Immunology Flashcards

Question

Type 4a hypersensitivity

Answer 1

Th1 - interferon gamme Monocytic inflammation Symptom: Eczema Chronology: 1-21 days

Answer 2

``` Th2 - interleukin 4 and 5 Eosinophilic inflammation Symptoms: maculopapular exanthem, DRESS Chronology: 1=several days for MPE 2-6 weeks for DRESS ```

Answer 3

Cytotoxic T cells (perforin, granzyme B, FasL) Keratinocyte death mediated by CD4 or CD8 cells Symptoms: Maculopapular exanthem, SJS/TEN, pustular exanthema Chronology: 1-2 days for fixed drug eruption 4-28 days for SJS/TEN

Answer 4

T cells (interleukin 8, CXCL8) Neutrophilic inflammation Symptoms: Acute generalised exanthematous pustolisis (AGEP) Chronology: 1-2 days but could be longer

Answer 5

Bacteria: Sepsis Viruses: CMV, EBV, varicella, resp and intestinal Fungi/parasite: Candida, P. carinii

Answer 6

Bacteria: Strep, staph, H influenzae Virus: enterovirsus/enteroviral encephalitis Fungi/parasite: Giardiasis

Answer 7

Bacteria: Staph, Pseudomonas, catalase +ve Virus: N/A Fungi/parasite: Candida, Aspergillus, Nocardia

Answer 8

Bacteria: Neisseria, pyogenic bacteria, encapsulated organisms Viruses: N/A Fungi/parasite: N/A

Answer 9

i. First line defense ii. Antigen non-specific, no immunological memory - recognition of molecular patterns (PAMPs) shared by groups of microbes not present in mammalian host eg. lipopolysaccharide (LPS) iii. Germ-line encoded iv. Limited diversity v. Components 1. External barriers a. Skin and mucous membranes – keratin hostile surface b. Antimicrobial chemicals i. Defensins – produced by neutrophils and function to put holes in bacterial membrane and kill them ii. Lactic acid – inhibits bacterial growth c. Mucous membranes – urinary, reproductive, GI, respiratory tracts i. Mucous – traps microbes and cilia move it out ii. Secretions – flush microbes away (E.g. urine) iii. Mucous, tears, saliva – contain lysozyme that dissolves cell walls microbes d. Hyaluronic acid – difficult for microbes to migrate through SC tissue 2. Proteins and bioactive molecules 3. Cellular – phagocytes and NK cells ``` • First line of defense • Standard response to any attack • Non-specific to antigen • No memory Components 1. Physical and mechanical barriers 2. Proteins and bioactive molecules – complement, cytokines, chemokines 3. Cellular – leukocytes, macrophages and NK cells (viral infection and tumor) ```

Answer 10

i. Antigen specific response 1. Mediated by receptors on cell surface (TCR/BCR) ii. Generate immunological memory – results in faster, targeted immune response iii. Components 1. Cellular – T cells (cell mediated) and B cells (humoral) 2. Immunoglobulin iv. Antigen presenting cells phagocytose Ag and present it to lymphocytes in lymph nodes • Second line of defense • Antigen specific response • Specific rapid response to secondary exposure • Immune memory Components 1. Blood proteins – cytokines, chemokines 2. Cellular – T cells (cell-mediated) and B cells (humoral)

Answer 11

i. Neutrophils ii. Eosinophils iii. Basophils

Answer 12

= able to present antigen to cells of the adaptive immune system (T cells) i. Dendritic cells ii. Monocytes iii. Macrophages iv. B cells

Answer 13

i. T cells ii. B cells iii. NK cells a. 25% of total WCC in peripheral blood b. CD34+ HSCT in BM (?) c. Circulating – T cells 85%, B cells 15%, NK cells 5% d. IL-2 = T, B and NK cell growth factor e. IL-7 + IL-15 = T and NK cell development

Answer 14

a. Includes i. Neutrophil ii. Monocyte iii. Macrophage b. Receptors i. Fc = Ig ii. C3b receptor = complement c. Process i. Attachment – binding of bacteria to phagocyte 1. Non-specific receptors that recognise common pathogens 2. Complement C3 receptor 3. Fc receptor – opsonised antigens bind at Fc receptor site (especially IgG) ii. Endocytosis 1. Antigen ingested and forms vacuole called phagosome iii. Digestion 1. Fusion with lysosome that contains hydrolytic enzymes

Answer 15

2. Primary lymphoid organs a. Thymus/ bone marrow b. Develop during first trimester of gestation c. Thymus = largest at birth, reaches peak mass at puberty then involutes d. Bone marrow i. Children, occupies medullary space of almost entire skeleton ii. Adults, limited to humerus and femur 3. Secondary lymphoid organs a. Spleen/ lymph nodes/ tonsils/ Peyer patches/ lamina propria – develop subsequently b. Peripheral lymphoid tissue ↑ during infancy and childhood, adult size by 6 years of age e. Lymph nodes i. Functions = cleanse lymph and site of T and B cell activation v. Parenchyma divided into: 1. Cortex = where germinal centres form in lymphatic nodules, and B cells differentiate into plasma cells 2. Medulla branched network of lymphocytes, macrophages, reticular cells, plasma cells f. Tonsils i. Patches of lymph at entrance to pharynx ii. Covered by epithelium and have deep tonsillar crypts lined by lymphatic nodules, enclosed by incomplete fibrous capsule iii. Three groups – pharyngeal (adenoids - nasopharyngeal), lingual, palatine (classic tonsils) g. Spleen i. Left hypochondriac region (under ribs 10-12) ii. Medial hilum = splenic artery/vein, lymphatic vessels iii. Red pulp 1. Consists of sinuses gorged with erythrocytes 2. Function = produce RBC in fetus and severe anaemia, RBC graveyard as macrophages consume old ones iv. White pulp 1. Consists of lymphocytes and macrophages along splenic artery 2. Function = antigen surveillance, gets rid of debris/bacteria in blood, regulates plasma volume

Answer 16

``` Function = rid of intracellular pathogens – • Viruses • Protozoa/parasites • Intracellular bacteria • Cancer cells • Transplant tissue/cell ``` Mechanism = cellular response • Cytotoxic T cells • Helper T cells assist • Memory T cells Activation • MHCI on all nucleated cells • MHCII on APCs

