic/pituitary dysfunction (DI, hypogonadism), myelopathy, small fiber neuropathy

— Occupational exposures (rule out berylliosis — aerospace, ceramics, electronics)

— TB risk factors, travel, endemic fungi (histoplasmosis, coccidioidomycosis)

— Medication review (immune checkpoint inhibitors can cause sarcoid-like reactions)

— Family history (mild familial clustering)

Key distinction: Erythema nodosum + bilateral hilar adenopathy = Löfgren = good prognosis. Lupus pernio = chronic, refractory, systemic disease = bad prognosis. Step 3 frequently tests this dichotomy as a prognostic anchor.

Pulmonary (>90%): dry cough, progressive exertional dyspnea, vague chest discomfort; wheeze possible from endobronchial granulomas; hemoptysis rare unless cavitary mycetoma in fibrotic stage

Constitutional: fatigue (often dominant), low-grade fever, weight loss, night sweats — mimics lymphoma or TB

Skin (~25%):

Ocular (~25%): anterior uveitis most common (red painful eye, photophobia); posterior uveitis, optic neuritis, lacrimal gland enlargement (sicca)

Cardiac (~5% clinically, ~25% subclinical):

Neurologic (~5–10%):

Renal/metabolic: hypercalcemia (~10%), hypercalciuria (~30%), nephrolithiasis, interstitial nephritis

Hepatic: mild transaminitis, hepatomegaly; cholestatic disease uncommon

Musculoskeletal: arthralgia (ankles in Löfgren), chronic arthritis, bone cysts (phalangeal lytic lesions)

Hematologic: lymphopenia, mild anemia, splenomegaly

Key history to extract:

Physical Exam Findings (and Multisystem Assessment)

— Often strikingly normal despite extensive imaging findings — classic mismatch

— Late disease: fine bibasilar or mid-lung crackles (note: sarcoid fibrosis is upper lobe predominant, unlike IPF), occasional wheeze

— Clubbing is uncommon — if present, reconsider diagnosis (think IPF, bronchiectasis, malignancy)

— Bradycardia or irregular rhythm (AV block)

— Signs of right heart failure in pulmonary hypertension (elevated JVP, RV heave, loud P2, peripheral edema)

— S3/S4 if cardiomyopathy

— Slit-lamp essential — anterior chamber cells/flare in uveitis

— Lacrimal/parotid enlargement; dry eyes/mouth

— Cranial nerve VII palsy — peripheral pattern (forehead involved)

— Order full vitals + ambulation pulse ox

— Examine skin, eyes (ophtho consult), lymph nodes, lungs, heart, abdomen, neuro

— Don't anchor on lungs — extrapulmonary findings often clinch the diagnosis and identify the safest biopsy site

CCS pearl: When sarcoidosis is on your differential, order an ECG on every patient at baseline — silent first-degree AV block or bundle branch block is a free clue that mandates a cardiac workup (echo ± cardiac MRI/FDG-PET).

Vitals: usually normal; low-grade fever possible; resting hypoxemia or exertional desaturation in advanced fibrotic disease — check ambulation SpO₂ in any suspected case with dyspnea

Pulmonary exam:

Cardiac:

HEENT/ocular:

Skin — full skin exam including scalp, scars, tattoos; document erythema nodosum, lupus pernio, papules around nose/eyelids

Lymph nodes: peripheral lymphadenopathy in ~30% — firm, mobile, nontender; cervical, supraclavicular, axillary, inguinal — easy biopsy targets

Abdomen: hepatomegaly, splenomegaly

Neuro: cranial nerve screen (especially VII), sensory exam for small fiber neuropathy (often missed — patients describe burning feet, autonomic complaints)

MSK: ankle swelling/tenderness; dactylitis from bone cysts

Bedside workflow on Step 3 CCS:

Diagnostic Workup — Initial Labs and Imaging

— Stage 0: normal (extrapulmonary only)

— Stage I: bilateral hilar lymphadenopathy alone

— Stage II: hilar adenopathy + parenchymal infiltrates

— Stage III: parenchymal infiltrates without adenopathy

— Stage IV: fibrosis (upper lobe predominant, honeycombing, traction bronchiectasis)

— Spontaneous remission: Stage I ~75%, Stage II ~50%, Stage III ~30%, Stage IV ~0%

— Often restrictive with decreased DLCO

— Can be obstructive (endobronchial disease) or mixed

— Six-minute walk with SpO₂ for functional baseline

— CBC (lymphopenia), CMP (transaminitis, creatinine)

— Serum and 24-hour urinary calcium — hypercalcemia/hypercalciuria from 1α-hydroxylase activity in granulomas converting 25-OH-D to 1,25-(OH)₂-D

— 25-OH vitamin D and 1,25-(OH)₂ vitamin D (1,25 elevated relative to 25-OH)

— ACE level — poor sensitivity and specificity, do NOT use to diagnose or monitor (commonly tested negative point)

— Soluble IL-2 receptor — emerging marker, not standard

Board pearl: ACE level is a trap. Sensitivity ~60%, specificity ~70%, elevated in many granulomatous and liver diseases. The USMLE wants you to know it should not be used to diagnose sarcoidosis or follow disease activity — order it and you may still need a biopsy, and a normal value does not rule it out.

