Allergy & Immunology

01 Immune System Anatomy & Physiology

The immune system is a distributed network of organs, cells, and soluble mediators that protects the host from pathogens, toxins, and aberrant cells. It is conventionally divided into innate immunity (rapid, non-specific, no memory) and adaptive immunity (slower onset, antigen-specific, generates immunological memory). Allergy and immunodeficiency arise from dysregulation or deficiency of these components.

Innate Immunity

The innate immune system provides immediate defense within hours. Key components include physical barriers (skin, mucosal epithelium, ciliary clearance), soluble factors (complement, lysozyme, defensins, interferons), and cellular effectors. Neutrophils are the most abundant circulating leukocytes (60–70% of WBCs) and the first responders to bacterial infection via phagocytosis and degranulation. Macrophages (tissue-resident monocyte derivatives) perform phagocytosis, antigen presentation, and cytokine secretion. Natural killer (NK) cells are large granular lymphocytes that kill virus-infected and tumor cells without prior sensitization via perforin/granzyme release. Dendritic cells (DCs) are the most potent antigen-presenting cells (APCs), bridging innate and adaptive immunity by processing antigens and presenting them via MHC molecules to T cells.

Mast Cells, Basophils, & Eosinophils

Mast cells are tissue-resident effectors found in skin, airways, and gut mucosa. They bear high-affinity IgE receptors (FcεRI) and are the central effectors of type I hypersensitivity. Cross-linking of surface-bound IgE by multivalent allergen triggers degranulation, releasing histamine, tryptase, heparin, proteases, and lipid mediators (prostaglandin D2, leukotriene C4). Basophils (<1% of circulating WBCs) also express FcεRI and release histamine and IL-4/IL-13, amplifying Th2 responses. Eosinophils (1–3% of WBCs) contain cytotoxic granules (major basic protein, eosinophil peroxidase, eosinophil cationic protein) and are key effectors in helminth defense, allergic inflammation, and eosinophilic disorders. Eosinophil survival is driven by IL-5 (the target of mepolizumab and benralizumab).

Adaptive Immunity — T Cells

T lymphocytes mature in the thymus and mediate cell-mediated immunity. CD4+ T helper (Th) cells recognize antigen presented via MHC class II on APCs and differentiate into functional subsets: Th1 (secrete IFN-γ, drive cell-mediated immunity against intracellular pathogens), Th2 (secrete IL-4, IL-5, IL-13; drive allergic inflammation, IgE class switching, eosinophilia), Th17 (secrete IL-17; mucosal defense, neutrophilic inflammation, autoimmunity), Treg (express FoxP3; suppress immune responses, maintain tolerance), and Tfh (follicular helper; support B-cell germinal center reactions). CD8+ cytotoxic T cells (CTLs) recognize antigen via MHC class I and directly kill infected or neoplastic cells via perforin/granzyme.

Adaptive Immunity — B Cells & Immunoglobulins

B lymphocytes mature in the bone marrow and produce antibodies (immunoglobulins). Upon antigen encounter and T-cell help, naïve B cells undergo class-switch recombination and somatic hypermutation in germinal centers, generating high-affinity antibody-secreting plasma cells and memory B cells. There are five immunoglobulin classes:

The Complement System

The complement system comprises >30 serum proteins activated via three pathways: classical (C1q binds antigen-antibody complexes — IgM or IgG), lectin (mannose-binding lectin binds pathogen surfaces), and alternative (spontaneous C3 hydrolysis, amplified on pathogen surfaces lacking complement regulatory proteins). All three converge on C3 convertase, which cleaves C3 to C3a (anaphylatoxin) and C3b (opsonin). C5 convertase generates C5a (most potent anaphylatoxin, neutrophil chemotaxis) and C5b, which initiates the membrane attack complex (MAC, C5b-9) that lyses target cells. Complement deficiencies predispose to specific infections: C1q/C2/C4 deficiency → SLE-like disease and encapsulated bacterial infections; C3 deficiency → severe pyogenic infections; C5–C9 (terminal) deficiency → recurrent Neisseria infections.

02 The Allergy & Immunology Evaluation

History

The allergy/immunology history is the single most important diagnostic tool. Key elements include: nature and timing of symptoms (seasonal vs perennial, immediate vs delayed), suspected triggers (foods, medications, stinging insects, environmental exposures), reproducibility of reactions, prior testing results, family history of atopy (allergic rhinitis, asthma, atopic dermatitis — the atopic triad), occupational exposures, and medication history (including OTC antihistamines, which must be held before skin testing). For immunodeficiency evaluation, document frequency and severity of infections, unusual organisms, failure to thrive, autoimmune manifestations, and family history of early death or immunodeficiency.

Physical Examination

Allergic signs include allergic shiners (infraorbital darkening from venous congestion), Dennie-Morgan lines (infraorbital skin folds), allergic salute (upward nose rubbing causing a transverse nasal crease), cobblestoning of posterior pharynx (lymphoid hyperplasia), pale/boggy nasal turbinates with clear rhinorrhea, and conjunctival injection with papillary reaction. Skin exam assesses for eczematous changes (flexural distribution in atopic dermatitis), urticaria (wheals), angioedema, and contact dermatitis patterns. Pulmonary exam assesses for wheezing, prolonged expiratory phase, and accessory muscle use. Lymphadenopathy, hepatosplenomegaly, and absence of tonsils/lymphoid tissue may suggest immunodeficiency.

Initial Laboratory Evaluation

03 Key Terminology & Abbreviations

Allergy and immunology uses a dense vocabulary of abbreviations across clinical documentation, research, and guidelines.