Answer 17

``` Function = rid of extra-cellular pathogens • Bacteria • Yeasts • Extra-cellular viruses/parasites • Toxins, venoms • Allergens • Mismatch blood transfusion ``` Mechanism • B cell and antibody mediated • Helper T cell assist • Memory T cells Activation • MHCII on APCs

Answer 18

o Any molecule that triggers an immune response o Epitopes – region of an antigen that stimulates the immune response o One antigen can have several different epitopes that stimulate immunity o Haptens – too small to be antigens in themselves but can stimulate immune response by binding to host macromolecule and creating epitope  This is often the mechanism for allergy

Answer 19

o Memory T and B cells produced in adaptive immunity to initial exposure o Primary response – initial immune reaction on exposure to antigen for first time  Initial 3-6 day lag  Peak 10 days - IgM  Peak 18 days - IgG  Low within a month o Secondary response  IgG rises within hours, peaks within few days  Low IgM  No illness

Answer 20

1. Key points a. 25% of total WCC in peripheral blood b. CD34+ haematopoietic stem cell in the BM (CD = cluster of differentiation) c. Common lymphoid progenitor d. Express CD3 and TCR i. CD3 complex is important for signaling ii. T cell receptors = recognize antigen in the context of MHC molecules (antigen presenting cells) 1. 95% alpha-beta 2. 5% gamma-delta e. Development i. Formed in bone marrow ii. Mature in thymus = differentiate from CD4+CD8+ to either CD4+ or CD8+ iii. Enter the circulation as naïve T cells and migrate to LNs, spleen and other lymphoid tissue (secondary lymphoid organs) 2. Development a. Begin as double negative TCR negative thymocytes (CD4- CD8-) b. As migrate through the cortex become double positive cells expressing both CD4+ and CD8+ molecules c. Gene rearrangement of VDJ segments to generate and express a functional T cell receptor d. Positive selection = recognition of self-HLA molecules by the TCR i. Class I or class II MHC ii. Medullary thymus epithelial cells express MHC iii. If no recognition  apoptosis e. Negative selection = recognition of self-Ag molecules presented in MHC i. Medullary thymus epithelial cells express MHC with self-antigen from peripheral site ii. If autoreactive  apoptosis f. If pass positive and negative selection leave thymus as naïve T cell as CD4+ or CD8+ T cell i. 5% of thymocytes survive positive and negative selection g. Note that gamma delta T cells are CD4 and CD8 negative (double negative), role poorly understood h. Process is mediated by AIRE gene – autoimmune regulator i. Induces the expression of peripheral tissue antigens that are normally only expressed in the periphery ii. Defects result in APS1 or APECED  autoreactive T cells  autoimmune disease 3. VDJ recombination a. Germline configuration contains variable (V), diversity (D) and joining (J) segments i. Only beta and delta TCR loci contain diversity segments b. One V, (D) and J segment are randomly spliced together in a sequentially ordered process c. Mediated by various enzymes d. Correlation to disease i. RAG1/RAG2 mutations -> SCID ii. Radiosensitivity SCID (eg. DNA Ligase IV, Artemis)

Answer 21

1. Key points a. CD3+ CD8+ b. Recognition Ag presented in context of HLA class I 2. Role a. Immune response to intracellular pathogens (eg. virus) 3. Two mechanisms a. Apoptosis via cytotoxicity = release of granules from cytoplasm in the immunological synapse (MHC class I)  perforin  punches holes in target cell  activate caspase cascade within the target cell b. Binding of FasL to Fas on surface of target cell which activates apoptosis pathway  cell death

Answer 22

1. Overview a. All CD4+ T cells are helper T cells and recognize antigen presented in the context of HLA class II b. Roles depend on specific subtype i. Enhance T/B cell response ii. Activate innate immune system Include: Th1, Th2, Th17, Treg

Answer 23

a. Promote cell mediated response - summary: activate/differentiate/accumulate macrophages and neutrophils, class switch to IgG, positive feedback on T cells b. Development i. IL-12 is secreted by APC and drives the switch from an undifferentiated Th cell to a Th1 cell ii. IL-12 also activates NK cells, which then secrete IFN-g which can promote differentiation of Th1 cells iii. IFN-g is also produced by Th1 cells and amplifies the differentiation of Th0 into Th1 cells iv. Tbet is a transcription factor that is a master regulator for Th1 production c. Function i. Activation of macrophages 1. IFN-γ activates macrophages and makes them efficient killers of pathogens a. Increase production of TNF-α an autocrine signal which induces production of antimicrobial agents such as NO and O2- b. Increased expression of MHC and costimulatory molecules c. Secrete IL-12 which acts as a positive feedback loop promoting Th1 differentiation 2. CD40L also interacts with CD30 to activate macrophages ii. Neutrophil activation = Th1 cells also secrete TNF and lymphotoxins (LT) which can activate neutrophils which also leads to enhanced microbial killing iii. Class switching = IgG iv. IL-2 production = induces T cell proliferation, increasing numbers of effector cells v. IL-3 GM-CSF = induces macrophage differentiation in the bone marrow vi. CCL2 = Causes macrophages to accumulate at the site of infection

Answer 24

a. Promote humoral response - summary: activate B cells, class switch IgE, stimulate eosinophils b. Development i. IL-4 drives Th2 production; major sources are NKT cells ii. IL-4 also is “self-amplifying” and promotes differentiation of Th0 cells into Th2 iii. GATA-3 is the transcription factor master regulator for Th2 production c. Function i. IL-4 = promoting B cell activation + class switching to IgE 1. IgE binds Fc receptors for IgE on the surface of mast cells 2. When cross-linked, they release cytotoxic granules ii. IL-5 = mobilises and activates eosinophils  IgE, mast cells and eosinophils are all critically important components of the immune defence against helminth iii. IL-13 = can modify macrophage activation, promote epithelial cell repair and mucous production, promotes smooth muscle contraction → physically expel parasite

Answer 25

- summary: eaerly response to extracellular bacteria and fungi, neutrophil recruitment, a. Development i. TGF-β and IL-6 = drives naïve T cells to differentiate into Th17 ii. IL-21 = self-amplifying cytokine iii. IL-23 = stabilises Th17 phenotype b. Function i. These cells secrete IL-17, IL-6 and TNF-alpha 1. IL-17 has an important role in protecting the body from extracellular pathogens eg. Klebsiella pneumoniae, Neisseria gonorrhoeae, Shigella, Staphylococcus aureus and fungal infections 2. May also have a role in anti-tumour immunity 3. Th17 secretes IL-17 at the site of infection which induces pro-inflammatory cytokines + neutrophil recruitment to site of infection ii. Early immune response to extracellular bacterial infections + fungal infections 1. Increase infiltration of neutrophils iii. Activate local endothelium iv. Induce cytokine and chemokine production v. Autosomal dominant hyperIgE syndrome (STAT3) – no Th17 cells 1. Susceptible to fungal infections

Answer 26

Regulatory T cells - down-modulate immune response a. Subset of circulating CD4+ T cells that down modulate immune responses i. Suppress CD4 and CD8 T cells, B cells and NK cells b. Cell surface expression of CD4 and CD25 c. Nuclear expression of FoxP3 - Transcription factor required for development d. Development i. Treg cell differentiation is driven by TGF-β e. Cytokine production = TGF-beta, IL-10  anti-inflammatory f. Disease i. IPEX = deficiency of FoXP3 ii. IL-10/IL-10R defects = early onset IBD

Answer 27

1. Key points a. BCR (clonally specific) – surface IgM and IgD b. Express CD19, CD20, CD40, CD79, MHC class II (antigen presenting cell), Fc gamma receptor, C3b receptor (CR1) and CD3d receptor (CR2) c. Mature in BM, then periphery (secondary lymphoid organs) (antigen independent development = bone marrow) d. After Ag cross-links Ig, B cells proliferate and differentiate into i. Plasma cells (in germinal centres of LNs), which lose surface BCR expression and secrete immunoglobulin (antigen-dependent development) ii. Memory B cell 2. Development a. Differentiation from haematopoietic stem cells in bone marrow = antigen independent b. Mature in peripheral lymphoid organs (eg. spleen, LN) = antigen dependent c. Cell surface markers alter throughout development 3. Antigen INDEPENDENT development - VDJ recombination a. First stage of B cell development is rearrangement of B cell receptor genes b. Heavy chain VDJ recombination  expressed with surrogate light chain  survival signals c. Subsequently light chain VJ recombination d. If no survival signal will not develop e. B cell receptor is either IgM or IgD – if successfully rearrange B cell receptor migrate to secondary lymphoid organs f. Once exposed to antigen undergo clonal expansion  plasma cell OR memory cell g. BTK mutation – X linked agammaglobulinaemia – cannot make a functional B cell 4. Antigen DEPENDENT development a. Second phase of B cell development occurs after encounter with antigen in secondary lymphoid organs (eg. lymph nodes and spleen) b. B cells are activated, proliferate and differentiate into i. Plasma cell = produce large amounts of Ab of particular antigen specificity ii. Memory B cell = long-lasting cells able to rapidly produce high-affinity antibodies in response to second antigen challenge c. Fate of activated B cell depends on antigen presentation and cytokine received – T dependent + independent

Answer 28

a. Requires the participation of T helper cells b. Majority of antibody responses to proteins and glycoproteins c. B cells located in lymphoid follicle + T cells in parafollicular cortex - interact at the edge of the follicle d. Process i. Cross-linking of immunoglobulin receptor (BCR)  Ag internalized and processed ii. Presentation of Ag on surface of B cell to circulating T helper cell iii. Activation signals from T helper cell iv. Results in formation of a germinal centre v. Further proliferation and differentiation into plasma cell vi. Induction of isotype switching and activation of somatic mutation e. Isotype switching i. Only occur in T dependent B cell activation ii. Naïve B cells express IgM and IgD iii. T cell derived cytokines induce isotype switching 1. CD40-CD40L interaction (CD40L is on T cells) – stimulates B cells to class switch 2. Mediated by various enyzmes (AID, UNG, APE1, DNA-PK) iv. Cytokine milieu determines antibody isotype produced 1. IL-10  IgG1/3 2. IL-4/IL-13  IgE 3. TGF-beta  IgA v. VDJ regions (encode for the BCR) are spliced to different heavy chain constant regions – alters the mRNA transcript and encodes a different protein and therefore antibody isotype f. Somatic hypermutation (SHM) i. Enables higher affinity Ig reduction ii. Single base-pair substitutions within the variable region of antibody gene segments iii. Produce antibody of higher affinity for antigen iv. Does not alter the antigen specificity

Answer 29

a. Some molecules can activate B cells directly - polysaccharides, lipopolysaccharides, polymeric proteins – repeating units that cross-link Ig on B cell surface b. Advantages i. Rapid response to pathogens of T cells c. Limitations i. Poor induction of memory B cells ii. Poor affinity maturation of antibody (SHM) iii. No isotype switching

Answer 30

1. Key points a. Produced by the humoral immune system b. Exquisitely specificity (usually) c. Range of affinities d. Low, uM to very high, pM e. Basis of most vaccines f. Essential for survival g. Great diversity of specificities – different 1013 to 1015 potential specificities 2. Structure a. Glycoproteins b. Monomers = pair of identical heavy + pair of light chains bound by disulfide bonds c. Each light and heavy chain has a variable (V) and constant (C) region d. Variable region is made from VDJ recombination – heavy (VDJ), light (VJ) e. Immunoglobulin monomers have two antigen binding arms of identical specificity i. Fab = antigen binding fragment ii. Fc = constant fragment which binds to various receptors on the surface of cells (eg. NK cells, macrophages) as well as complement 1. Fc receptor interaction 2. Complement 3. Binding to a specific receptor responsible for recirculating Ab 3. Antibody function a. Activate B lymphocytes b. Acts as opsonins c. Causes antigen clumping and inactivation of bacterial toxins d. Activates antibody-dependent cellular activity via NK cells e. Triggers mast cell degranulation  parasite, helminth f. Activates complement (alternative complement pathway) 4. Immunoglobulin with age a. IgG – maternal at birth, reaching adult levels at about 5 years i. Nadir 3-6months due to passive running out and own kicking in slowly ii. Often present with Ab deficiencies b. IgM – reach adult levels at 1 year c. IgA – reach adult levels at adolescence

Answer 31

Structure + Half life • Monomer • Half-life 3 days • 1% of Ig Properties • Not secreted • Transmembrane protein (receptor) of B cells Function • Cell surface receptor • No effector function

Answer 32

Structure/half life • Monomer or pentamer (10 binding sites) • Half-life 5 days • 10% of Ig Properties • Transmembrane protein (receptor) of B cells • Low affinity and high avidity • Forms a pentamer when secreted – NOT lost in protein-losing enteropathy • Synthesis begins at 6 days of life, rises to adult levels at 1y Function • Primary immune response – 1st Ab secreted in the adaptive immune response (made rapidly) • Responsible for blood group reactions • Fixes complement in its uncomplexed form • Low in newborn period  impaired phagocytosis  susceptibility to GN bacteria

Answer 33

``` Structure/half life • Monomer or dimer (rarely trimer) – 4 binding sites • Dimer – secretory • Half-life 6 days • 10-20% of Ig ``` Properties • 2 subclasses- IgA1 and IgA2 • Major antibody in mucosal surfaces eg. gut, lungs • Highest rate of production but serum concentration < IgG as lost through secretion Function • Mucosal protection • Relatively common immunodeficiency, results in regular gastrointestinal infections • Passive immunity in newborn

Answer 34

Structure/half life • Monomer • Half-life 21-28 days • 70-75% of antibody pool – most abundant in internal body fluids Properties • 4 sub-classes (IgG1-IgG4) • Major serum antibody – peaks 10-14 days after infection • B cells receive help from Th cells -> isotype switch to IgG Function • Responsible for secondary immune response • Fixes complement • Antibody-dependent cellular cytotoxicity (ADCC) – Ab bind Fc receptors on NK cells • Opsonisation • Neonatal immunity – crosses placental barrier during pregnancy; maternal Ig depleted by 6-8 m, adult levels not reached until 7-8 y

Answer 35

Structure/half life • Monomer • Half-life 2 days Properties • Serum levels usually very low Function • Specialised to fight helminths • Causes allergy • Interacts with mast cells, eosinophils and basophils via Fc receptors – stimulates release of histamine and other mediators

Answer 36

1. Key points a. Derived from common lymphoid progenitor - develop in bone marrow b. Do not express antigen-specific receptors i. Recognize antigen via germline encoded receptors for pathogen associated molecular patterns ii. Inhibited by encounter with self-molecules through inhibitory receptors on sell surface c. IL-7/IL-15 for development d. IL-2 for growth e. CD3-CD16+ or CD3-CD56+ f. Produce cytokines after activation eg. IFN-g g. Recognition of target cell by i. Fc receptor binding to antibody on the surface of the target cell ii. TLR iii. Lack of MHC class I expression or down-regulation of this  identifies as abnormal 2. Function a. Kill virally infected cells and tumour cells i. Direct/ cell mediated cytotoxicity 1. Release granules that directly kill cells (perforin) ii. Antibody-dependent cellular toxicity (ADCC) via CD16 1. Pathogen with antibody on surface b. Cytokine production (IFN-g, IL-5, IL-13) c. Contraction of the adaptive immune response