Chest X-ray (Scadding staging) — historic but still tested:

High-resolution CT chest: gold standard imaging — perilymphatic micronodules along bronchovascular bundles and fissures, upper/mid lobe predominance, mediastinal and bilateral hilar adenopathy (often symmetric, sometimes calcified "eggshell")

PFTs:

Initial labs:

ECG on everyone — screen for AV block, BBB, arrhythmia

Slit-lamp ophthalmologic exam — even asymptomatic patients (occult uveitis common)

TB testing: IGRA or PPD before steroids; HIV test

Urinalysis for proteinuria, hematuria (renal involvement)

Diagnostic Workup — Confirmatory Studies and Tissue

— Compatible clinical and radiographic picture

— Histologic confirmation of noncaseating granulomas

— Exclusion of alternative causes (TB, fungal, beryllium, lymphoma, drug)

— Classic Löfgren syndrome (fever + EN + bilateral hilar adenopathy + ankle arthralgia) — clinical diagnosis acceptable

— Heerfordt syndrome with classic features

— Asymptomatic Stage I disease in a young patient — many experts observe

— Skin lesions (not erythema nodosum — that shows septal panniculitis, nonspecific)

— Peripheral lymph node, lacrimal/parotid gland

— Conjunctival nodule

— Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) of mediastinal nodes — first-line for thoracic-limited disease, yield 80–90%

— Transbronchial lung biopsy if parenchymal disease

— Mediastinoscopy if EBUS inconclusive

— Avoid open lung biopsy when possible

— Echo (regional wall motion, basal septal thinning)

— Cardiac MRI with late gadolinium enhancement (patchy, non-coronary distribution)

— FDG-PET for active inflammation

— Endomyocardial biopsy low yield (patchy disease)

Step 3 management: Confirmed sarcoidosis requires a multisystem screening evaluation at diagnosis: PFTs, ECG, echo if symptoms, ophthalmology, calcium/renal panel, LFTs, CBC. Document baseline before initiating immunosuppression.

Diagnostic triad (no single test is pathognomonic):

When biopsy can be deferred:

Biopsy site selection — least invasive first:

Histology: tight, well-formed noncaseating epithelioid granulomas with multinucleated giant cells; asteroid bodies and Schaumann bodies are classic but not specific

Always rule out infection on tissue: AFB stain + mycobacterial culture, fungal stains/cultures

Cardiac sarcoidosis workup (if symptoms, abnormal ECG, or unexplained cardiomyopathy):

Neurosarcoidosis: MRI brain/spine with contrast (leptomeningeal enhancement, hypothalamic involvement), LP (lymphocytic pleocytosis, elevated protein, elevated CSF ACE nonspecific)

Risk Stratification and First-Line Management Logic

— Pulmonary: symptomatic disease with declining PFTs (FVC drop ≥10%, DLCO drop ≥15%), worsening imaging, hypoxemia

— Cardiac involvement (any) — high mortality

— Neurologic involvement (any except isolated facial palsy that resolves)

— Ocular disease refractory to topical therapy

— Symptomatic hypercalcemia, renal involvement, or nephrolithiasis

— Severe constitutional symptoms or hepatic dysfunction

— Disfiguring/extensive skin disease (lupus pernio)

— African American race

— Age >40 at onset

— Lupus pernio

— Chronic uveitis

— Cardiac, neurologic, or upper airway involvement

— Stage III/IV radiographs

— Nephrocalcinosis

— Löfgren syndrome

— Stage I disease

— Acute onset

— White ethnicity (in US data)

— Smoking cessation (though smokers oddly have lower incidence, cessation still benefits lung health)

— Low-calcium, low–vitamin D diet if hypercalcemic; avoid sun exposure and vitamin D supplements unless documented deficiency and closely monitored

— Vaccinations updated before immunosuppression (pneumococcal, influenza, COVID, shingles in age-eligible; live vaccines contraindicated once on high-dose immunosuppression)

Board pearl: Vitamin D supplementation in a patient with sarcoidosis and hypercalcemia is a classic iatrogenic harm test item — granulomas autonomously activate vitamin D, so giving more precipitates hypercalcemic crisis and nephrolithiasis.

Core principle: not all sarcoidosis needs treatment. Treat when there is organ dysfunction, threatened function, or significant symptoms — not for asymptomatic radiographic findings or asymptomatic mild hypercalcemia alone (though severe hypercalcemia is treated)

Asymptomatic Stage I disease: observation with serial PFTs and imaging every 3–6 months; ~75% remit

Indications to treat (any organ system):

Prognostic markers favoring chronicity:

Favorable markers:

Counseling at diagnosis:

Pharmacotherapy — First-Line Regimens

— Pulmonary sarcoidosis: prednisone 20–40 mg/day for 4–6 weeks, then taper over 6–12 months to maintenance 5–10 mg/day; total course often 12 months minimum

— Cardiac sarcoidosis: prednisone 30–40 mg/day, longer course; combine early with steroid-sparing agent

— Neurosarcoidosis: prednisone 0.5–1 mg/kg/day; severe disease may need IV methylprednisolone pulse

— Ocular: topical steroids for anterior uveitis; systemic for posterior or refractory disease (ophthalmology-directed)