04 Allergic Rhinitis

Allergic rhinitis (AR) affects 10–30% of adults and up to 40% of children worldwide. It is an IgE-mediated inflammatory condition of the nasal mucosa triggered by aeroallergens, causing sneezing, rhinorrhea, nasal congestion, and pruritus. AR significantly impairs quality of life, sleep, and work/school productivity and is the strongest risk factor for developing asthma.

Pathophysiology

Inhaled allergens are processed by mucosal dendritic cells, which present peptides to Th2 cells. This drives IgE production by B cells, with IgE binding to FcεRI on nasal mast cells. Re-exposure causes allergen cross-linking of IgE, triggering the early-phase response (minutes: histamine, tryptase, prostaglandins, leukotrienes → sneezing, rhinorrhea, pruritus) and the late-phase response (4–8 hours: eosinophil and basophil recruitment via IL-5, RANTES, eotaxin → persistent nasal congestion). This late-phase inflammation underlies the concept of "priming" — repeated allergen exposure lowers the threshold for symptom triggering.

ARIA Classification

Management

Allergen avoidance is foundational but often insufficient alone. Intranasal corticosteroids (INCS) are first-line for moderate-severe AR (fluticasone propionate 1–2 sprays/nostril daily, mometasone, budesonide) — most effective single agent for all nasal symptoms including congestion. Second-generation antihistamines (cetirizine 10 mg, loratadine 10 mg, fexofenadine 180 mg daily) are first-line for mild AR and add-on for moderate-severe. Intranasal antihistamines (azelastine 1–2 sprays/nostril BID) have faster onset than INCS (15 min vs days). The combination of INCS + intranasal antihistamine (e.g., fluticasone/azelastine [Dymista]) is superior to either alone for moderate-severe AR. Montelukast 10 mg daily is modestly effective but carries an FDA black box warning for neuropsychiatric events (2020). Intranasal cromolyn is safe but less effective; useful in pregnancy. Allergen immunotherapy (SCIT or SLIT) is disease-modifying and indicated for moderate-severe AR inadequately controlled with pharmacotherapy.

05 Non-Allergic Rhinitis

Non-allergic rhinitis (NAR) accounts for ~25% of rhinitis cases and is a diagnosis of exclusion (negative skin testing/sIgE). It presents with nasal congestion and rhinorrhea but typically lacks sneezing and pruritus. Recognizing NAR subtypes prevents unnecessary allergen avoidance and immunotherapy.

Subtypes

06 Chronic Rhinosinusitis & Nasal Polyps

Chronic rhinosinusitis (CRS) is defined as sinonasal inflammation lasting ≥12 weeks with at least 2 of: nasal obstruction/congestion, mucopurulent drainage, facial pain/pressure, and hyposmia/anosmia — confirmed by objective evidence (endoscopic findings or CT changes). CRS affects ~12% of adults and is divided into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), which have distinct pathophysiology and treatment approaches.

CRS Without Nasal Polyps (CRSsNP)

Predominantly Th1/neutrophilic inflammation. Often associated with recurrent bacterial sinusitis, anatomic obstruction (deviated septum, concha bullosa), and biofilm formation. Management: saline irrigations, INCS (mometasone or budesonide irrigations), short-course antibiotics for acute exacerbations, and functional endoscopic sinus surgery (FESS) for refractory cases.

CRS With Nasal Polyps (CRSwNP)

Predominantly Th2/eosinophilic inflammation with elevated tissue IL-4, IL-5, IL-13, and local IgE. Polyps arise from edematous mucosa in the middle meatus and ethmoid sinuses. Strongly associated with asthma (especially severe/eosinophilic), AERD (Samter's triad: nasal polyps + asthma + NSAID sensitivity), and allergic fungal sinusitis (AFS). Management: INCS (high-volume budesonide irrigations), short oral steroid courses (prednisone 0.5 mg/kg × 5–7 days for flares), FESS for refractory obstruction, and biologics for recurrent polyps post-surgery.

Biologics for CRSwNP

Allergic Fungal Sinusitis (AFS)

AFS is a subset of CRSwNP caused by a hypersensitivity response to colonizing fungi (most commonly Aspergillus, Alternaria, Bipolaris). Diagnostic criteria (Bent-Kuhn): (1) nasal polyposis, (2) eosinophilic mucin with fungal hyphae on histology, (3) positive fungal stain or culture, (4) type I hypersensitivity to fungi (positive SPT or sIgE), and (5) characteristic CT findings (unilateral or asymmetric opacification with areas of hyperattenuation/"double density" sign). Treatment requires FESS for debridement, followed by INCS irrigations, systemic steroids for recurrence, and possibly antifungal therapy (itraconazole) in refractory cases.

07 Asthma Pathophysiology & Phenotypes

Asthma is a chronic inflammatory airway disease characterized by variable airflow obstruction, bronchial hyperresponsiveness, and airway remodeling. It affects ~300 million people worldwide with prevalence of 5–10% in adults and up to 15% in children.

Pathophysiology

Allergen exposure in genetically predisposed individuals drives Th2 inflammation: IL-4 and IL-13 stimulate goblet cell hyperplasia, mucus hypersecretion, and smooth muscle contraction; IL-5 recruits eosinophils; IgE sensitizes airway mast cells. Chronic inflammation leads to airway remodeling: subepithelial fibrosis, smooth muscle hypertrophy, neovascularization, and goblet cell metaplasia, causing fixed airflow obstruction. Airway hyperresponsiveness (AHR) — exaggerated bronchoconstriction to stimuli (cold air, exercise, methacholine) — is a hallmark feature.