Answer 37

``` HLA = human leukocyte antigen MHC = major histocompatibility complex ``` a. HLA class I i. HLA-A, B, C ii. All nucleated cells iii. Present endogenous peptides (intracellular/ cytosolic) eg. tumour, virus, bacteria iv. Alpha 1 and 2 contact peptide v. One leg in membrane vi. Binds peptides 8-10 amino acids long (fit inside groove) vii. Activate CD8 T cells viii. Type 1 Bare Lymphocyte Syndrome b. HLA class II i. HLA-DP, DQ, DR ii. APCs iii. Present exogenous peptides (extracellular) eg. bacteria, killed vaccines iv. Alpha 1, 2 and Beta 1, 2 peptide chains = BOTH CHAINS POLYMORPHIC v. Alpha 1 and Beta 1 contact peptide vi. 2 Transmembrane regions vii. Binds peptides 13-17 amino acids long (hang outside groove) viii. Activate CD4 T cells ix. Type 2 Bare Lymphocyte Syndrome

Answer 38

1. Key points a. MHC/HLA molecules present antigen to T cells i. Unable to recognise soluble antigen b. Oligopeptides with antigen-binding groove c. NO gene rearrangements (unlike BCR/TCR) d. Variability occurs in the peptide binding region i. MHC class I = α1 and α2 region ii. MHC class II = β1 and α1 region e. Sequence of genes highly conserved = only some differences between humans and mice h. Codominant expression i. All alleles expressed in an individual ii. Each offspring statistically different (4 alleles at each loci – inherit 2) i. HLA on short arm of chromosome 6 3. Antigen presenting cells a. Also derived from bone marrow precursors b. Present antigen to T cells c. Include i. Dendritic cells ii. Macrophage + monocyte iii. B cells d. Express i. HLA class I and class II ii. Accessory molecules (B7 molecules CD80/CD86) e. Activation of T cell require 2 signals i. Activation of antigen ii. Activation signal f. Without 2 signals become anergic g. After activation, release cytokines which activate other cells Lymphocyte activation a. 2 signals to become activated i. Antigen ii. Accessory molecule on surface of 1. APC eg. B7 (CD80/CD86)  activation of T cell a. ICOS deficiency (similar to CD28) type of CVID 2. CD4 T cell eg. CD40 (CD154)  activation of B cell iii. Results in proliferation, cytokine synthesis, effector function b. If only 1 signal become anergic

Answer 39

* Sentinels of the immune system * Relatively rare (0.1% of cells in spleen/lymph node) • Key features o Dendritic morphology maximises contact with T cells (single dendritic cell can present antigen to several T cells) o Short lifespan (3 days) o Critically important in vaccination • Function o Migrate from blood stream to enter skin/ epithelial surfaces o Internalizes self and foreign antigens o Present antigen via MHC II o T cell differentiation o The only APC that activates naïve T cells and initiate an immune response • Classification o Bone marrow derived  Myeloid progenitor • Produces ‘classical dendritic cells’ – inc Langerhan cells • Attracted to infection by chemokines • Present antigen via MHC 2 • Also interact with T cells via CD40/CD40 ligand interaction to stimulate IL-12 production and encourage T cell differentiation  Lymphoid progenitor • Produces plasmacytoid dendritic cells o Mesenchyme derived  Follicular dendritic cells – role in activation of B cell  Lack class II MHC  Bind antigen via complement receptors, attract B cells in lymphoid tissues

Answer 40

* Granulocyte = eosinophil, neutrophil, basophil | * Mononuclear = monocyte, macrophage

Answer 41

* SCF, IL-3, IL-6, IL-11, GM-CSF and GCSF * Fc gamma receptor * Arise from bone marrow – arises from granulocyte * Nucleus with 3-5 lobes * Neutrophils survive for 6-12 hours in the circulation * Move to site of infection, phagocytose and kill via oxidative pathway • Function o Phagocytose bacteria – mainly intracellular action o Release antimicrobial chemicals via NADH oxidation pathway – release of highly toxic lysosomal enzymes around cell to kill bacteria (and self)  NADPH oxidase generates large amounts of superoxide (O2-) from molecular oxygen  hydrogen peroxide  Myeloperoxidase catalyses reaction of H2O2 to create hypochlorous acid (H-O-Cl) • Activation process o Adhere to vascular endothelium via CD18 / L -selectin  This process also involves Siayl Lewis X receptor that binds to e-selectin o Transmigrate into tissues o Ingest and kill microbes o Release chemotactic signals to recruit more neutrophils

Answer 42

• CFU-GM  monoblast  promonocyte  monocyte • Features o 3-5% WBC o Structure – kidney shaped nucleus, cytoplasm with small granules o Arise in BM o Monocytes in circulation o Macrophages in tissue (liver/ lungs) o Express Fc gamma R and complement R1 o Larger than neutrophil o Cytoplasm filled with granules containing hydrolytic enzymes o Can survive for weeks – months • Function o Phagocytose = receptors for Fc gamma and C3b o Kill = via oxidative pathways and cytotoxicity o Stimulate Th cells  Occurs in response to intracellular pathogens  Macrophages release IL12 + TNF alpha • IL12 stimulates T cells to release IFN gamma • TNF alpha amplifies macrophage activation

Answer 43

• SCF (stem cell factor), IL-3, IL-5 and GM-CSF (granulocyte-macrophage colony stimulating factor) • Features o 2-5% of blood leukocytes o Non dividing, fully-differentiated cells o Bilobed nucleus o Stain reddish brown with eosin o Contain proteins that are cytotoxic for parasites o Structure – 2 large nuclei with pink granules in cytoplasm o Increase in response to parasitic infection, allergy, collagen, spleen/ CNS disease • Functions o Phagocytose antigen-antibody complexes, allergens and inflammatory chemicals o Degranulate and release major basic protein  Implicated in multicellular organisms too large to be phagocytosed o Secrete proinflammatory cytokines – IL 1,3,4,5, 9 and 13 • Regulation o Recruited to inflammatory tissues by eotaxin o Binds to endothelial ligand, marginate between tight junctions of endothelial cells o Major mediators: IL-5, RANTES, monocyte chemotactic protein MCP3, MCP4

Answer 44

• Key features o Origin – granulocyte o <0.5-1% of WCC o Structure – violet granules in cytoplasm o Increases in VZV, DM, myxoeedema, sinusitis, polycythaemia • Functions o Degranulate and release heparin, histamine and other chemical mediators  Improves blood flow to tissue o Fc epipsilon receptor (IgE) • Mast cells similar function

Answer 45

a. Secreted proteins that are important for i. Growth ii. Differentiation iii. Activation b. Produced by i. Antigen presenting cells ii. Phagocytes iii. T lymphocytes c. Action i. Paracrine – act on neighboring cells ii. Autocrine – act on same cell that releases them 3. Cytokine signaling a. Most cytokines signal through the same receptor process b. Cytokine receptor on cell surface c. Binding of cytokine  phosphorylation of JAK  activation of STAT  form dimer and translocate to nucleus  activate gene transcription d. Defects in cytokine signaling causes primary immunodeficiency i. SCID 1. Common gamma chain (X-linked) 2. JAK3 3. IL-7Ra ii. STAT3 (hyper IgE syndrome) iii. STAT1 GOF (chronic mucocutaneous candidiasis)

Answer 46

1. Key points a. Important effector component of innate and adaptive immunity b. >30 plasma and cell surface proteins i. Sequential activation c. Unlike immunoglobulins i. Heat labile ii. Part of the innate immune system d. Function i. Opsonise – complement receptor mediated phagocytosis ii. Lyse cells – bacteria, tumour cells, allografts iii. Mediate inflammation – recruit inflammatory cells 4. Complement components a. Components are either i. Activating ii. Regulatory b. Regulation i. C1 inhibitor ii. Factors H and I and CD46 iii. CD55 and CD59 c. Deficiencies of regulation i. Hereditary angioedema (C1 esterase inhibitor) ii. Atypical HUS Factors H and I and CD46 iii. PNH

Answer 47

2. Activation pathways a. Classical i. Requires antibody (IgG, IgM) activated by Ag-Ab immune complexes ii. Sequential activation of C1 (C1qrs), C4 and C2 (C1qrs complex binds Fc portion of IgG/IgM) b. Alternative i. Direct activation of C3 ii. Recognition of microbial components on cell surface iii. No inhibitory/regulators present on microbial cells c. Lectin (mannose binding lectin) i. Requires binding of MBL to mannan (surface sugar) on microbial cell surface ii. Mannose present on particular pathogens – particularly bacteria - activates C4 3. Function a. C5a and C3b → phagocytosis i. C3b opsonizes pathogen and can bind to CR1 on macrophage ii. C5a binding to its receptor on macrophages stimulates the cell to phagocytose C3b coated bacteria iii. In the absence of C5a, C3b binding to CR1 is not enough to stimulate phagocytosis b. C3a, C4a, C5a → inflammation i. The C5a peptide is a POTENT anaphylotoxin which activates the immune system (major antagonist being produced) ii. C5a generates chemotactic gradients – lots of C5a is liberated surrounding the point of infection and diffuses out into the circulation → leukocytes follow this signal iii. Summary 1. Increase vascular permeability and cell-adhesion molecules 2. Increased permeability allows fluid leakage from blood vessels allowing Ig and complement to enter interstitial space 3. Increased permeability and adhesion promotes migration of leukocytes c. Membrane attack complex → lysis i. Consists of C5b, C6, C7, C8, C9 ii. 10-16 molecules of C9 bind to form a pore in the membrane iii. Results in osmotic lysis

Answer 48

• Immunoglobulin o IgG actively transported across placenta (term infant concentration = maternal) o Specificity depends on mother’s exposure and response o Other immunoglobulins not transferred o Lack effect against E. Coli • Complement o Bactericidal against E. Coli, opsonin in phagocytosis of GBS o No transplacental passage o Synthesized from first trimester but  concentration and activity of complement components ( in preterms) ``` • Neutrophils o  migration (chemotaxis) o  adhesion, aggregation o  phagocytosis if stress o  oxidative respiratory burst of neonatal neutrophils o Neutropenia  risk of sepsis ```

Answer 49

• Expressed in epithelial cells, endothelial cells and APCs • Transmembrane receptors • Sense components of microbes (cell wall or membranes of bacteria/fungi) and modified nucleic acids or bacteria/ virus • IRAK4/MyD88 - impaired TLR o Susceptible to pneumococcal

Answer 50

* Bacterial toxins eg. S aureus Toxic Shock Syndrome Toxin 1 (TSST-1), S pyogenes * Bind MHC II and TCR beta chain, providing signal to T cell * NOT processed and do not interact with MHC II via peptide groove * No specificity and no memory * Can activate up to 20% (vs 0.001%) of T cells  massive cytokine release

Answer 51