— Hypercalcemia: prednisone 20–40 mg/day plus hydration; avoid thiazides (worsen Ca); loop diuretics cautious

— Cutaneous (limited): topical/intralesional steroids first; hydroxychloroquine adjunct

— Methotrexate 10–20 mg weekly with folate — most widely used; monitor LFTs, CBC, creatinine; avoid in pregnancy

— Azathioprine 2 mg/kg/day — check TPMT activity before starting

— Mycophenolate mofetil — preferred for neurosarcoidosis in some centers

— Leflunomide — alternative if MTX intolerance

— Hydroxychloroquine — best for cutaneous disease, hypercalcemia, and mild musculoskeletal disease; annual eye exam after 5 years

— Infliximab (anti-TNF) — refractory pulmonary, neurosarcoidosis, lupus pernio, cardiac sarcoid

— Adalimumab as alternative

— Screen for latent TB and hepatitis B before TNF inhibitors — high-yield safety point

— Rituximab, JAK inhibitors emerging

— Bone protection: calcium and vitamin D cautious (give only if low; monitor Ca); bisphosphonates if prolonged ≥3 months at ≥5 mg/day

— Glucose monitoring (steroid-induced DM)

— PPI if GI risk, PJP prophylaxis if prednisone ≥20 mg/day for ≥4 weeks

Step 3 management: Initiate prednisone and plan the taper and steroid-sparing strategy simultaneously — chronic high-dose steroid monotherapy is a Step 3 wrong answer when disease is likely to be prolonged.

Glucocorticoids — first-line for systemic disease

Steroid-sparing / second-line agents (when steroid taper fails, intolerable side effects, or chronic disease):

Third-line / refractory:

Steroid side effect mitigation (always test on Step 3):

Procedures and Advanced Management

— Permanent pacemaker for high-grade AV block

— ICD for sustained VT, prior cardiac arrest, LVEF ≤35%, or extensive LGE on MRI even with preserved EF

— Antiarrhythmics (amiodarone, sotalol) for VT

— Catheter ablation refractory cases

— Heart transplantation in end-stage disease — sarcoidosis can recur in graft but outcomes good

— Step 3 trap: a young patient with new AV block needs cardiac sarcoid workup before routine pacemaker placement decisions are finalized — granulomatous inflammation may reverse with immunosuppression

— Suspect with disproportionate dyspnea, DLCO <60% predicted, RV dysfunction on echo

— Right heart catheterization confirms

— Treat underlying disease; PAH-specific therapy selectively

— Long-term oxygen therapy when resting SpO₂ ≤88%

— Pulmonary rehabilitation

— Lung transplantation for advanced fibrotic disease — refer when FVC <50%, DLCO <40%, PH, or progressive disease despite therapy

— Aspergilloma in fibrotic cavities — surgical resection if hemoptysis, otherwise observation or antifungal

CCS pearl: In a Step 3 CCS case of young adult with syncope and complete heart block, after stabilization (atropine, transcutaneous pacing, transvenous pacer), order cardiac MRI and FDG-PET, refer to EP and sarcoid specialist — don't place a permanent pacemaker on day 1 without considering reversible granulomatous inflammation; advance the clock and reassess.

EBUS-TBNA is the workhorse diagnostic procedure for mediastinal/hilar adenopathy — outpatient, low complication, yield 80–90% with rapid on-site evaluation

Bronchoalveolar lavage adjunct: CD4/CD8 ratio >3.5 supports sarcoidosis (specificity ~94%, sensitivity ~50%); lymphocytic alveolitis; not diagnostic alone

Cardiac sarcoidosis interventions:

Pulmonary hypertension from sarcoidosis (Group 5 PH):

End-stage pulmonary disease:

Neurosarcoidosis refractory: infliximab, mycophenolate; surgical CSF diversion for hydrocephalus

Renal stones from hypercalciuria: hydration, dietary modification, citrate; treat underlying disease

Skin (lupus pernio): intralesional steroids, hydroxychloroquine, infliximab for disfiguring disease

Special Populations — Elderly and Renal/Hepatic Impairment

— Second incidence peak, especially women

— More likely to present with extrapulmonary disease (ocular, cardiac) or with insidious dyspnea misattributed to age, deconditioning, or COPD

— Greater steroid toxicity risk: hyperglycemia, osteoporosis, cataracts, infection, delirium

— Lower starting prednisone doses (e.g., 20 mg) and earlier introduction of steroid-sparing agents

— Mandatory DEXA at baseline and bone protection with calcium (cautious if hypercalcemic), vitamin D (cautious), and bisphosphonate when prolonged steroid course expected

— Comprehensive geriatric assessment: falls risk, cognition, polypharmacy review

— Cataract and glaucoma screening — both from disease (uveitis) and steroids

— Sarcoidosis itself causes granulomatous interstitial nephritis, nephrocalcinosis from chronic hypercalciuria, and nephrolithiasis

— Always evaluate UA, urine protein/creatinine ratio, serum creatinine at baseline

— Drug dosing:

— Methotrexate: avoid if CrCl <30; dose-reduce 30–60

— Hydroxychloroquine: standard dose, monitor for retinal toxicity

— Mycophenolate: no major renal adjustment but watch cytopenias

— Azathioprine: dose-adjust in CKD

— NSAIDs for Löfgren arthritis — avoid in CKD

— Hypercalcemia management: IV saline preferred; loop diuretics cautious in CKD; calcitonin short-term; prednisone is mainstay (suppresses granulomatous calcitriol production)

— Hepatic granulomas common (~50–80% on biopsy) but symptomatic liver disease rare

— Watch for cholestatic pattern, portal hypertension (rare)

— Methotrexate hepatotoxicity — avoid with active hepatitis, fatty liver with fibrosis, heavy alcohol use; check baseline LFTs, hepatitis B/C serologies; periodic FibroScan if long-term use

— Azathioprine and leflunomide also hepatotoxic — monitor LFTs every 1–3 months

— Vaccinate against hepatitis A/B if seronegative

Board pearl: In elderly sarcoidosis patients on chronic prednisone ≥5 mg/day for ≥3 months, start a bisphosphonate (steroid-induced osteoporosis prevention) — this is a frequently tested Step 3 omission.

Older adults (>50):

Renal impairment:

Hepatic impairment:

Special Populations — Pregnancy, Pediatrics, and Other Subgroups

— Sarcoidosis often improves during pregnancy (endogenous cortisol, immune shift) and may flare postpartum

— Preconception counseling: optimize disease control, adjust medications

— Safe: prednisone (use lowest effective dose; risk of GDM, hypertension, cleft palate at high first-trimester doses small), hydroxychloroquine, azathioprine (yes — safer than alternatives), certolizumab (minimal placental transfer)

— Avoid: methotrexate (teratogen — stop 3 months pre-conception in both partners traditionally; current data ≥1 cycle for women), mycophenolate (teratogen — REMS program, stop 6 weeks before conception), leflunomide (long half-life — cholestyramine washout)

— Monitor for hypercalcemia (vitamin D physiologic rise); avoid supplemental vitamin D unless deficient

— Cardiac sarcoid patients need pre-pregnancy cardiology evaluation

— Postpartum surveillance: PFTs, imaging, clinical exam at 6 weeks and 3 months

— Rare; two patterns:

— Early-onset (<5 years, "Blau syndrome"–like): triad of arthritis, uveitis, rash without lung disease — consider NOD2 mutation

— Older children/adolescents: adult-like multisystem disease with pulmonary involvement

— Growth and development monitoring on steroids; favor steroid-sparing agents early

— Pediatric rheumatology/pulmonology co-management

— Increasingly recognized — bilateral hilar adenopathy and granulomas in oncology patients

— Often does not require ICI discontinuation if asymptomatic

— Differentiate from malignancy progression with biopsy

— Chronic beryllium disease is histologically identical — ask aerospace, nuclear, electronics workers; confirm with beryllium lymphocyte proliferation test (BeLPT) — critical Step 3 distinction

Key distinction: In an aerospace worker with bilateral hilar adenopathy and noncaseating granulomas, you must order a BeLPT before labeling the disease sarcoidosis — chronic beryllium disease has occupational, legal, and compensation implications.

Pregnancy:

Pediatric sarcoidosis:

Immune checkpoint inhibitor–associated sarcoid-like reactions:

Occupational sarcoidosis mimics:

Complications and Adverse Outcomes

— Sudden cardiac death from VT/VF

— Complete heart block requiring pacing

— Heart failure with reduced ejection fraction

— Apical and basal aneurysms

— Permanent cranial neuropathies

— Hypothalamic-pituitary dysfunction (central DI, panhypopituitarism)

— Hydrocephalus from basilar meningitis

— Seizures, cognitive impairment, myelopathy

— Posterior synechiae, cataracts (disease and steroid-induced), glaucoma, blindness from chronic uveitis or optic nerve involvement

— Hypercalcemic crisis with AKI

— Nephrolithiasis, nephrocalcinosis, CKD progression

— Granulomatous interstitial nephritis

— Steroid-related: osteoporosis, fractures, DM, hypertension, weight gain, cataracts, glaucoma, AVN of femoral head, infection, adrenal suppression

— PJP pneumonia on prolonged high-dose steroids — give TMP-SMX prophylaxis when prednisone ≥20 mg/day for ≥4 weeks

— TB reactivation, hepatitis B reactivation with TNF inhibitors

— Methotrexate pneumonitis (can mimic disease progression — high-yield distinction)

— Hydroxychloroquine retinopathy after >5 years use

Board pearl: A sarcoid patient on methotrexate presenting with new dyspnea, dry cough, and bilateral infiltrates — don't reflexively escalate immunosuppression; methotrexate pneumonitis must be ruled out by stopping the drug and reassessing.