Asthma Phenotypes

08 Asthma Severity & Stepwise Management

GINA/NAEPP Severity Classification (Treatment-Naïve Patients)

GINA Stepwise Approach (Adults/Adolescents ≥12 years, 2023 Update)

Asthma Control Assessment (GINA)

09 Acute Asthma Exacerbation

Exacerbation Severity Classification

Disposition Criteria

Discharge criteria: PEF ≥70% predicted, SpO2 ≥94% on room air, able to speak in full sentences, adequate medication understanding, and access to follow-up within 1–2 days. Discharge with: oral prednisone 40–50 mg daily × 5–7 days, SABA PRN, and controller therapy (initiate or step up ICS). Admission criteria: PEF <40% after initial treatment, persistent hypoxemia, prior ICU admission for asthma, multiple ED visits, or concerning social factors. ICU criteria: PEF <25%, PaCO2 ≥42 mmHg, altered mental status, hemodynamic instability, or need for non-invasive/invasive ventilation.

10 Asthma Biologics & Advanced Therapies

Biologic therapies target specific inflammatory pathways in severe asthma (GINA Step 5) and have transformed management of patients with T2-high disease. Selection is guided by phenotyping (blood eosinophils, FeNO, IgE, comorbidities).

Other Advanced Therapies

Long-acting muscarinic antagonists (LAMA): Tiotropium Respimat 2.5 μg/day is add-on at Step 4–5; reduces exacerbations independent of eosinophil status. Azithromycin 250–500 mg 3×/week may reduce exacerbations in non-eosinophilic asthma (AMAZES trial). Bronchial thermoplasty delivers radiofrequency energy to reduce airway smooth muscle mass; considered for severe refractory asthma not responsive to biologics (AIR2 trial showed reduction in severe exacerbations and ED visits).

11 Asthma-COPD Overlap & Special Phenotypes

Asthma-COPD Overlap (ACO)

ACO describes patients with persistent airflow limitation (post-bronchodilator FEV1/FVC <0.70) and features of both asthma (reversibility, eosinophilia, atopy, variable symptoms) and COPD (smoking history, age >40, progressive decline). ACO affects ~15–25% of patients with obstructive lung disease and carries worse outcomes than either condition alone (more exacerbations, faster FEV1 decline, poorer quality of life). Treatment: ICS-LABA is cornerstone (unlike pure COPD, where ICS are not first-line); add LAMA for persistent symptoms; avoid SABA-only or LABA-only; consider blood eosinophil levels to guide ICS use.

Occupational Asthma

Accounts for 10–25% of adult-onset asthma. Two forms: sensitizer-induced (IgE-mediated or T-cell-mediated; requires latency period; >400 known agents including isocyanates, flour dust, latex, animal dander) and irritant-induced (reactive airways dysfunction syndrome [RADS]; no latency, follows massive irritant exposure). Diagnosis requires demonstrating temporal relationship to workplace (serial PEF monitoring over 2–4 weeks), specific inhalation challenge, or positive sIgE to occupational allergen. Complete removal from exposure is the ideal treatment; continued exposure leads to irreversible obstruction.

Exercise-Induced Bronchoconstriction (EIB)

Occurs in up to 90% of asthmatics and 10–15% of the general population (especially elite athletes). Diagnosis: ≥10% fall in FEV1 from baseline within 30 minutes of a standardized exercise challenge (6–8 min of vigorous exercise at 85–90% max HR). Management: SABA 15 min before exercise (most effective single agent), daily ICS for athletes with frequent EIB, LTRA as alternative or add-on, adequate warm-up (induces refractory period of ~2 hours).

12 Anaphylaxis

Anaphylaxis is an acute, potentially fatal, multi-organ system hypersensitivity reaction. Incidence is ~50–112 episodes per 100,000 person-years; lifetime prevalence is 0.5–2%. Most common triggers are foods (children), medications (adults), and stinging insects. Mortality rate is 0.5–1% of anaphylaxis cases, with death occurring most commonly from airway compromise (food-triggered) or cardiovascular collapse (drug/venom-triggered).

NIAID/FAAN Diagnostic Criteria for Anaphylaxis

Anaphylaxis is highly likely when any 1 of 3 criteria is met:

Biphasic Anaphylaxis

A second phase of symptoms occurs in 1–20% of cases (most estimates 5–10%), typically 1–72 hours after resolution of the initial episode (median 8–10 hours). Risk factors: severe initial reaction, delayed epinephrine, unknown trigger, and previous biphasic reactions. All patients should be observed for at least 4–6 hours post-treatment (some guidelines recommend 12–24 hours for severe reactions). Prescribe epinephrine auto-injectors (minimum 2) and develop an anaphylaxis action plan at discharge.

13 Urticaria (Acute & Chronic)

Urticaria presents as pruritic, erythematous, raised wheals (hives) that are transient (<24 hours per individual lesion) and migratory. Classified as acute (<6 weeks duration) or chronic (≥6 weeks).

Acute Urticaria

Affects ~20% of people at some point in life. Most common causes: viral infections (especially in children), foods (nuts, shellfish, eggs, milk), medications (antibiotics, NSAIDs, opioids), insect stings, and latex. Often self-limited. Treatment: second-generation H1 antihistamine (cetirizine, loratadine, fexofenadine); if inadequate, add first-generation H1 antihistamine at night (hydroxyzine 25 mg, diphenhydramine 25–50 mg); short oral steroid course for severe episodes (prednisone 40 mg × 3–5 days).

Chronic Spontaneous Urticaria (CSU)

CSU occurs without a consistent external trigger. Most cases (80–90%) are idiopathic; autoimmune mechanisms (IgG anti-FcεRI or anti-IgE autoantibodies) are found in ~30–50% of cases. Associated with thyroid autoimmunity (check anti-TPO). Workup: CBC, ESR/CRP, TSH, anti-TPO; further testing only if clinical suspicion (e.g., complement levels, cryoglobulins, hepatitis serologies). Routine allergy testing is NOT indicated for CSU.