• Local response to tissue injury or infection • Functions o Limit spread of pathogens and destroy them o Remove debris and damaged tissue o Initiate repair ``` • Cardinal signs o Swelling o Redness o Heat o Pain (due to bradykinin and prostaglandins that stimulate pain receptors) ``` • Stages 1. Vasodilation and vascular permeability a. Histamine, kinins and leukotreines secreted by basophils, mast cells, damaged cells = vasodilation and increased capillary permeability b. Increased blood flow leading to leukocytes quickly to area 2. Endothelial adhesion and leukocyte recruitment a. Endothelial cells produce selectins which adhere circulating leukocytes and draw them into area of inflammation = extravasation b. Results in margination of leukocytes (adherence to endothelium) c. Diapedesis follows where leukocytes go through endothelial wall d. Emigration when enter tissue fluid where inflammation/injury 3. Neutrophil recruitment and action a. Chemotaxis – leukotrines and bradykinin guide neutrophils to site of inflammation b. Neutrophils undertake phagocytosis 4. Macrophage migration and clean up a. Neutrophils secrete cytokines which attract macrophages b. Arrive at site 8-12hours after injury c. Engulf and destroy bacteria, damaged host cells, dead neutrophils d. Act as APCs to trigger specific immunity for next exposure e. Pus = yellow fluid with dead neutrophils, macrophages, cells and tissue debris 5. Repair a. Platelets and endothelial cells secrete platelet-derived growth factor that stimulates fibroblasts to multiple and synthesis collage for repair

Answer 52

• Elevation of body temperature • Causes – infection, trauma, drug reaction, brain tumor • Functions to facilitate repair o Promotes interferon activity o Elevates BMR to accelerate tissue repair o Inhibits reproduction of bacteria and viruses • Physiology o Neutrophils/macrophages phagocytose bacteria and product pyrogen IL-1 o IL1 acts at anterior hypothalamus to secrete prostaglandin E o PGE raises hypothalamic set point  Response is feeling “cold” – increase temperature by shivering (increase metabolic rate), vasoconstriction o Decrease set point once infection cleared  Response is feeling “hot” – decrease temperature by vasodilation, flushing, sweating

Answer 53

i. C45 = pan-leukocyte ii. CD3 = T cell iii. CD3/CD4 = helper iv. CD3/CD8 = cytotoxic v. CD19 or CD20 = B cell vi. CD16 and CD56 positive and CD3 negative = NK cell

Answer 54

B-CELL DEFICIENCY IgG, IgM, IgA, and IgE levels Isohemagglutinin titers Ab response to vaccine antigens (e.g., tetanus, diphtheria, pneumococci, Haemophilus influenzae) T-CELL DEFICIENCY Lymphocyte count Chest x-ray examination for thymic size* Delayed skin tests (e.g., Candida, tetanus toxoid) PHAGOCYTIC DEFICIENCY WBC count, morphology Respiratory burst assay COMPLEMENT DEFICIENCY CH50 activity C3 level C4 level

Answer 55

1. Summary of tests a. Screening tests i. Lymphocyte count ii. CXR (thymic size) iii. Delayed skin tests b. Advanced tests i. T cell subset enumeration ii. Proliferative responses to mitogens, antigens, allogeneic cells iii. HLA typing iv. Chromosome analysis 2. FBE and lymphocyte subsets a. CD3 – T cell b. CD3/CD4 – helper T cell c. CD3/CD8 – cytotoxic T cells d. Measurement of naïve T cells = marker of thymic output i. CD3 and CD4/CD8 v. Soluble CD25 (soluble IL-2RA) – increases in malignancy infection, inflammation, HLH 7. Naïve T cells a. Mature T cells that have migrated from thymus b. Unique antigen-specific TCR, express CD3 and CD4/8 f. TREC – measure of naïve T cells i. T cell receptor excision circle formed by excision of DNA segments in the process of TCR gene rearrangement ii. Can be measured in peripheral blood as a surrogate marker of T cell development and thymic output iii. Absence of TREC on Guthrie card  screen for inadequate thymic output; possible SCID 1. Hoping to add this to the newborn screening test

Answer 56

1. B cells a. FBE and lymphocyte subsets i. B cells (CD19 or CD20) ii. Normally 8-10% of circulating lymphocytes are B cells iii. Absent = X linked agammaglobulinaemia iv. Present = CVID, IgA deficiency, HperIgM b. Memory B cells (deficiency associated with CVID) i. CD27+ ii. IgD/M +ve or IgD/M –ve c. Transitional B cells/ plasmablasts 2. Immunoglobulins a. Total immunoglobulins i. IgG, IgA, IgM (in terms of adult levels: IgM > IgG > IgA) b. Isohaemagluttinins = antibodies to A + B RBC polysaccharide antigens i. May be absent in first 2 years of life ii. ALWAYS absent if child is blood type AB iii. Assesses capacity to make IgM antibodies c. Vaccine specific antibodies i. Tetanus (T dependent B cell response) = protein + polysaccharide ii. Pneumovax 23 (T independent B cell response) = polysaccharide ONLY 3. Done in children > 2-3 years of age (Children < 2 do not tend to have lasting response to polysaccharide antigens) d. Specific antibodies by age i. Changes with age 1. IgG = maternal at birth, reaching adult levels by 5 years a. Physiological nadir of IgG production at 6 – transient hypogammaglobulinaemia of infancy 2. IgM = reaches adult levels by 1 year, IgA = reach adult levels at adolescence 4. NOTE: IgG subclasses and IgA deficiencies tend to be over diagnosed ii. T dependent vs T independent response 1. T independent a. Polysaccharide antigens directly activate B cells (without costimulation of T cells) b. Results in IgM production c. Children < 2 do not tend to have lasting response to polysaccharide antigens i. Susceptible to PS-encapsulated bacteria 2. T dependent a. Protein-polysaccharide vaccines: protein is processed and presented to CD4 Th cell. b. T cell then makes IL-4, costimulates via CD40-CD40 ligand  IgG antibody c. Neonates have this form of immune response

Answer 57

Unclear how significant (in Boast notes) 1. Screening a. FBE – neutrophil count 2. Oxidative burst 3. Advanced tests a. Adhesion molecule assays (CD11b/ CD 18/selectin ligand) i. CD18 evaluates adhesion function ii. Tested if suspect LAD

Answer 58

1. NK cell degranulation a. Identifies defects in the granulation process b. Surface expression of CD107a 2. Intracellular perforin expression 3. NK cell cytotoxicity a. Increasing ratios of effector: target cells (K562 cells)

Answer 59

1. Key points a. Complement concentrations i. C3 and C4 –adult levels by 3 months b. Complement haemolytic activity i. Classical pathway – adult activity by 3 months ii. Alternative pathway – adult activity by 1 year 2. Testing for complement deficiency a. Do not screen for complement deficiencies with C3 and C4 only b. If you are looking for a complement deficiency measure the Classical Pathway Activity (CH50 or THC) and Alternative Pathway Activity (AP50) 3. Recommended tests a. C3/C4 i. Both low – suggests classical pathway ii. Normal C4, low C3 – suggests alternative pathway b. Classical pathway activation (CH50 or THC) i. Reliable screen for homozygous deficiency in an integral component of classical pathway ii. Measures capacity of patient’s serum to lyse sheep erythrocytes coated with Ig iii. All nine components of classical pathway (C1-C9) are required for normal CH50 iv. Heterozygous deficiency – normal CH50 as the level of a component must be reduced by >50% before the CH50 is altered c. Alternative pathway activity (AP50) i. Assesses Factor D, B and Properdin Interpretation - classic normal, alternative 0 = properdin, factor B or D deficiency - classic 0, alternative normal = C1, 2, 4 deficiency - both 0 = C3, C5-9 Inhibitors (look up diagram) - C1 esterase inhibitor (C1) - Factor H, I, CD46 (C3b) - CD 55 and 59 (MAC)

Answer 60

(More in allergy notes/cards) 1. Allergen specific IgE a. In blood – RAST b. Via skin prick testing (histamine release) 2. Mast cell tryptase a. Detectable at 15 minutes b. Time to peak 1-2 hours c. Return to baseline in 6 hours (half-life 90 minutes) d. Anaphylaxis and mastocytosis e. Useful for unexpected severe reactions eg. intra-operative, idiopathic 3. DDx of elevated total IgE a. Atopic disease, especially atopic dermatitis* b. Parasitic infestation* c. ABPA* d. PID eg. Wiskot-Aldrich, Hyper IgE* e. Hodgkins f. Churg Strauss g. IgE myeloma * h. * Asssociated with IgE >1000 IU/L

Answer 61

a. Hypersensitivity = reproducible reaction to stimulus i. Objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by a normal person b. Allergy = reaction initiated by specific immunological mechanisms c. Intolerance = reaction mediated by non-immunological mechanisms d. Atopy i. Ability to form IgE antibodies to common inhaled aeroallergens resulting in immune dysregulation ii. Genetic predisposition e. Atopic disease i. Includes asthma, atopic dermatitis, rhinoconjunctivitis, IgE mediated food allergy ii. Usual progression of atopic diseases: eczema (<12months)  asthma  allergic rhinitis 2. Gell + Coombs classification a. Immediate = within 1 hour, IgE mediated b. Delayed = most >6 hours after starting

Answer 62

Immediate Mechanism • IgE mediated • Onset: o Seconds (<30m, 30-120m if ingested) must have previous exposure o Delayed response 2-12hrs • Trigger: allergen binds IgE on basophils/mast cells • Mechanism: o Cross linking of IgE causes degranulation mast cells o Immediate release of vasoactive amines (histamine, tryptase, leukotrienes, PG, PAF) o Delayed inflammatory response (INF, TNF, GMSCF) o Effects: oedema, secretions, smooth muscle spasm (upper/lower RT), skin reactions (angioedema, urticaria), GIT (vomiting, diarrhoea, cramps) Antigens - Pollen - Food - Venom - Drugs Examples - Anaphylaxis - Urticaria - Angioedema - Atopy – asthma, rhinitis

Answer 63

Subacute, cytotoxic antibody Mechanism • Antibody-dependent cytotoxic • Onset: mins-hrs after exposure • Trigger: IgG/IgM/IgA attacks antigens on cell surface • Mechanism: o Complement activation o Lysis or opsonization with phagocytosis (macrophages) of target cell (often RBC, platelet) Antigens - RBC - Platelets Examples - Autoimmune hemolytic anaemia - Goodpasture syndrome - Blood transfusion reaction - Myasthenia or Graves

Answer 64

Immune complex Mechanism • Immune complex • Onset: 1-3 weeks after exposure • Duration: 10-15hours • Mechanism: o IgG/IgM form Ag-Ab complexes which deposit beneath endothelium of vessels/tissues o Activate complement and trigger inflammation (neutrophils) with tissue destruction Antigens - Blood vessel - Liver - Spleen - Kidney - Lung Examples - SLE - GN - HSP - Serum sickness-LIKE reaction eg. ceflacor

Answer 65

Delayed, cell mediated Mechanism • Cell mediated • Onset: 2-7days, must have previous exposure • Trigger: APCs display antigens to T helper cells • Mechanism: o T lymphocyte drive  release cytokines & interferons  macrophages + cytotoxic T cells o Infiltration caused by macrophages Examples - Contact dermatitis and allergies to haptens (cosmetics) - Type I diabetes - Transplant rejection - TB skin test - TEN/SJS

Answer 66

1. Epidemiology a. Strong familial predisposition b. 60-70% heritability in twin studies c. One parent with allergic disease, child 25% risk d. If both parents have allergic disease, child 50-75% risk 3. Pathogenesis a. Rapid expansion of Th2 cells -> secrete IL4, IL5, IL 13 -> IgE synthesis/isotype switching + eosinophilia 4. Components of allergic response a. IgE i. Involves cross linking of receptor bound IgE molecules by allergen ii. IgE receptor found on surface of APCs (+ mast cells/ basophils) b. Eosinophils i. Contain granules -> damage epithelial cells, induce airway hyper-responsiveness and cause degranulation of basophils and mast cells iii. Also secrete prostaglandins + leukotrienes c. Mast cells iv. Secrete tryptase + chymase, histamine/ proteases/ proteoglycans/cytokine v. Activation occurs with cross linkage of IgE-IgE receptor with multivalent antigen 5. Phases of allergic response a. Early phase response i. Mast cell degranulation and release of preformed mediators -> increase vascular permeability –> leakage of plasma proteins, tissue swelling –> itching/ sneezing/ wheezing etc iii. 10 mins after allergen exposure, resolves w/i 1-3hrs b. Late phase response i. Infiltration of neutrophils/eosinophils/macrophages, within hours of allergen exposure, resolves by 24 hours ii. Oedema/ redness induration , nasal blockage, persistent wheezing c. Chronic allergic disease i. Tissue inflammation persists for days to years ii. Repeated stimulation of mast cells, basophils, eosinophils and Th2 cells iii. Th2 cytokines induce tissue remodeling 6. Treatment a. Antihistamines i. Reversible ii. Competitive inhibition of histamine by binding to H1 receptor iii. First generation = lipophilic and cross BBB leading to central effects (sedation, cognitive impairment) iv. Second generation = cetirizine, fexofenadine (less sedating) b. Allergen immunotherapy i. Gradually increasing doses of allergens ii. Used in seasonal rinoconjunctivitis, asthma and insect venom sensitivity iii. NOT recommended for < 5 except for insect venom therapy iv. NOT recommended for (no evidence) food allergy, atopic dermatitis, acute/ chronic urticarial