Pulmonary fibrosis (Stage IV) — upper lobe predominant, traction bronchiectasis, honeycombing; leads to respiratory failure, pulmonary hypertension, cor pulmonale

Aspergilloma (mycetoma) in fibrocavitary disease — massive hemoptysis is leading cause of disease-specific mortality in advanced sarcoid; manage with bronchial artery embolization or surgical resection

Pulmonary hypertension (Group 5) — disproportionate dyspnea, low DLCO, right heart failure; poor prognostic sign

Cardiac sarcoidosis complications:

Neurosarcoidosis sequelae:

Ocular:

Metabolic/renal:

Hematologic: severe lymphopenia, splenic sequestration, rarely myelophthisis

Iatrogenic complications:

Psychosocial: fatigue (often disabling and persistent even after disease control), depression, "small fiber neuropathy" syndrome with autonomic dysfunction

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

— Hypercalcemic crisis (Ca >14 mg/dL or symptomatic) — IV fluids, calcitonin, IV steroids

— Acute respiratory failure or severe hypoxemia

— Massive hemoptysis from aspergilloma — airway protection, embolization

— New high-grade AV block, sustained VT, syncope from cardiac sarcoid — telemetry, EP consult, consider temporary pacing

— Acute neurosarcoidosis with encephalopathy, seizures, optic neuritis, or spinal cord involvement — IV methylprednisolone pulse, neurology

— Acute kidney injury from interstitial nephritis or hypercalcemia

— Adrenal crisis in steroid-dependent patient with intercurrent illness — stress-dose hydrocortisone

— Pulmonology: every newly diagnosed patient for staging and longitudinal care

— Cardiology / EP: any ECG abnormality, syncope, palpitations, or unexplained heart failure in a sarcoid patient

— Ophthalmology: slit-lamp evaluation at diagnosis for every patient regardless of symptoms; routine surveillance

— Neurology: any new neurologic symptom; LP, MRI

— Nephrology: AKI, persistent hypercalciuria, recurrent stones, proteinuria

— Dermatology: lupus pernio, refractory cutaneous disease

— Rheumatology: chronic arthritis, multisystem coordination

— ENT: upper airway involvement (sinonasal, laryngeal — can cause stridor)

— New syncope or palpitations in known sarcoid → admit, telemetry

— Rapidly progressive dyspnea with hypoxemia → CT to rule out PE, infection, progression

— Visual changes → same-day ophthalmology

— Severe headache, confusion, focal deficits → MRI brain

— Fever on immunosuppression → broad infectious workup, including opportunistic infections (PJP, fungal, TB, CMV)

Step 3 management: A sarcoid patient on chronic prednisone presenting with fever and dyspnea gets a full sepsis workup, PJP coverage considered (TMP-SMX), stress-dose steroids if hemodynamically unstable, and broad imaging — assume immunocompromise.

ICU/inpatient admission criteria:

Consult triggers:

Outpatient → urgent inpatient transition red flags (Step 3 favorites):

Key Differentials — Same-Category (Granulomatous and Interstitial) Causes

— Caseating granulomas (vs noncaseating in sarcoid)

— Upper lobe cavitary disease, often unilateral; mediastinal adenopathy often necrotic

— AFB smear/culture, NAAT, IGRA positive

— Must rule out before steroid therapy

— Histoplasmosis (Ohio/Mississippi River valleys) — can produce bilateral hilar adenopathy, granulomas, even erythema nodosum

— Coccidioidomycosis (Southwest US) — similar; erythema nodosum common ("desert rheumatism")

— Blastomycosis — skin and lung

— Serologies, urine antigens, fungal cultures

— Histologically indistinguishable from sarcoid

— Occupational exposure (aerospace, ceramics, nuclear, dental labs)

— Diagnosis: BeLPT on blood or BAL

— Antigen exposure (birds, molds, hot tubs)

— Poorly formed granulomas, lymphocytic infiltrate (CD4/CD8 <1, opposite of sarcoid)

— Centrilobular ground-glass nodules, mosaic attenuation; mid-lung predominance

— c-ANCA/PR3 positive

— Necrotizing granulomas, vasculitis, upper airway destruction, glomerulonephritis

— Cavitary lung nodules rather than perilymphatic micronodules

— Hypogammaglobulinemia, recurrent sinopulmonary infections

— Check immunoglobulin levels in atypical or recurrent presentations

Key distinction: Sarcoidosis = perilymphatic nodules, upper lobe, CD4/CD8 >3.5, noncaseating; Hypersensitivity pneumonitis = centrilobular nodules, mid-lung, CD4/CD8 <1, poorly formed granulomas, identifiable antigen.

Tuberculosis:

Endemic fungal infections:

Chronic beryllium disease:

Hypersensitivity pneumonitis:

Granulomatosis with polyangiitis (GPA):

Common variable immunodeficiency (CVID) with granulomatous-lymphocytic interstitial lung disease:

Drug-induced granulomas: methotrexate, interferons, ICIs, BCG, TNF inhibitors (paradoxical)

Foreign body / talc granulomatosis: IV drug use

Idiopathic pulmonary fibrosis: lower lobe, subpleural honeycombing (vs sarcoid upper lobe fibrosis), older patients, no granulomas

Key Differentials — Other-Category Causes

— Bilateral hilar/mediastinal adenopathy

— B symptoms overlap (fever, weight loss, night sweats)

— Sarcoid-lymphoma syndrome — patients with sarcoidosis have increased lymphoma risk

— Excisional lymph node biopsy is critical when imaging or clinical features atypical (asymmetric adenopathy, bulky nodes, rapid growth, elevated LDH)

— Lacrimal/parotid swelling (mimics Heerfordt), pancreatic, retroperitoneal involvement