CSU Stepwise Management (EAACI/GA2LEN/WAO Guidelines)

14 Angioedema

Angioedema is localized, non-pitting swelling of deep dermal, subcutaneous, or submucosal tissue. The critical distinction is between histaminergic (mast cell–mediated) and bradykinin-mediated angioedema, as treatment differs fundamentally.

Histaminergic vs Bradykinin-Mediated Angioedema

ACE Inhibitor–Induced Angioedema

Occurs in 0.1–0.7% of ACE inhibitor users; 3–5× more common in Black patients. Can occur at any point during treatment (even after years of use). Mechanism: ACE normally degrades bradykinin; inhibition leads to bradykinin accumulation. Treatment: discontinue ACE inhibitor permanently (do NOT substitute another ACE inhibitor; ARBs are generally safe with ~1–2% cross-reactivity). For acute episodes: supportive care, airway management, consider icatibant (off-label) or fresh frozen plasma. Antihistamines, epinephrine, and steroids are ineffective.

Hereditary Angioedema (HAE)

HAE Treatment

Acute attack treatment: C1-INH concentrate (Berinert 20 IU/kg IV, or Cinryze 1000 IU IV), icatibant (bradykinin B2 receptor antagonist, 30 mg SC), ecallantide (kallikrein inhibitor, 30 mg SC), or recombinant C1-INH (Ruconest 50 IU/kg IV). FFP is an alternative if specific therapies are unavailable. Long-term prophylaxis: lanadelumab (anti-kallikrein monoclonal Ab, 300 mg SC q2w; reduced attacks by 87% in HELP trial), berotralstat (oral kallikrein inhibitor, 150 mg PO daily; APEX trial), C1-INH concentrate prophylaxis (Cinryze 1000 IU IV q3–4 days, or Haegarda 60 IU/kg SC 2×/week). Short-term prophylaxis (before dental/surgical procedures): C1-INH concentrate 1–2 hours before procedure.

15 Drug Hypersensitivity & Desensitization

Gell-Coombs Classification of Hypersensitivity

Penicillin Allergy

~10% of patients report penicillin allergy, but >90% are NOT truly allergic upon evaluation. Penicillin allergy evaluation reduces unnecessary use of broad-spectrum antibiotics (vancomycin, fluoroquinolones, carbapenems) and decreases healthcare costs, C. difficile, and antimicrobial resistance. Evaluation: History risk-stratify into low-risk (remote, non-severe reactions >10 years ago), moderate-risk (urticaria/mild symptoms), and high-risk (anaphylaxis, DRESS, SJS/TEN). Low-risk: direct oral amoxicillin challenge (500 mg, observe 1 hour). Moderate-risk: skin testing with penicilloyl polylysine (major determinant), penicillin G (minor determinant), ampicillin, amoxicillin; negative predictive value ~97–99%; if negative, followed by oral amoxicillin challenge. High-risk (SJS/TEN, DRESS): do NOT skin test or challenge — permanently avoid penicillins and carbapenems.

Drug Desensitization

Drug desensitization is a temporary induction of tolerance to a medication to which a patient has a type I (IgE-mediated) hypersensitivity. It works by gradual, incrementally increasing sub-threshold doses that do not trigger mast cell degranulation. It is indicated when there is no adequate alternative (e.g., penicillin for neurosyphilis, aspirin for AERD, chemotherapy hypersensitivity, insulin allergy). Desensitization is performed in a monitored setting (ICU or step-down unit) with epinephrine at bedside. Typical protocols involve 12–16 steps doubling the dose every 15–30 minutes. The desensitized state is temporary — if the drug is interrupted for >2 half-lives, the patient reverts to the allergic state and requires re-desensitization.

Severe Cutaneous Adverse Drug Reactions (SCARs)

16 Serum Sickness & Immune Complex Reactions

Serum sickness is a type III hypersensitivity reaction caused by circulating immune complexes that deposit in blood vessels and tissues, activating complement and causing inflammation. Classic serum sickness follows administration of heterologous serum (e.g., antithymocyte globulin, equine-derived antivenoms) or, less commonly, certain drugs.

Clinical Features

Onset 7–21 days after initial exposure (shorter with re-exposure). Classic triad: fever, urticaria/rash (often at hands/feet borders), and polyarthralgia/arthritis (multiple joints, migratory). Other features: lymphadenopathy, splenomegaly, glomerulonephritis, vasculitis. Laboratory findings: low C3 and C4, elevated ESR, proteinuria, positive circulating immune complexes. Treatment is usually self-limited after trigger removal; NSAIDs or prednisone 0.5–1 mg/kg/day tapered over 2–3 weeks for severe cases.

Serum Sickness–Like Reaction (SSLR)

SSLR is a clinically similar but immunologically distinct entity (no immune complexes, complement levels normal). Most common in children after cefaclor, but also seen with other beta-lactams, bupropion, and infliximab. Presents with fever, rash (urticarial or morbilliform), and arthralgias 1–3 weeks after drug exposure. Self-limited upon drug discontinuation; treated symptomatically with antihistamines and short steroid course if needed.

17 IgE-Mediated Food Allergy

IgE-mediated food allergy affects ~6–8% of children and ~3–4% of adults. It causes reproducible symptoms within minutes to 2 hours of ingestion. Nine foods account for >90% of food allergies in the US: milk, egg, peanut, tree nuts, wheat, soy, fish, shellfish, and sesame (added to major allergen list in 2023).

Clinical Manifestations

Diagnosis

Diagnosis requires clinical history of reproducible symptoms + evidence of sensitization (positive SPT or sIgE). Neither SPT nor sIgE alone confirms clinical allergy (sensitization ≠ allergy). Component-resolved diagnostics (CRD) improves specificity: e.g., peanut Ara h 2 sIgE ≥0.35 kU/L has >95% PPV for clinical peanut allergy; Ara h 8 (PR-10 protein) positivity with negative Ara h 2 suggests oral allergy syndrome only (low anaphylaxis risk). The oral food challenge (OFC) is the gold standard — open or double-blind, placebo-controlled food challenge (DBPCFC) in a supervised setting with graded doses over 2–4 hours, with observation period of 2 hours post-last dose.