Answer 67

* Allergic disease – atopic conditions * Respiratory – eosinophilic pneumonia, ABPA * GIT – eosinophilic gastroenteritis, allergic colitis, IBD * Infections – helminthic infection * Neoplastic – eosinophilic leukemia, Hodgkin disease * Drug induced

Answer 68

* Allergic disease – atopic conditions (eczema most common) * Helminthic infection * Hyper IgE syndrome * ABPA * Wiskott/Aldrich syndrome * Bone marrow transplant * Hodgkin disease * Bullous pemphigoid * Idiopathic nephritic syndrome

Answer 69

Skin prick test, serum IgE assays (RAST, radioallergosorbent testing), intradermal testing, complement resolved diagnosis 1. Key principles a. Be specific in what you want b. Do NOT perform to foods if already ingesting with no history of immediate reaction c. Does NOT predict severity of future reaction (only the likelihood of a reaction) d. Accuracy SPT/ssIgE always depends on history i. Receny of reaction + size ii. BUT would not perform OFC if recent history of reaction and positive SPT (3mm+) or ssIgE (>0.35 KuA/L) e. Each food has own cut-off values for SPT and ssIgE 2. Purpose of investigations a. Confirm diagnosis of IgE mediated food allergy b. Determine when safe to proceed to oral supervised food challenge c. NOTE i. Strength of positivity of test associated with likelihood of true allergy ii. NEITHER predict severity of allergic reaction 3. When should they not be used? a. Tolerating food already without IgE reaction (‘what is my eczema due to doctor’) b. Food intolerances c. Chronic idiopathic urticaria d. Most non-IgE mediated food allergies (unless concurrent IgE mediated food allergy) e. NOTE: IgG ‘food panel’ testing NOT useful; IgG physiological reaction to food; multiple positive reactions and do NOT assist in diagnosis/ management of food allergy/ intolerance)

Answer 70

i. Commercial allergen scratched onto skin (usually back or volar aspect of arm) ii. Read after 15 minutes – wheal size, average of height and width (L+W/2) iii. Positive = >=3 mm above saline control iv. Key points 1. Sensitive, inexpensive and rapid 2. Based on presence of antibodies (which does not necessarily mean allergies) a. Allergen crosslinks with IgE bound to mast cells b. Activates cells to release histamines and other cytokines v. Controls = saline (negative), histamine (positive) vi. Size of SPT influenced by 1. Allergen extract used 2. Site of application (back >>> arm) 3. Pressure applied by operator 4. Device used for SPT 5. Skin integrity (eczema) 6. Drawing of wheal not ‘exact science’ 7. Oral antihistamines – none for 4-5 days pre test vii. Other factors influencing test result 1. Recent anaphylaxis 2. Dermatographism viii. Interpretation = pre-test probability + likelihood ratio  post-test probability (Fagan’s nomogram) 1. The larger the SPT size, the more likely an IgE mediated reaction will occur 2. Does NOT tell you a. Severity of reaction b. Non-IgE mediated reaction 3. Negative predictive value ~50% 4. +ve test and +ve hx  suggestive of allergy 5. -ve test and +ve hx  need to do food challenge c. Intradermal testing i. Involves injecting 0.01-0.02 L o dilute allergen extract into the dermis

Answer 71

ssIgE i. Blood test (in vitro) ii. Allergen on a well iii. Add patient serum and then anti-IgE marker and measure signal (ELISA) iv. Interpretation= predictive value of test dependent on 1. Patient factors 2. Food allergens a. Cow’s milk, egg, peanut vs wheat – soybean/wheat/tree nut not as good tests; fish, peanut, milk and egg better b. Raw vs cooked egg - positive if >0.35 KuA/L - ?no specific contraindications (cf SPT where can't do if severe eczema, oral antihistamines, dermatographism, +/- recent anaphylaxis) Complement resolved diagnosis (CRD) i. ssIgE – however specific allergen protein is purified ii. More expensive and in clinical practice usually only peanut CRD used (Ara h 2) iii. Very expensive iv. Used if SPT 3-8 mm and/or ssIgE 0.35-15 KuA/L (grey zone) 1. Distant clinical reaction 2. Sensitisation only v. Arah 1,2,3 and 8 1. Usually order Ara h 2 – as expensive if order 1,2,3 and 8 2. High Ara h 2 don’t challenge

Answer 72

DO affect - antihistamine (generally cease 4 days prior) - H2 antagonist (1 day e.g. ranitidine) - antidepressant (7 days) - prochlorperazine - neuroleptics (up to 2 weeks, e.g. chlorpromazine, quetiapine, fluphenazine) NO effect - leukotriene receptor antagonists - decongestants - SABA/LABA - glucocorticoids - theophylline (oral) - cyclosporine

Answer 73

1. Key points a. Do not allow children with anaphylaxis to stand or walk b. Most reactions occur within 30 minutes of exposure to a trigger but can occur up to 4 hours c. Treatment of anaphylaxis is IM adrenaline 10 micrograms/kg or 0.01ml/kg of 1:1000 (maximum 0.5ml), into lateral thigh which should be repeated after 5 minutes if the child is not improving 2. Definition (uptodate) Anaphylaxis is highly likely when any ONE of the following three criteria is fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING: A. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia) B. Reduced BP* or associated symptoms of end-organ dysfunction (eg, hypotonia, collapse, syncope, incontinence) 2. TWO OR MORE OF THE FOLLOWING that occur rapidly after exposure to a LIKELY allergen for that patient (minutes to several hours): A. Involvement of the skin mucosal tissue (eg, generalized hives, itch-flush, swollen lips-tongue-uvula) B. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, hypoxemia) C. Reduced BP* or associated symptoms (eg, hypotonia, collapse, syncope, incontinence) D. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 3. Reduced BP* after exposure to a KNOWN allergen for that patient (minutes to several hours): A. Infants and children - Low systolic BP (age-specific)* or greater than 30% decrease in systolic BP B. Adults - Systolic BP of less than 90 mmHg or greater than 30% decrease from that person's baseline b. NOTE (Boast notes): i. For insect bite/sting gastrointestinal symptoms ALONE is sufficient for treatment as anaphylaxis with adrenaline ii. Lip swelling is NOT considered airway involvement RCH: Anaphylaxis is a multi-system severe allergic reaction characterised by an acute onset of cardiovascular (eg hypotension) or respiratory (eg bronchospasm) symptoms. It is usually associated with typical skin features (urticarial rash or erythema/flushing and/or angioedema) and/or persistent severe gastrointestinal symptoms. 3. Epidemiology a. Egg is most common food allergy b. Trigger of anaphylaxis – peanut, tree-nut, cow milk c. Death in infants from anaphylaxis is very rare <4 years 4. Aetiology a. Foods - Peanut, tree nuts, cow milk, eggs, soy, shellfish, fish, wheat b. Bites/stings - Bee, wasp, jack jumper ants c. Medications- Beta-lactams d. Other - exercise, idiopathic Newer monoclonal antibody therapies may produce delayed anaphylactic reactions and rebound symptoms that occur more than 12 hours after the initial reaction NB: a cause is not identified in 20% of cases

Answer 74

5. Risk factors for fatal anaphylaxis - Delay to administration of adrenaline or emergency response services - Poorly controlled asthma - Allergy to nuts, shellfish, drugs and insect stings - Adolescence - Pre-existing cardiac and respiratory conditions ``` Respiratory (Most common in children) • Persistent cough • Wheeze • Tongue swelling • Stridor • Hoarse voice or change in character of the cry • Subjective feeling of swelling or tightness/tingling in the throat • Dysphagia ``` ``` Cardiovascular • Pale and floppy (infant) • Palpitations • Tachycardia • Bradycardia • Hypotension • Collapse with or without unconsciousness • Cardiac arrest ``` Neurological • Headache (usually throbbing) • Dizziness • Altered consciousness/ confusion ``` GIT • Nausea • Vomiting • Diarrhoea • Abdominal/pelvic pain ``` Dermatological • Urticarial rash • Erythema/flushing • Angioedema 8. Types of anaphylactic reactions a. Uniphasic = 90% b. Biphasic i. Initial symptom resolution with treatment ii. Then rebound symptoms (mild-severe) 1-72 hours later iii. 5% of paediatric cases presenting to ED iv. Potential risk factors include >1 dose adrenaline and/or need for IV fluids c. Protracted i. Lasts for hours to days with incomplete resolution

Answer 75

10. Investigations a. Anaphylaxis is a clinical diagnosis b. Tryptase = helpful if diagnosis is unclear (eg. anaesthetic reaction) i. NO role in acute management of anaphylaxis ii. Should be obtained 15 minutes to 3 hours post anaphylaxis iii. Second level 24 hours is used for comparison iv. If level is >11.4 or elevated by 20% above baseline – diagnosis confirmed RX: a. Remove allergen (if still present) b. Posture i. Do not allow the child to stand or walk ii. Fatality can occur within seconds if the child stands or sits suddenly iii. Movement = empty heart syndrome c. IM 10 micrograms/kg or 0.01ml/kg of 1:1000 (maximum 0.5ml), into lateral thigh i. Repeated after 5 minutes if the child is not improving – x2 doses call PICU ii. Do not use SC adrenaline, as absorption is less reliable than the IM route. iii. Do not use IV bolus adrenaline unless cardiac arrest is imminent. iv. Use an adrenaline autoinjector if unable to calculate exact dose or to avoid delay, including in children <1 year - continue IM adrenaline as needed every 5 minutes until IV access obtained d. Adrenaline infusion i. If the child is not improving after repeated doses of IM adrenaline (> 2 doses), consider adrenaline infusion (0.05 - 5 mcg/kg/min) ii. Should only use 1:1000 adrenaline iii. Never give IV bolus of adrenaline (unless in cardiac arrest); due to risk of cardiac ischaemia e. Adjunctive treatment - O2 if necessary i. Fluid bolus = if hypotensive ii. Nebulised adrenaline 1. Not recommended as first-line therapy 2. May be a useful adjunct to IM adrenaline if upper airway obstruction or bronchospasm is present (commonly used in children) iii. Oxygen + Salbutamol = recommended if the child has respiratory distress with wheezing and consider other anti-asthma medications iv. Antihistamines = may be given for symptomatic relief of pruritus 1. Second generation antihistamines are preferred (avoid promethazine as it can cause hypotension) v. Corticosteroids, antihistamines and leukotriene antagonists have no proven immediate benefit on life threatening anaphylaxis 1. No evidence reduces risk of biphasic reactions 2. May be useful if concurrent asthma f. Glucagon infusion i. Consider in those with severe anaphylaxis and beta2 blockade ii. Acts on glucagon receptors in the heart by exerting positive inotropic (BP) and chronotropic (HR) effects by increasing cardiac cAMP iii. Independent of adrenaline effect iv. NO effect on bronchi