— Elevated serum IgG4; storiform fibrosis with IgG4+ plasma cells on biopsy

— Mediastinal adenopathy (lymphoma, mycobacterial), opportunistic infections

— IRIS can produce sarcoid-like granulomatous reactions after ART initiation

— Lyme carditis (tick exposure, endemic area, erythema migrans)

— Giant cell myocarditis (rapidly progressive, fulminant)

— Chagas disease (Latin American origin)

— Familial cardiomyopathy with conduction disease (lamin A/C mutations)

— Primary hyperparathyroidism (high PTH; sarcoid has suppressed PTH, high 1,25-D)

— Malignancy (PTHrP, lytic lesions)

— Vitamin D toxicity

— Other granulomatous diseases (TB, fungal, GPA, berylliosis — all activate 1α-hydroxylase)

Board pearl: In a sarcoidosis patient with rapidly enlarging asymmetric lymphadenopathy or new B symptoms despite stable disease, biopsy to rule out lymphoma — sarcoid-lymphoma association is a tested vignette.

Lymphoma (Hodgkin and non-Hodgkin):

Metastatic malignancy: lung primary, breast, head/neck, GU cancers can produce mediastinal adenopathy; PET-CT and biopsy

Castleman disease: HHV-8 associated multicentric form mimics multisystem inflammatory disease with adenopathy

IgG4-related disease:

Systemic lupus erythematosus / Sjögren / RA: overlap with arthralgia, sicca, fatigue; ANA, RF, anti-CCP, anti-Ro/La

Behçet disease: uveitis, oral/genital ulcers, vasculitis

HIV-related disease:

Berylliosis (cross-listed — occupational mimic)

Cardiac differentials in young patient with AV block:

Hypercalcemia differentials:

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Goal: lowest effective dose of immunosuppression that controls organ disease

— Steroid taper to ≤10 mg/day prednisone equivalent by 6 months when possible

— Continue steroid-sparing agent for at least 12 months after disease quiescence before considering taper

— Plan for relapses — common in first 2–3 years after stopping therapy; many patients need lifelong low-dose therapy

— TMP-SMX for PJP prophylaxis if prednisone ≥20 mg/day for ≥4 weeks or on combination immunosuppression

— Calcium 1000–1200 mg/day and vitamin D 800 IU/day — only if no hypercalcemia/hypercalciuria and 25-OH-D low; otherwise withhold and counsel sun avoidance

— Bisphosphonate (alendronate or zoledronic acid) for any patient on ≥5 mg prednisone for ≥3 months expected duration, especially postmenopausal women and men >50

— PPI if NSAID use or GI risk

— Annual influenza (inactivated)

— Pneumococcal (PCV20 or PCV15→PPSV23 sequence)

— COVID-19 boosters per current schedule

— Recombinant zoster (Shingrix) age ≥19 if immunocompromised

— Tdap booster

— Hepatitis B if seronegative, especially before TNF inhibitor

— Avoid live vaccines (MMR, varicella, yellow fever, live zoster, intranasal flu) on high-dose immunosuppression

— Smoking cessation, alcohol moderation (hepatotoxicity with MTX)

— Sun protection if hypercalcemic

— Pulmonary rehabilitation for symptomatic patients

— Cardiac rehab if cardiac involvement

— Mental health: screen for depression and fatigue at every visit

— Driving restrictions if cardiac sarcoid with arrhythmia history (per state DMV/ICD guidelines)

Step 3 management: Every patient discharged on chronic glucocorticoids needs a written steroid sick-day plan (stress-dose education), a bone health prescription, PJP prophylaxis when indicated, and vaccinations updated — these are the most-tested secondary prevention items.

Disease-modifying maintenance:

Standing prophylaxis on immunosuppression:

Vaccination plan (give before immunosuppression escalation when possible):

Lifestyle and counseling:

Follow-Up, Monitoring Parameters, and Rehab/Counseling

— Untreated mild disease: every 3–6 months for first 2 years, then annually if stable, for at least 3 years after apparent remission (relapses common)

— Treated active disease: every 4–6 weeks initially during induction, then every 3 months once stable

— Lifelong follow-up for chronic disease

— PFTs with DLCO every 3–6 months on therapy, annually if stable

— Chest imaging (CXR or HRCT) every 6–12 months depending on activity

— 6-minute walk test for functional decline

— Pulse oximetry at rest and ambulation

— ECG annually in all sarcoid patients

— Echo if symptoms or ECG changes

— In known cardiac sarcoid: serial cardiac MRI and/or FDG-PET to assess inflammation; Holter for arrhythmia surveillance

— Methotrexate: CBC, LFTs, Cr every 4–8 weeks; folate daily; alcohol minimization

— Azathioprine: TPMT activity baseline; CBC, LFTs

— Hydroxychloroquine: baseline and annual eye exam after 5 years (or sooner if risk factors); ECG (QT)

— Infliximab: latent TB and HBV screening; infusion reactions; CHF caution

— Prednisone: BP, glucose/A1c, weight, DEXA every 1–2 years, lipid panel

— Pulmonary rehab improves exercise capacity and quality of life

— Fatigue management: graded exercise, sleep hygiene, screen for OSA (sarcoid + obesity + upper airway involvement)

— Smoking cessation counseling at every visit

— Patient education on infection precautions while immunosuppressed: hand hygiene, food safety (listeria), avoid sick contacts, travel counseling

— Disability assessment for chronic fatigue or severe disease — connect to social work, vocational support

CCS pearl: Advance the clock on a sarcoid follow-up case and order serial PFTs (especially FVC and DLCO), CXR, ECG, and CMP — the parser rewards systematic surveillance over reactive testing.