Natural History

Most childhood milk, egg, wheat, and soy allergies resolve by age 5–10 (milk ~80% by age 16, egg ~70%). Peanut, tree nut, fish, and shellfish allergies are more persistent (~80% lifelong for peanut; ~90% for tree nut). Declining sIgE levels over time predict clinical tolerance; periodic re-evaluation with OFC is appropriate.

Food Allergy Prevention

The LEAP trial (2015) demonstrated that early introduction of peanut (at 4–6 months) in high-risk infants (those with severe eczema and/or egg allergy) reduced peanut allergy by 81% compared to avoidance. Current guidelines (AAP, NIAID): introduce peanut protein early (~4–6 months) in high-risk infants, after SPT or sIgE screening; no restriction of allergenic foods during pregnancy or lactation.

Oral Immunotherapy (OIT)

Palforzia (peanut allergen powder) is FDA-approved for peanut allergy ages 4–17 years. Protocol: initial dose escalation (day 1, observed, starting at 0.5 mg), up-dosing (biweekly escalation over ~6 months to 300 mg maintenance), then daily maintenance (300 mg indefinitely). PALISADE trial showed 67% of treated patients tolerated 600 mg peanut protein at exit OFC vs 4% placebo. Risks: GI side effects (~90%), anaphylaxis (~14% during up-dosing), eosinophilic esophagitis (~3%). Patients must continue to carry epinephrine and avoid exercise 2 hours after dosing.

18 Non-IgE Food Allergy (FPIES) & Mixed Disorders

Food Protein–Induced Enterocolitis Syndrome (FPIES)

FPIES is a non-IgE-mediated food allergy presenting in infancy (typically <9 months) with profuse vomiting 1–4 hours after ingestion of a trigger food, often followed by diarrhea, lethargy, and pallor. Severe episodes can cause dehydration, hypothermia, methemoglobinemia, and shock-like presentation (15–20% of acute episodes). Most common triggers: cow's milk, soy, rice, oats. Diagnosis is clinical (no reliable biomarker; sIgE and SPT are usually negative). OFC is confirmatory but not always needed if history is classic. Treatment of acute episodes: IV fluids, ondansetron 0.15 mg/kg IV/IM (shown to stop vomiting in acute FPIES). Most children outgrow FPIES by age 3–5 (milk/soy by 1–3 years; rice/oat by 3–5 years).

Food Protein–Induced Allergic Proctocolitis (FPIAP)

Benign condition in breast-fed infants presenting with mucousy, blood-streaked stools in an otherwise healthy, thriving infant. Most commonly triggered by cow's milk protein in maternal diet. Diagnosis is clinical. Management: maternal elimination of cow's milk (and sometimes soy, egg); if formula-fed, switch to extensively hydrolyzed formula or amino acid formula. Resolves by 12 months in most cases.

Food Protein–Induced Enteropathy (FPE)

Non-IgE-mediated small bowel inflammation causing chronic diarrhea, malabsorption, failure to thrive, and hypoalbuminemia in infants. Most common trigger: cow's milk. Villous atrophy on biopsy (mimics celiac disease but no anti-tTG/anti-DGP antibodies). Treatment: avoidance of trigger; most outgrow by age 2–3.

19 Eosinophilic Esophagitis

Eosinophilic esophagitis (EoE) is a chronic, immune/antigen-mediated esophageal disease characterized by symptoms of esophageal dysfunction and eosinophilic infiltration of the esophageal mucosa. Prevalence has increased dramatically (~1 in 2000); predominantly affects males (3:1), with peak incidence in the 30s–40s.

Clinical Presentation

Adults: dysphagia (most common, ~70%), food impaction (15–20% present as emergency food bolus), chest pain, heartburn refractory to PPI. Children: feeding difficulties, vomiting, failure to thrive, abdominal pain. Strongly associated with atopy (~70% have concomitant allergic diseases: allergic rhinitis, asthma, AD, food allergy, or peripheral eosinophilia).

Diagnosis

Requires both: (1) symptoms of esophageal dysfunction AND (2) esophageal biopsy showing ≥15 eosinophils per high-power field (eos/hpf) in ≥1 biopsy specimen. Take biopsies from proximal AND distal esophagus (2–4 biopsies from each location). PPI-responsive esophageal eosinophilia is now considered part of the EoE spectrum (not an exclusion). Endoscopic findings: linear furrows, white plaques/exudates, concentric rings ("trachealization"), edema, stricture, narrow-caliber esophagus (crepe paper mucosa).

Management

20 Oral Allergy Syndrome & Alpha-Gal Syndrome

Oral Allergy Syndrome (Pollen-Food Allergy Syndrome)

OAS results from cross-reactivity between aeroallergen pollen proteins and homologous proteins in raw fruits, vegetables, and nuts. Symptoms are typically limited to the oropharynx: oral/pharyngeal pruritus, tingling, and mild swelling of lips/tongue/palate within minutes of eating raw trigger foods. Symptoms resolve spontaneously within 30 minutes. Systemic reactions are rare (<2%). Cooking denatures the cross-reactive proteins and is usually tolerated.