Answer 76

11. Observation a. All children with anaphylaxis should be observed for at least 4 hours in a supervised setting with facilities to manage deterioration b. Admission for a minimum 12 hour period of observation is recommended if: i. Further treatment is required within 4 hours of last adrenaline administration (biphasic reaction) ii. Previous history of biphasic reaction iii. Poorly controlled asthma iv. The child lives in an isolated location with delay to emergency services 12. Long-term management a. Update medical record b. Refer to allergist/ paediatrician c. Confirm with SPT/ ssIgE d. Avoid the food trigger(s) +/- dietician involvement e. Prescribe adrenaline auto-injector (and demonstrate its use) i. <20 kg = EpiPen Jnr® (150 µg) ii. > 20 kg = EpiPen® (300 µg) f. Provide ASCIA red action plan g. Review i. Nuts/seafood – tends to persist; review every 5 years ii. Egg, wheat, milk – vast majority cease; review 12-18 months 13. Epipen prescribing a. Anyone with anaphylaxis to food requires an adrenaline auto-injector b. Ensure educated on use and gone through action plan c. Dose depends on weight i. 150 mcg (junior) <20 kg ii. 300 mcg if 20 kg + Consider prescribing epipen without anaphylaxis if risk factors e.g. adolescence, asthmatic, nuts/shellfish, remote living / concerns re seeking medical attention

Answer 77

• Anaphylaxis-like reaction • Occurs due to direct mast cell activation eg. red man syndrome o Ie. Non-IgE mediated activation of mast cells/basophils Typical triggers - Often drugs – opiates, contrast, vancomycin, NSAIDs, blood products

Answer 78

1. Key points a. Inflammatory disorder of the nasal mucosa b. Often related conjunctivitis, sinusitis, otitis media, serous otitis, hypertrophic tonsils and adenoids, and eczema c. Associated with 3x fold increased risk in asthma at an older age d. Symptoms usually appear in infancy; diagnosis established by age 6 2. Risk factors a. Family history of atopy b. Elevated IgE by age 6 c. Children whose mothers smoke heavily d. Heavy exposure to indoor allergens e. LUSCS associated with atopy in children with family history of atopy 4. Pathogenesis a. Exposure of an atopic host to an allergen  IgE production b. Bridging of IgE molecules  mast cell activation + degranulation  release of pre-formed inflammatory mediators (histamine, prostaglandin, leukotrienes) c. Late phase allergic response (4-8 hours)  eosinophils, neutrophils and mast cells infiltrate nasal mucosa  leukotrienes, eosinophil peroxidase, major basic protein + IL-3, IL-5, GCSF 5. Phases a. Acute – sneezing, itch, rhinorrhoea (due to histamine) b. Delayed – nasal congestion (due to infiltration inflammatory cells)

Answer 79

Intermittent - <4 days/week or <4 weeks at a time Persistent - >4 days or 4 weeks as above Mild - Normal sleep, daily activities, work, school - No troublesome symptoms Mod-severe - one or more of: abnormal sleep, impaired daily activities/sport/leisure, difficulties at work or school, troublesome symptoms 6. Clinical classification a. Seasonal – airborne pollens (typically grasses) b. Perennial – indoor allergens (house dust mite, mould, dander, animal) c. Episodic/occupational – intermittent exposure to allergens (E.g. pets at visiting house) 7. ARIA classification a. Episodic - <4 weeks b. Persistent - >4 weeks c. Mild – nil below features d. Moderate to severe – sleep disturbance, school interruption

Answer 80

9. Exclude a. Non allergic causes of rhinitis (e.g. vasomotor rhinitis, bacterial and viral infections, sinusitis) b. Overuse of decongestant sprays (less common) c. Tumours or vocal cord dysfunction (rare) 10. Investigations a. Serum specific IgE to assess for specific allergen if history indicates 11. Treatment a. Non-pharmacological i. Allergen avoidance ii. Nasal irrigation b. Pharmacological i. Topical inhaled corticosteroids 1. First line treatment for perennial and seasonal allergic rhinitis 2. Take for 2-4 weeks before maximum benefit is achieved 3. Continue for a minimum 3-6 months - this should be continuous treatment 4. Useful for sneezing and eye symptoms 5. Mometasone furorate - children over 3 years 6. Budesonide - children over 6 years 7. Fluticasone fluroate - children over 12 years 8. Beclomethasone dipropionate -children over 6 years 9. Triamcinolone acetonide - children over 12 years ii. Antihistamines 1. Manage itching, sneezing and eye symptoms; LESS HELPFUL FOR NASAL CONGESTION iii. Decongestants 1. Short term use ONLY (<3 days) – long-term associated with rebound symptoms 2. Reduce nasal congestion 3. AE = hypertension, CNS effects such as insomnia, agitation, anxiety 4. NOT for use in young children (<6 years)

Answer 81

1. Key points a. Features i. Defective skin barrier ii. Reduced skin innate immune response iii. Exaggerated T cell responses to environmental allergens (Th2 response) b. Two forms have been identified i. Atopic eczema = associated with IgE mediated sensitivity occurs in 70-80% ii. Non-atopic eczema = NOT associated with IgE 2. Epidemiology a. Most common chronic relapsing skin disease b. Affects 10-30% of children worldwide c. Associated with other atopic conditions d. 80% outgrow by 5 years 3. Pathogenesis a. Genetic predisposition i. Defective epidermal barrier function 1. Allows allergens to penetrate barrier and interact with immune cells 3. Severely dry skin is a hallmark of AD 4. Filaggrin is a structural protein in the epidermis a. Mutations in filaggrin gene family identified in up to 50% of patients with severe AD ii. Immune dysregulation 1. Circulating T cells (/cutaneous) produce increased levels of Th2 cytokines (IL-4, IL-13) -> isotype switching to IgE b. Environmental factors i. Environmental irritants – all patients 1. Drying agents - water, soaps, shampoo, chlorine 2. Abrasive clothing - wool, nylon, acrylic (patient and carers) 3. Abrasive surfaces - carpet when crawling, sandpits, lamb wool covers 4. Heat – only in active eczema 5. Chemicals – fragrance, preservatives (e.g. in sorbelene/topical steroids) ii. Infections – all patients 1. Staph colonization can exacerbate inflammatory process due to exotoxin that acts as superantigen, stimulating T cells to produce more IgE via Th2 response iii. Airborne – some patients 1. House dust mite (important for infants that don’t grow out of it), pollens, grasses (important from first year onwards) 2. Identified with SPTs and RAST iv. Food tolerance – some patients 1. 40% have co-existing food allergy 2. Ingestion breast milk, formula, solids 3. Most significant first 1-2years (CAN ALTER MATERNAL DIET) 4. Eggs/nuts > cows milk > wheat 5. Identified with skin prick or RAST testing

Answer 82

a. Typically begins in infancy i. Onset as infants = 50% <12months 1. Usually 2-6 months 2. Uncommon >6 months 3. Distribution infants up to 18 months - cradle cap, nape of the neck, trunk and extensor surfaces of limbs, spares flexures and nappy region ii. After 2 years = 30% diagnosed between 1 and 5 years 1. Resolves (most) 2. Chronic and moves on into flexures and lichenification (exaggeration of normal creases) b. Key features i. Intense pruritis ii. Cutaneous reactivity iii. Skin lesions 1. Types a. Acute = erythematous papules b. Subacute = erythematous, excoriated, scaling papules c. Chronic = lichenification, fibrotic papules 2. Distribution a. Infancy = face, scalp, extensor; diaper area spared b. Older children = flexural folds c. Triggers i. Food – cow milk, egg, peanut, tree nuts, soy, wheat ii. Aeroallergens iii. Infection – HSV, staphylococcus, molluscum iv. Reduce humidity + dryness + excessive sweating v. Irritants – water, soap, saliva, urine/faeces, fabrics, additives, sand/chlorine vi. Heat

Answer 83

a. Overview i. Manage triggers ii. Reduce inflammation iii. Treat super-infections b. Non-pharmacological i. Avoidance of triggers = irritants, foods, aeroallergens, infections ii. Moisturizers = usually twice daily adequate iii. Wet dressings c. Pharmacological i. Cutaneous steroids 1. Face a. 1% hydrocortisone E.g. DermAid, Sigmacort, Cortic b. Pimecrolimus – E.g. Elidel – for moderate facial eczema 2. Trunk and limbs – avoid face + genitals a. Methylprednisolone 0.1% - E.g. Advantan fatty ointment b. Mometasone furoate 0.1% - E.g. elocon 3. Adverse effects a. Perioral dermatitis – if used around the face b. No long-term risk of skin thinning, tachyphylaxis, facial telangiectasia (face; reversal) c. Can contribute to striae – must be striae prone area in a striae prone individual d. Theoretically can cause suppression of HPA – but practically does NOT occur (1 tube of potent steroids/week on 6 month old is safe) 4. Key points a. Aim to clear eczema then stop - clearing bursts rather than daily b. Use strong (efficient) cortisones c. Do not use ‘sparingly’; prescribe large quantities ii. Systemic immunosuppression 1. Pharmacological a. Topical Calcineurin inhibitors = pimecrolimus ointment b. Systemic corticosteroids - rare c. Cyclosporine d. Azathioprine = most commonly used e. Methotrexate 2. Phototherapy a. UVB = anti-inflammatory iii. Adjuncts 1. Tar preparations 2. Antihistamines - Do NOT directly benefit eczema iv. Treat infections 1. Bleach bath 2. Systemic antibiotics or antiviral

Answer 84

7. Prognosis a. More severe and persistent in young children b. Periods of remission more common with age c. Predictive factors of poor prognosis = widespread AD in childhood, filaggrin gene mutations, concomitant allergic rhinitis and asthma, family history, early age at onset, very high IgE d. Trouble shooting of no response i. ECMA ii. E = existing diagnosis correct? iii. C = co-existent disease process? 1. Infection 2. Scabies 3. Immunodeficiency = hyperIgE, Wiskott-Aldrich, SCID iv. E = environmental v. M = medication adequate vi. A = allergy or intolerance 1. History clues a. Exacerbation with exposure b. Fluctuating erythema – usually reacting to breast feeds c. Nocturnal itch – dust mite allergy d. Constant topical steroid therapy 2. Examination clues a. Morphology of dermatitis (white dermographism and pronounced erythema) b. Extent and distribution – around mouth and nappy rash if food c. Pattern of facial involvement – eyes and forehead in dust mite 3. Investigations = SPT and RAST testing 4. Management = investigation and avoidance

Answer 85

1. Staphylococcus aureus a. Frequent infection b. Signs – honey crusting, folliculitis, pyoderma c. Treatment = remove crust, oral antibiotics, bleach baths d. Long-term oral bactrim prophylaxis e. Topical antibiotics (IN) 2. Viral infections a. Herpes simplex = most common i. Involved skin painful and itchy ii. Signs – punched out erosions, haemorrhagic crusts and/or vesicles iii. Treatment = oral antiviral therapy b. Enterovirus c. Molluscum contagiosum 3. Fungal infection a. Tinea infections more common in patients with eczema, can be treated with standard topical or oral antifungals b. Malessezia furfur yeast (normal component of skin flora) can be exacerbating factor in head/neck eczema

Answer 86