Monitoring cadence:

Pulmonary monitoring:

Cardiac monitoring:

Ocular: ophthalmology every 6–12 months even if asymptomatic; sooner if active disease

Metabolic/renal: serum and urine calcium, creatinine, UA every 3–6 months

Hepatic: LFTs every 1–3 months on MTX/azathioprine/leflunomide

Hematologic: CBC every 1–3 months on immunosuppression

Drug-specific monitoring:

Rehabilitation and counseling:

Ethical, Legal, and Patient Safety Considerations

— Document discussion of infection risk (including opportunistic), malignancy risk (esp. with prolonged TNF inhibitor or azathioprine — skin cancer, lymphoma), teratogenicity, and long-term steroid toxicities

— Discuss uncertainty of natural history — many patients remit; shared decision-making about whether to treat asymptomatic Stage I disease is essential

— Patients with cardiac sarcoid and sustained VT, ICD shocks, or syncope have driving restrictions (typically 6 months after event for private driving, longer for commercial; varies by state)

— Commercial pilots, drivers, heavy machinery operators with significant pulmonary or cardiac disease may require occupational reassignment — coordinate with employer/occupational medicine

— Physicians may have mandatory reporting obligations to state DMV for impaired drivers in some jurisdictions — know your state law

— Chronic beryllium disease (sarcoid mimic) — workers' compensation eligible; failure to test BeLPT in at-risk occupations is a legal and clinical safety issue

— Document occupational history meticulously

— At hospital discharge, ensure continuation of prednisone with explicit taper schedule — abrupt discontinuation causes adrenal crisis

— Reconcile that patient understands stress-dose steroid plan for illness/surgery

— Ensure outpatient follow-up scheduled with pulmonology within 2–4 weeks; medication adherence review

— Communicate active sarcoid medications to all providers — TNF inhibitors and high-dose steroids change perioperative and infectious risk assessments

— Medication reconciliation: avoid OTC vitamin D and calcium supplements without checking hypercalcemia status

— Lung transplant candidates: balance recurrence risk; counsel honestly

— Sarcoid patients are generally not excluded from organ donation but case-by-case

— Discuss teratogenic medications (MTX, mycophenolate, leflunomide) with both partners; contraception during treatment; pre-conception medication switch

— Document discussion in the chart

— Sarcoidosis disproportionately affects Black Americans yet historically underrepresented in research — encourage equitable trial enrollment

Board pearl: A young patient with cardiac sarcoidosis and a recent VT episode who continues to drive a commercial truck — your duty includes counseling cessation, documenting it, and reporting per state law even when the patient objects; patient safety and public safety override autonomy in mandated reporting jurisdictions.

Informed consent for immunosuppression:

Driving and occupational safety:

Occupational disease and workers' compensation:

Transition-of-care risks (Step 3 high-yield):

Living donor and transplant ethics:

Reproductive counseling:

Research participation and equity:

High-Yield Associations and Rapid-Fire Clinical Facts

Step 3 management: When you see bilateral hilar adenopathy + erythema nodosum + ankle arthralgia + low-grade fever in a young patient, the answer is observation with NSAIDs — not steroids and not biopsy.

Löfgren syndrome = fever + bilateral hilar adenopathy + erythema nodosum + ankle arthralgia → excellent prognosis, often no biopsy needed

Heerfordt syndrome = uveitis + parotitis + facial nerve palsy + fever

Lupus pernio = chronic facial plaques, predicts refractory multisystem disease

Scadding Stage IV = irreversible fibrosis, upper lobe predominant

CD4/CD8 ratio on BAL >3.5 supports sarcoid (vs HP <1)

Noncaseating granulomas with asteroid bodies and Schaumann bodies

Hypercalcemia mechanism: 1α-hydroxylase in granulomas → ↑1,25-(OH)₂-vitamin D → ↑gut Ca absorption; PTH suppressed

ACE level = unreliable, do not use for diagnosis or monitoring

Most common cranial nerve affected = CN VII (facial)

Most common cardiac manifestation = conduction disease (AV block) in young adult

Most common ocular finding = anterior uveitis

Most common cutaneous finding = erythema nodosum (acute) / lupus pernio (chronic)

Most common cause of mortality in advanced disease = pulmonary fibrosis with respiratory failure; cardiac sudden death increasingly recognized

Demographic anchor = young Black woman, Scandinavian

Vaccines before immunosuppression: pneumococcal, influenza, COVID, Shingrix, HBV; avoid live vaccines once immunosuppressed

PJP prophylaxis when prednisone ≥20 mg/day ≥4 weeks

Bisphosphonate when prednisone ≥5 mg/day ≥3 months

Latent TB and HBV screen before TNF inhibitor

Sarcoid-lymphoma syndrome — increased lymphoma risk

Methotrexate pneumonitis mimics disease progression — stop drug to differentiate

Beryllium lymphocyte proliferation test in occupational exposures

Lyme carditis vs cardiac sarcoid — both cause AV block in young patients; geography, exposure, EM rash distinguish

Vitamin D supplementation in sarcoid → can precipitate hypercalcemia → avoid unless deficient and monitored

Bilateral facial nerve palsy in young adult — think sarcoid, Lyme, GBS, HIV

Board Question Stem Patterns

Board pearl: When a stem gives you young adult + new AV block + bilateral hilar adenopathy on CXR, the test wants cardiac MRI/PET, not immediate device placement, and steroids before pacemaker in the treatment plan.