Alpha-Gal Syndrome (Mammalian Meat Allergy)

Alpha-gal syndrome is an IgE-mediated allergy to galactose-α-1,3-galactose (alpha-gal), an oligosaccharide present on non-primate mammalian tissues. Sensitization occurs through Lone Star tick (Amblyomma americanum) bites, which introduce alpha-gal from tick saliva. Unique features: delayed reaction onset (2–6 hours after eating mammalian meat — beef, pork, lamb), which is unusual for IgE-mediated allergy (explained by time required for fat digestion and alpha-gal liberation). Symptoms range from urticaria/GI symptoms to anaphylaxis. Diagnosis: positive sIgE to alpha-gal (≥0.35 kU/L) + clinical history. Management: avoidance of mammalian meat, dairy (some patients tolerate dairy), gelatin, and certain medications derived from mammalian sources (cetuximab, gelatin-containing vaccines, heparin). Patients must carry epinephrine. Some patients lose sensitivity over 1–5 years if tick re-exposure is avoided.

21 Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) is a type IV (delayed, T-cell-mediated) hypersensitivity reaction to an external substance (hapten) that contacts the skin. It requires prior sensitization (1–2 week induction period) and manifests 24–72 hours after re-exposure. ACD affects ~15–20% of the general population and is a leading cause of occupational skin disease.

Common Contact Allergens

Diagnosis — Patch Testing

Patch testing is the gold standard for diagnosing ACD. The standard series (T.R.U.E. Test or expanded North American Contact Dermatitis Group series, 70–80+ allergens) is applied to the upper back under occlusion for 48 hours. Readings at 48 hours (upon removal) and 72–96 hours (delayed reading, most important). Results graded: negative, irritant reaction, 1+ (erythema + papules), 2+ (erythema + papules + vesicles), 3+ (bullous reaction). Clinical relevance must be established (does the positive patch test explain the patient's dermatitis distribution and exposure history?).

Management

Allergen avoidance is the definitive treatment. Provide patients with specific avoidance lists (e.g., CAMP database for nickel-free products). Acute ACD: mid- to high-potency topical corticosteroids (triamcinolone 0.1% for body, hydrocortisone or desonide for face/intertriginous areas). Widespread/severe ACD: systemic prednisone 0.5–1 mg/kg/day tapered over 2–3 weeks (shorter courses risk rebound, especially with poison ivy). Chronic ACD: calcineurin inhibitors (tacrolimus 0.1%, pimecrolimus 1%) as steroid-sparing alternatives. Barrier creams for occupational prevention.

22 Atopic Dermatitis

Atopic dermatitis (AD) is a chronic, relapsing, intensely pruritic inflammatory skin disease affecting up to 20% of children and 7–10% of adults. It is the first manifestation of the "atopic march" (AD → food allergy → allergic rhinitis → asthma) and results from genetic (filaggrin mutations in ~30%), immunologic (Th2-skewed skin inflammation), and barrier dysfunction (transepidermal water loss).

Diagnostic Criteria (Hanifin-Rajka, Simplified)

Must have pruritus plus ≥3 of: (1) typical morphology and distribution (flexural in older children/adults; facial/extensor in infants), (2) chronic or relapsing course, (3) personal or family history of atopy, (4) xerosis (dry skin). No definitive laboratory test; diagnosis is clinical. Elevated total IgE and peripheral eosinophilia are common but non-specific.

Severity Assessment

Management Ladder

23 Latex Allergy

Latex allergy is an IgE-mediated (type I) hypersensitivity to natural rubber latex proteins (Hevea brasiliensis). Prevalence: 1–6% in the general population, 10–17% in healthcare workers, up to 73% in children with spina bifida (repeated surgical exposures). Can cause contact urticaria, rhinitis, asthma, and anaphylaxis. Cross-reactivity with plant proteins produces latex-fruit syndrome: banana, avocado, chestnut, kiwi (highest cross-reactivity).

Diagnosis

SPT with commercial latex extract (where available); sIgE to latex (k82); CRD: Hev b 5 and Hev b 6.01 (most associated with latex anaphylaxis), Hev b 8 (profilin — cross-reactive, lower risk). Patch testing diagnoses type IV (delayed) latex allergy (contact dermatitis from rubber accelerators, not latex protein).

Management

Complete latex avoidance: non-latex gloves (nitrile, vinyl), latex-free medical supplies, MedicAlert identification. Healthcare facilities should maintain latex-free operating rooms. Premedication (antihistamines + steroids) does NOT prevent IgE-mediated anaphylaxis and should NOT replace avoidance. Patients must carry epinephrine auto-injectors.

24 B-Cell (Antibody) Deficiencies

Antibody deficiencies are the most common primary immunodeficiencies, accounting for ~50% of all PIDs. They present with recurrent sinopulmonary infections (pneumonia, sinusitis, otitis media) from encapsulated organisms (S. pneumoniae, H. influenzae), GI infections (Giardia), and bronchiectasis from chronic infection.

Major B-Cell Deficiencies

25 T-Cell & Combined Immunodeficiencies

Severe Combined Immunodeficiency (SCID)

SCID is a pediatric emergency — untreated, it is fatal within the first 1–2 years of life. SCID presents with severe, recurrent infections from bacteria, viruses, fungi, and opportunistic organisms (PJP, CMV, Candida) beginning in the first months of life, chronic diarrhea, failure to thrive, and absent thymic shadow on chest X-ray. SCID is detected by newborn screening using T-cell receptor excision circles (TRECs) — absent or very low TRECs indicates T-cell lymphopenia. Definitive treatment is hematopoietic stem cell transplant (HSCT) — survival >90% if performed before 3.5 months of age (before infections occur). Gene therapy is available for ADA-SCID and X-linked SCID.

DiGeorge Syndrome (22q11.2 Deletion)

DiGeorge syndrome results from 22q11.2 microdeletion causing defective development of the 3rd and 4th pharyngeal pouches. Classic features (mnemonic: CATCH-22): Cardiac defects (conotruncal: tetralogy of Fallot, interrupted aortic arch, truncus arteriosus, VSD), Abnormal facies, Thymic hypoplasia/aplasia, Cleft palate, Hypocalcemia (absent parathyroids). Immunodeficiency ranges from mild T-cell lymphopenia (partial DiGeorge, ~75% of cases, often improves with age) to complete DiGeorge (absent T cells, SCID-like, requires thymus transplant). Diagnosis: FISH or chromosomal microarray for 22q11.2 deletion.