``` • Unknown etiology • Starts with eczema at one site for any reason • Skin breaks out in ‘sympathy’ patches • Predominantly a vicious cycle • Treatment o Topical steroids o Wet dressings o Sunlight/UVB o Systemic immunosuppression ```

Answer 87

Perioral eczema is CONTINUOUS with lips, perioral dermatitis has a zone of sparing Perioral dermatitis - zone of sparing - variant of rosacea - occurs as rebound effect from corticosteroids - treat with erythromycin/tetracycline

Answer 88

1. Key points a. Usually IgE mediated reactions i. Stings from venomous insects of the order Hymenoptera or from ticks, spiders, scorpions ii. Hymenoptera – apids (honeybee, bumblebee), vespids (yellow-jacket wasp, hornet), formicids (fire and harvester ants) b. Anaphylaxis rare 3. Classification a. Local reaction b. Large local reaction c. Generalised cutaneous reaction d. Systemic reaction – anaphylaxis e. Serum sickness 4. Risk factors a. Elevated tryptase b. Absence of cutaneous signs c. Latency < 5 minutes d. Age e. Honey bee venom f. Concurrent beta blocker/ ACE inhibitor use 5. Diagnosis a. History of exposure b. Serum specific IgE c. Tryptase d. Venom specific skin prick testing i. Negative tests can occur if – loss of skin sensitivity with time, anergic phase (too close to recent reaction – within 6 weeks), false negative ii. If negative, double check with serum IgE 1. Repeat test 1-6 months later 2. If both skin test + IgE is negative, likely not anaphylactic but cases of anaphylaxis have occurred

Answer 89

1. LOCAL REACTION a. Clinical manifestations i. Consist of symptoms confined to the tissues contiguous with the sting site ii. Redness and painful swelling (1-5cm) at the site of the sting iii. Usually mild and transient – develops within minutes and resolves within a few hours; occasionally last for one to two days iv. Nil systemic symptoms b. Complications i. Large local reactions ii. Secondary bacterial infection c. Treatment i. Remove stingers ii. Cold compress 2. GENERALISED CUTANEOUS REACTION a. Progress within minutes b. Includes cutaneous symptoms of urticaria, angioedema and pruritis 3. LARGE LOCAL REACTION a. Approx 10% of individuals develop exaggerated redness and swelling at the site of the sting b. Thought to be IgE mediated c. Clinical manifestations i. Gradually enlarges over 1-2 days ii. Peak at approximately 48 hours and gradually resolve over 5 to 10 days iii. Area of swelling typically measures about 10 cm in diameter d. Treatment i. Cold compress ii. Oral prednisolone given as single dose or rapidly tapered may help to reduce swelling iii. NSAID for pain iv. Pruritis treated with anti-histamine e. Future reactions i. Patients with a history of an LLR often have the same response to subsequent stings ii. It is not known if the risk of recurrent LLRs changes over time iii. The risk for systemic allergic reaction in the future is 7% NOTE: Vomiting + Abdominal pain with venom -> TREAT AS ANAPHYLAXIS

Answer 90

* Hymenoptera VIT is highly effective (95-97%) in decreasing risk of anaphylaxis * Risk of systemic reaction for those who experienced a large local reaction is no more than 5-10%  VIT not indicated * HOWEVER there is evidence to show that VIT can reduce the size and duration of large, local reactions * Takes 3-5 years • Mechanism o Shift T cell phenotype from Th2 (IL-4, IL-5) to Th1 (IFN-gamma) or Treg (IL-10) o Produce IgG rather than IgE • Indications o Specific IgE to venom allergen o Generalised urticaria OR systemic reaction • Adverse effects o Large local reaction (50%) o Systemic reaction (2-15%) ``` • Risk of relapse o More severe allergic o Honey bee allergy o Reaction during VIT o < 5 years of treatment ```

Answer 91

1. Allergic conjunctivitis a. Most common hypersensitivity reaction b. Caused by direct exposure of the mucosal surface of the eye to environmental allergens c. Seasonal allergic conjunctivitis typically associated with allergic rhinitis d. Perennial allergic conjunctivitis triggered by HDM or animal dander – symptoms usually less severe e. Clinical manifestations i. Ocular itching ii. Tearing iii. Bilateral injected conjunctivae with vascular congestion iv. May progress to chemosis or conjunctival swelling and watery discharge 2. Vernal keratoconjunctivitis a. Severe bilateral chronic inflammatory process of the upper tarsal conjunctival surface b. May threaten eyesight if there is corneal involvement c. Most frequently occurs in children with seasonal allergies, asthma, or atopic dermatitis d. Affects primarily children in temperate areas, with exacerbations in the spring and summer e. Clinical manifestations i. Ocular itching exacerbated by exposure to irritants, light or perspiration ii. Giant papillae occur predominantly on the upper tarsal plate – described as Cobblestoning iii. Long eyelashes 3. Atopic conjunctivitis a. Chronic inflammatory ocular disorders most commonly involving the lower tarsal conjunctiva b. May threaten eyesight if there is corneal involvement c. Almost all patients have atopic dermatitis, significant number have asthma d. Rarely presents before late adolescence 4. Giant papillary conjunctivitis a. Linked to chronic exposure of FB such as contact lenses, ocular prostheses and sutures 5. Contact allergy a. Involves eyelids usually but can involve the conjunctivae b. Associated with exposure to topical medications, contact lens solutions and preservatives

Answer 92

= Pruritic, elevated skin lesions surrounded by erythematous base commonly described as "hives", d/t transient extravasation of plasma into the dermis • Urticaria = swelling of the dermis • Angioedema = swelling of dermis, subcutaneous tissues, mucous membranes • Urticaria + angioedema occurs in 50% of patients – the remaining 50%, 40% have urticaria alone and 10% have angioedema ALWAYS CONSIDER ANAPHYLAXIS 1. Key points a. Self-limited process b. Represents reaction pattern to variety of stimuli c. Due to mast cell degranulation d. Can be due to hypersensitivity e. Can be due to toxic reactions or intolerance f. Triggers = reasons that cause the mast cells to suddenly become sensitive g. Exacerbating factors = reasons that cause spillage of products from sensitize mast cell h. Once triggered, can be active for days, weeks, months or years 2. Pathogenesis a. IgE mediated = occurs when allergen activates mast cells in the skin b. Non-IgE mediated = activation of mast cells by other agents eg. radiocontrast, viruses, NSAIDs 3. Classification a. Acute = < 6 weeks i. Infection in 80% ii. Infestation and insects iii. Medications/foods b. Chronic = > 6 weeks (either persistent/ recurrent) – kinin mediated i. 75-90% idiopathic ii. Other causes 1. Hereditary angioedema 2. ACE inhibitor 3. Rheumatological/ endocrine/ neoplastic causes

Answer 93

Aetiology (mostly idiopathic or viral) - Foods - Medications - Insect stings - Infections - Contact allergy - Transfusion reactions 5. Exacerbating factors a. Heat b. Pressure dermographism c. Salicylates – acidic foods d. Viruses and other immune stimuli e. Sweating – cholinergic urticaria f. Cold g. Sun 6. Clinical manifestations a. Urticarial lesions – circumscribed, raised, erythematous plaques often with central pallor or duskiness i. May be round, annular or serpiginous ii. May appear flatter if individual taking h1 antihistamine iii. Transient, each lesion lasts a few hours to one day then resolves without leaving a mark iv. Lesions extremely pruritic – worse at night v. NOTE: urticaria associated with serum-sickness reactions, SLE or other vasculitides – burn more than itch, last >24 hours, do not blanch, blister, heal with scarring, may be associated with purpura b. Angioedema – episodic submucosal or subcutaneous swelling that is usually asymmetric in distribution, affects non-dependent parts of the body over minutes to hours, and is non-pitting c. NOTE: angioedema involving the throat, tongue or lips, WITHOUT urticaria should prompt consideration for drug-induced angioedema (eg. seen with ACE), hereditary angioedema, or acquired C1 inhibitor deficiency d. Dermographism common

Answer 94

7. DDx a. Urticaria vasculitis (including HSP) i. Longer lasting lesions (>24 hours) ii. Evidence of purpura or may leave bruising iii. More likely to have arthralgia + systemic symptoms b. Erythema multiforme How to distinguish? EM is: - Usually not itchy - Does not move around - individual lesions persist for days - Has target lesions with a central papule, blister, purpura or ulcer. - Often has mucosal involvement c. Annular erythema d. Other viral and drug eruptions e. Cutaneous lupus Investigations: Usually not indicated for acute urticaria Treatment: Remove identifiable cause if any If symptomatic: Cool Compresses Avoid aggravating factors such as avoiding excessive heat or spicy foods Aspirin and other NSAIDs should also be avoided as they often make symptoms worse Anti-histamines to alleviate itching. A non-sedating antihistamine is preferred Cetirizine (Zyrtec) 0.25mg/kg/dose (adult 10mg) 12-24H oral. Can give up to 4 times the recommended dose to a maximum total daily dose of 40mg. Can be used in children from 6 months of age Steroid creams do not work. For severe cases, not responding to increased doses of non-sedating antihistamines, a single dose of oral prednisolone may be considered

Answer 95

1. Key points a. 50% have associated angioedema b. No external allergic cause or contributing disease in 80-90% c. Self-limited disorder in most patients; lasts 2-5 years - chronic = >6 weeks 2. Definition a. Recurrent urticaria +/- angioedema b. Lasts for 6 weeks or longer c. 50% of cases of chronic urticaria accompanied by angioedema d. Angioedema WITHOUT urticaria often due to allergy but raises question about other diagnoses • Approximately 30% of chronic urticaria cases are physical urticaria and 60-70% are idiopathic Aetiology (PREDAN) - P = physical - cold, pressure, heat - R = rheumatological - SLE, JIA - E = endocrine - hypo/hyper thyroid - D = drugs - ACE inhibitor - A = angioedema - hereditary, acquired - N = neoplastic - lymphoma, leukaemia