Stem 1 — Incidental hilar adenopathy: 32-year-old asymptomatic Black woman, routine chest film for employment shows bilateral hilar adenopathy, otherwise well. Best next step? Answer: HRCT chest, PFTs, ophthalmologic exam, ECG, calcium, TB testing; biopsy if any atypical features. Treatment: observation if asymptomatic.

Stem 2 — Löfgren presentation: Young woman with fever, painful red shin nodules, ankle swelling, bilateral hilar adenopathy. Answer: clinical diagnosis of Löfgren; NSAIDs for symptoms; no steroids, no biopsy needed if classic.

Stem 3 — Cardiac sarcoid: 35-year-old man with syncope, ECG shows complete heart block. Best next step beyond temporary pacing? Answer: cardiac MRI with gadolinium and/or FDG-PET; do not place permanent pacemaker before evaluating for treatable granulomatous inflammation; consider ICD criteria.

Stem 4 — Hypercalcemia: Sarcoidosis patient with Ca 12.5, low PTH, elevated 1,25-vitamin D. Management? Answer: hydration, prednisone, avoid vitamin D and calcium supplements, sun protection.

Stem 5 — ACE level distractor: Patient with bilateral hilar adenopathy, ACE normal. Does this rule out sarcoid? Answer: no — ACE has poor sensitivity; do not use to diagnose or exclude.

Stem 6 — Methotrexate pneumonitis: Sarcoid patient on MTX with new dyspnea and infiltrates. Next step? Answer: stop MTX, rule out infection (BAL), reassess.

Stem 7 — Bilateral facial palsy: Differential includes sarcoidosis, Lyme, GBS, HIV.

Stem 8 — Berylliosis mimic: Aerospace worker with bilateral hilar adenopathy and noncaseating granulomas. Next step? Answer: BeLPT.

Stem 9 — Pregnancy: Sarcoid woman planning pregnancy on methotrexate. Action? Answer: discontinue MTX before conception; switch to azathioprine, hydroxychloroquine, or low-dose prednisone; folate.

Stem 10 — Steroid bone disease: Patient on prednisone 15 mg/day for 6 months. Order? Answer: DEXA, bisphosphonate, calcium/vitamin D titrated to Ca levels.

Stem 11 — Stage IV with hemoptysis: Sarcoid fibrosis, new massive hemoptysis. Diagnosis? Answer: aspergilloma in cavity; bronchial artery embolization.

Stem 12 — Uveitis screening: New sarcoidosis. Why ophthalmology referral if asymptomatic? Answer: occult uveitis prevalence; preserve vision.

Stem 13 — Lung transplant referral: FVC <50% predicted with progressive disease. Answer: transplant evaluation.

One-Line Recap

Sarcoidosis is a multisystem noncaseating granulomatous disease that, on Step 3, is diagnosed by a compatible clinico-radiographic picture plus tissue confirmation and exclusion of mimics — treated with glucocorticoids and steroid-sparing agents only when organ function is threatened, with vigilant surveillance of lungs, heart, eyes, and calcium.

Board pearl: The Step 3 sarcoidosis vignette rewards restraint — observe when you can, treat when an organ is at risk, taper to the lowest effective dose, and never forget the heart, eyes, and calcium.

Diagnostic anchor: bilateral hilar adenopathy in a young adult (often Black or Scandinavian) — confirm with EBUS-TBNA biopsy showing noncaseating granulomas; ACE level is unreliable and CD4/CD8 >3.5 on BAL supports diagnosis; always exclude TB, fungal disease, beryllium, and lymphoma.

Treatment decision rule: treat only for organ dysfunction or significant symptoms — Stage I asymptomatic disease is observed; classic Löfgren syndrome is managed with NSAIDs alone; cardiac, neurologic, ocular, severe pulmonary, hypercalcemic, or renal involvement warrants prednisone with planned steroid-sparing transition (methotrexate, azathioprine, mycophenolate, hydroxychloroquine, or infliximab for refractory disease).

Safety bundle on immunosuppression: vaccinate before starting (avoid live vaccines after), screen for latent TB and HBV before TNF inhibitors, add PJP prophylaxis at prednisone ≥20 mg/day ≥4 weeks, start bisphosphonate for prolonged steroids, avoid vitamin D supplementation if hypercalcemic, and counsel reproductive-age patients about teratogenic agents.

Surveillance and red flags: serial PFTs (FVC, DLCO), annual ECG, ophthalmology every 6–12 months, calcium and renal function checks; escalate immediately for new arrhythmia or syncope (cardiac sarcoid), visual change (uveitis/optic neuritis), neurologic deficits (neurosarcoidosis), massive hemoptysis (aspergilloma), or asymmetric lymphadenopathy (sarcoid-lymphoma syndrome).