Other Combined Immunodeficiencies

26 Phagocytic & Complement Deficiencies

Phagocytic Defects

Complement Deficiencies

27 Immunoglobulin Replacement Therapy

Immunoglobulin replacement is the cornerstone of treatment for antibody deficiencies (XLA, CVID, specific antibody deficiency, secondary hypogammaglobulinemia). The goal is to maintain trough IgG levels ≥500 mg/dL (some experts target ≥700–800 mg/dL, especially if infections continue).

IVIG vs SCIG

Monitoring

Check trough IgG level before each IVIG dose (or periodically for SCIG) until steady state is reached. Adjust dose to maintain trough ≥500–800 mg/dL. Monitor renal function (risk of osmotic nephrosis with sucrose-containing products), CBC (hemolysis screening), LFTs, and clinical infection frequency. Annual pulmonary function testing and CT chest to monitor for bronchiectasis progression.

28 Secondary Immunodeficiency

Secondary (acquired) immunodeficiencies are far more common than PIDs and result from external factors that impair immune function.

Major Causes

Rituximab-Induced Hypogammaglobulinemia

Rituximab (anti-CD20) causes B-cell depletion lasting 6–12 months per course. Repeated cycles lead to cumulative hypogammaglobulinemia in 20–60% of patients, with risk increasing with each cycle. Monitor quantitative immunoglobulins before each cycle and at least every 6–12 months. IgG replacement is indicated for IgG <400 mg/dL with recurrent infections.

29 Immune Dysregulation Syndromes

These rare disorders involve immune system overactivity or dysregulation rather than simple deficiency, leading to autoimmunity, lymphoproliferation, and/or hyperinflammation.

Key Immune Dysregulation Syndromes

30 Skin Testing & In Vitro Diagnostics

Skin Prick Testing (SPT)

SPT is the primary diagnostic tool for IgE-mediated sensitization. A drop of allergen extract is placed on the volar forearm or back, and the skin is pricked through the drop with a lancet. A positive result is a wheal ≥3 mm greater than the negative control (saline) at 15–20 minutes. Positive control: histamine (should produce wheal ≥3 mm; if negative, consider antihistamine interference). Sensitivity: ~85–90%; specificity: ~80–85%. SPT can test dozens of allergens simultaneously and provides results in 15 minutes.

Medications That Suppress SPT (Must Be Held)

Intradermal Testing (IDT)

More sensitive but less specific than SPT. A small volume (0.02–0.05 mL) of dilute allergen is injected intradermally, creating a 2–3 mm bleb. Positive: wheal ≥3 mm increase over initial bleb at 15 minutes. Used primarily for venom allergy and drug allergy (penicillin) testing when SPT is negative but clinical suspicion remains high.

In Vitro Testing — Specific IgE (ImmunoCAP)

Serum allergen-specific IgE measurement (ImmunoCAP platform). Advantages: not affected by antihistamines, no risk of systemic reaction, useful in patients with extensive dermatitis or dermatographism. Disadvantages: lower sensitivity than SPT for some allergens, more expensive, results take days. Values ≥0.35 kU/L are considered positive (Class 1); clinical significance increases with higher levels but varies by allergen.

Component-Resolved Diagnostics (CRD)

CRD measures sIgE to individual allergenic proteins rather than whole allergen extracts, improving diagnostic precision. Key applications:

31 Pulmonary Function & Bronchial Provocation

Spirometry

Spirometry is essential for asthma diagnosis, severity assessment, and monitoring. Key measurements: FEV1 (forced expiratory volume in 1 second), FVC (forced vital capacity), and FEV1/FVC ratio. Asthma shows an obstructive pattern: reduced FEV1/FVC ratio (<0.70 or below the lower limit of normal). Bronchodilator reversibility confirms asthma: ≥12% AND ≥200 mL improvement in FEV1 after SABA (albuterol 400 μg). Normal spirometry does not exclude asthma (variable airflow obstruction).

Fractional Exhaled Nitric Oxide (FeNO)

FeNO measures airway eosinophilic inflammation. Normal <25 ppb in adults, <20 ppb in children. Elevated FeNO (≥25 ppb adults, ≥35 ppb high) supports eosinophilic/allergic asthma diagnosis and predicts response to ICS and anti-IL-4/IL-13 biologics. FeNO >50 ppb strongly suggests eosinophilic airway inflammation and likely ICS responsiveness. False elevations: viral URI, allergen exposure, dietary nitrate. False low: smoking, bronchoconstriction at time of testing.

Bronchial Provocation Testing

Methacholine challenge is the most common bronchoprovocation test. Inhaled methacholine (a direct muscarinic agonist) is administered in increasing concentrations. A positive test is a ≥20% decline in FEV1 (PC20 or PD20). Interpretation: PC20 <4 mg/mL = positive (significant AHR); 4–16 mg/mL = borderline; >16 mg/mL = negative. Methacholine challenge has high sensitivity (~95%) but moderate specificity (~80%) for asthma — best used to EXCLUDE asthma (high negative predictive value). Contraindications: severe obstruction (FEV1 <60% predicted), recent MI/stroke, uncontrolled hypertension, aortic aneurysm.

Other Provocation Tests

Exercise challenge: Standardized exercise at 85–90% max HR for 6–8 min with serial FEV1 measurements for 30 min post-exercise; positive = ≥10% FEV1 decline. Eucapnic voluntary hyperventilation (EVH): Most sensitive for exercise-induced bronchoconstriction; used in Olympic athlete screening. Mannitol challenge: Indirect challenge via osmotic stimulus; FDA-approved (Aridol); positive = ≥15% FEV1 decline; higher specificity than methacholine.

32 Allergen Immunotherapy (SCIT & SLIT)

Allergen immunotherapy (AIT) is the ONLY disease-modifying treatment for allergic rhinitis, allergic asthma, and stinging insect allergy. It induces immune tolerance by shifting from Th2 to Th1/Treg responses, increasing blocking IgG4 antibodies, and reducing allergen-specific IgE over time.

Subcutaneous Immunotherapy (SCIT)

Safety: Observe 30 minutes after each injection. Risk of systemic reaction: ~0.1–0.2% per injection (local reactions are common and expected). Fatal reactions: ~1 per 2.5 million injections. Contraindications: uncontrolled/severe asthma (FEV1 <70%), beta-blocker use (relative — increases risk of refractory anaphylaxis), medical conditions where epinephrine is contraindicated.

Sublingual Immunotherapy (SLIT)

FDA-approved SLIT tablets in the US:

First dose of any SLIT tablet must be administered under medical supervision (30 min observation). Subsequent doses are self-administered at home. Most common side effect: local oropharyngeal pruritus/swelling (resolves within 1–2 weeks). Anaphylaxis rate: ~1 per 100 million SLIT doses (much lower than SCIT).

33 Venom Immunotherapy

Venom immunotherapy (VIT) is indicated for patients with a history of systemic allergic reaction to Hymenoptera stings (bees, wasps, hornets, yellow jackets, fire ants) AND positive venom-specific IgE (SPT or sIgE). VIT is the most effective form of immunotherapy: reduces risk of systemic reaction from ~60% to <5% on re-sting.

Indications & Contraindications

Indicated: Systemic reaction (urticaria/angioedema remote from sting site, respiratory symptoms, cardiovascular symptoms, anaphylaxis) + positive venom testing. NOT indicated: Large local reactions only (normal physiologic response), cutaneous-only systemic reactions in children <16 years (low risk of progression to anaphylaxis, ~1–3%), or negative venom testing. Elevated baseline tryptase (>11.5 ng/mL) or known mastocytosis is an indication for lifelong VIT (higher risk of fatal sting anaphylaxis).

Protocol

Build-up: weekly injections over 8–12 weeks (conventional) or 1–2 days (rush protocol; higher systemic reaction rate ~10–15% but acceptable in supervised settings). Maintenance dose: 100 μg of each relevant venom per injection (300 μg for mixed vespid). Maintenance interval: every 4 weeks for year 1, then extend to every 6–8 weeks for years 2–5. Duration: minimum 5 years; consider lifelong in patients with prior near-fatal anaphylaxis, elevated baseline tryptase, or mastocytosis.

34 Drug Challenge & Desensitization Protocols

Drug Provocation Testing (Drug Challenge)

A graded drug challenge is used to exclude drug allergy in patients with a low-risk history or negative skin testing. The suspected drug is administered in incrementally increasing doses (typically 2–3 doses over 1–2 hours) with observation. It is a diagnostic test (different from desensitization, which is therapeutic). Common scenarios: amoxicillin challenge after negative penicillin skin test, NSAID challenge in patients with unclear NSAID reaction history, local anesthetic challenge (true allergy is extremely rare — <1%).

Aspirin Desensitization for AERD

Patients with AERD (Samter's triad) who require aspirin for cardiovascular indications or who would benefit from aspirin's anti-inflammatory effect on nasal polyps undergo aspirin desensitization in a monitored setting. Protocol: begin with aspirin 20–40 mg, escalate every 90–180 minutes through 40, 81, 162, 325, 650 mg. Watch for bronchospasm, naso-ocular symptoms, and GI reactions. Once 325–650 mg is tolerated, maintain BID dosing indefinitely (interruption >48 hours requires re-desensitization). Benefits: reduced nasal polyp recurrence, improved smell, decreased oral steroid requirements, better asthma control.

Chemotherapy Desensitization

Indicated for patients with confirmed type I hypersensitivity to carboplatin, oxaliplatin, paclitaxel, or monoclonal antibodies who have no alternative agent. Standard 12-step protocol (Castells protocol): three sequential solutions of increasing concentration (1/100, 1/10, full strength), each administered at escalating rates (2×, 5×, 10×, 25×, etc.), achieving full therapeutic dose over ~5.8 hours. Success rate >95%. Requires ICU or step-down unit setting. Must be repeated for each subsequent cycle.

35 Imaging & Diagnostics Table

36 Classification Systems (All)

ARIA Classification of Allergic Rhinitis

GINA Asthma Severity (Treatment-Naïve)

GINA Asthma Control Assessment

Sampson Severity Grading of Anaphylaxis

Ring & Messmer Anaphylaxis Grading

EAACI Food Allergy Severity Grading

HAE Severity Classification

EoE Endoscopic Reference Score (EREFS)

37 Medications Master Table

Antihistamines

Intranasal Corticosteroids

Inhaled Corticosteroids (ICS) for Asthma

Leukotriene Modifiers

Epinephrine

Biologics Summary

Immunosuppressants Used in Allergy/Immunology

38 Abbreviations Master List

39 Risk Factors & Comorbidities

Risk Factors for Atopic Disease

The Atopic March

The atopic march describes the sequential development of atopic diseases: atopic dermatitis (infancy, often first manifestation) → food allergy (infancy/early childhood) → allergic rhinitis (school age) → asthma (school age/adolescence). Not all atopic children follow this progression, but early severe AD is a strong predictor of subsequent respiratory allergy. Epicutaneous sensitization through a defective skin barrier (FLG mutations) may drive subsequent food and aeroallergen sensitization.

Comorbidity Associations