Answer 96

4. Clinical manifestations a. Cutaneous i. Urticaria ii. Angioedema b. Systemic i. Headache, fatigue, pain or swelling of joints, wheezing, flushing, GI symptoms, palpitations c. Triggers i. Physical factors ii. Anti-inflammatory – NSAIDs (20-50%) iii. Stress iv. Variations in dietary habits an alcohol 5. Differential diagnosis a. Erythema mutiforme b. Dermatitis herpetiformis c. Bullous pemphigoid d. Mastocytosis e. Urticaria pigmentosa f. Muckle-Wells syndrome = SNHL, amyloidosis, arthralgias, skeletal abnormalities g. Schnitzler syndrome = chronic urticaria, macroglobulinaemia, bone pain, anaemia, fever, fatigue and wt loss

Answer 97

6. Investigations a. Often not required b. Limited screen may be indicated i. FBE – eosinophilia should prompt evaluation for atopic disorder or parasitic infection ii. CRP/ESR – usually normal iii. TSH level c. Allergy testing (SPT or RAST) i. If <18/12 ii. Suggestive for food on history iii. Parental pressure test IgE 7. Treatment a. Reassurance b. Explain aetiology c. Explain prognosis – days, weeks, months, year d. Avoidance of exacerbating factors e. Role of therapy is to alleviate symptoms whilst waiting for natural resolution f. Dietary manipulations (controversial) g. Pharmacotherapy i. Antihistamine 1. Prophylactically 2. Only help with itch and elevation of wheal ii. Glucocorticoids – temporary 1. If acute and/or severe 2. Start with 1 mg/kg and wean down over 1/52 – may need longer 3. Explain potential for recurrence after finishing course iii. Second line options 1. LT receptor antagonist 2. H2 blockers 3. Sodium cromoglycate 4. UVB 5. Omalizumab (monoclonal antibody to free IgE, indicated for maintenance treatment of moderate-to-severe allergic asthma in patients treated with inhaled corticosteroids and with raised serum IgE levels, severe chronic rhinosinusitis with nasal polyps inadequately controlled with intranasal corticosteroids, chronic spontaneous urticaria inadequately controlled with antihistamines)

Answer 98

1. Key points a. Angioedema supposed to represent deeper variant (cf urticaria) i. Deferent presentations for some situation such as adults taking ACE inhibitors ii. Nonspecific swelling b. Some areas of urticaria show much more swelling as skin tension is less i. Lips and eyes ii. Involvement of these sites not inherently concerning 2. Aetiology of recurrent angioedema a. Idiopathic angioedema b. Type I hereditary angioedema c. Type II hereditary angioedema d. Hereditary angioedema with normal C1 inhibitor (type III) e. Acquired C1 esterase inhibitor deficiency f. Vasculitis 3. Screen for cause on H+E a. Fever b. General well-being c. Food ingestion – urticaria usually commence head and neck d. Medication history e. Localising signs for infection/ rheumatological disease 4. Assess for associated anaphylaxis a. Wheeze b. History of coughing/voice change c. Vomiting d. Altered conscious state e. Tongue swelling

Answer 99

1. Key points a. Recurrent episodes of angioedema without urticaria or pruritis b. Usually affects skin or mucosal tissue of upper respiratory or GIT c. Swelling self-limited and lasts 2-5 days d. Laryngeal involvement may cause fatal asphyxiation 2. Genetics + pathogenesis a. AD (type I and II) – spontaneous mutation in 25% b. Classification i. Type I = C1 inhibitor deficiency -> protein and functional levels of C1INH are low ii. Type II = C1 inhibitor dysfunction -> function is low but protein levels are normal or elevated d. C1-INH i. Synthesized by hepatocytes and monocytes ii. Inhibits C1 -> unchecked activation of C1 causes cleavage of C4 and C2 1. Levels of C3 are normal iii. Also inhibits other components of the fibrinolytic, clotting and kinin pathways (kallikrein), e.g. bradykinin -> bradykinin results in vasodilation + increased vascular permeability -> oedema

Answer 100

a. 40% have first attack by age 5 years b. Repeated attacks in pre-adolescent children uncommon c. Attack frequency increases in puberty d. Diagnosis usually made in 2nd-3rd decade e. Triggers i. Physical triggers ii. Medication = oestrogen containing, tamoxifen, ACE-I iii. Hormonal change in women f. Attacks i. Cutaneous attack 1. Most commonly localised to hand or foot – can involve genitalia 2. Onset in childhood and severe during adolescence 3. Swelling becomes more severe over 1.5 days then resolves over same period 4. May have preceding erythema marginatum ii. Gastrointestinal attack 1. Caused by oedema of mucosa of GIT – results in colic, N+V, diarrhoea 2. May be severe and mimic acute abdomen iii. Laryngeal/pharyngeal attack 1. Can result in complete respiratory obstruction 2. Life-threatening attacks are uncommon 3. 50% of all patients experience a laryngeal attack 4. Predyspnoea phase (first noticeable symptom of sensation of lump or feeling tight in throat/ swallowing phase) -> dyspnoea -> loss of consciousness -> death

Answer 101

4. Investigations a. C1 inhibitor deficiency = type I and II b. Low C4 (substrate for C1 esterase) – during acute and quiescent phases c. C2 levels low during attacks only 5. Treatment a. Does NOT respond to adrenaline, antihistamines or glucocorticoids b. Varies based on underlying cause c. First line therapies for severe i. Human plasma-derived C1 inhibitor concentrate = Berinert/Cinryze ii. Recombinant human C1 inhibitor iii. Icatibant – bradykinin B2 receptor antagonist iv. Ecallantide – kallikrein inhibitor d. Mild attacks i. Tranexamic acid – partially inhibits bradykinin pathway, no effect on C4 levels ii. Danazol – attenuated androgen – causes C4 levels to return to normal by increasing hepatic production of C1 esterase inhibitor 1. Indications – post-pubertal children, pre-pubertal if life threatening event in past, peri-operative

Answer 102

1. Key points a. Serum sickness = systemic, immune-complex mediated hypersensitivity vasculitis triggered by heterologous or chimeric protein therapeutic b. Serum sickness-like reaction (SSLRs) = caused by other drugs 2. Aetiology a. Proteins from other species i. Anti-venom ii. Monoclonal antibodies b. Drugs i. Antibiotics = cefaclor (serums-sickness like reaction), penicillins, bactrim, minocycline, meropenem 1. In children – SSLR are 15x more likely with cefaclor than other antibiotics 2. SSLRs occur in 0.024 to 0.2% of courses ii. Neurologic = bupropion, carbamazepine, phenytoin, sulfonamides, barbiturates iii. Hepatitis B 3. Pathogenesis a. Class III hypersensitivity – caused by Ag-Ab complexes i. Small complexes – circulate harmlessly ii. Large complexes – cleared by reticuloendothelial system iii. Intermediate complexes = may deposit in blood vessel wall and tissues – trigger vascular (leukocystoclastic vasculitis) and tissue damage (activation of C’) b. Immune complexes involving heterologous (animal) serum proteins and complement activation c. Serum-sickness like reaction may be attributed to drug allergy, particularly triggered by antibiotics (celcor) i. Do NOT exhibit the immune complexes, hypocomplementaemia, vasculitis and renal lesions

Answer 103

1. Clinical manifestations (rash/urticaria, fever, arthralgia/arthritis) a. 7-21 days after foreign material - onset accelerated if previous exposure b. Cutaneous i. Site of injection erythematous and oedematous ii. Mucous membranes NOT involved iii. Rashes = urticaria and morbilliform (can be other) iv. Usually pruritic rash c. Polyarthritis/arthralgia d. Other – oedema, myalgia, lymphadenopathy, arthralgia or arthritis, GI complaints e. Symptoms resolve in 2 weeks (as long as 2-4 months) f. Serum-sickness like reactions i. Fever, pruritis, urticaria + arthralgia ii. Begin 1-3 weeks after drug exposure iii. Urticarial eruption increasingly erythematous and can evolve into dusky centre with round plaques 2. Complications a. Carditis b. Glomerulonephritis c. Guillain-Barre syndrome d. Peripheral neuritis 3. Investigations a. Thrombocytopenia, neutropenia b. Elevated ESR and CRP c. Urinalysis shows proteinuria +/ haematuria d. Low C3 + C4 (nadir day 10) + total haemolytic complement (CH50) e. Skin biopsy (if done) = findings similar to those seen with urticaria; IgM, IgA, IgE C3 deposits 4. Treatment a. Supportive + withdrawal of culprit agent b. Antihistamines, NSAIDs c. Steroids sometimes used

Answer 104

1. Classification a. Immediate = IgE mediated b. Delayed = Non-IgE mediated i. Food protein proctocolitis ii. Food protein enteropathy iii. Food protein induced enterocolitis syndrome (FPIES) iv. Eosinophilic oesophagitis/ gastritis/ enteritis/ colitis v. Multiple food protein intolerance (MFP1) c. Mixed reactions d. Non-immunological 3. Epidemiology a. 2-5% overall b. >10% of 12 month old infants in Melbourne c. 5-10% of children overall d. Risk factors i. Australian born infant with 2 Asian born parents 20% risk ii. Severe eczema 40% chance of allergy e. Children i. Egg, milk (most common food allergy), peanut (most common cause anaphylaxis) ii. Soy, wheat, fish iii. Other allergens = tree nut, shellfish f. Persistent into adulthood i. Peanut, tree nut, shellfish – 80% persist g. Overall prevalence in children i. Cow’s Milk = 2.5% in first two years of life 1. Most develop by 12 months ii. Egg = 1-2% of young children 1. Most by 18 months iii. Peanut and tree nut = 0.4-1.3% of children 1. Median age of first reaction is 14 months iv. Wheat = 0.4-1% of children v. Seafood = <1% of children vi. Strawberries = Rare 5. Natural history a. Most children with egg, cow milk and wheat allergy will outgrow i. 30% by 3 years ii. 50% by 5 years iii. 80% by 12 years b. Fish, shellfish and nut allergy much more difficult to outgrow and most are allergic lifelong (peanut, tree nut 10-20% chance tolerance by 5 years of age)

Answer 105

a. IgE mediated reactions i. Onset 30 minutes to 1 hour ii. Multisystem features: 1. Skin – erythema/ angioedema/ urticarial 2. GI – vomiting /diarrhoea/ cramps 3. Resp – cough/ stridor / wheeze/ hoarse voice 4. CVS – hypotension/ pale / floppy infants iii. Reproducible iv. Skin and GI symptoms the most common ssIgE/SPT positive b. Non-IgE mediated i. Eg FPIES / food protein induced colitis ii. 1-48 hours onset iii. Features 1. Vomiting /diarrhoea 2. FTT/ LOW 3. Abdominal pain 4. Hypotension can occur – but only due to fluid loss ssIgE/SPT negative c. Mixed i. Tend to have onset 1-48 hours ii. Features 1. Eczema 2. Vomiting/ diarrhoea 3. FTT/LOW 4. Abdominal pain 5. GOR

Answer 106

8. Management a. Allergen avoidance b. Dietary education if excluding major food groups c. Risk minimization i. Action plan ii. Adrenalin, indicated if 1. Hx of anaphylaxis 2. Adolescents 3. Remote location 4. Poorly controlled asthma 5. Allergy to peanut/ treenuts iii. Control asthma d. Annual review e. Allergist referral if: i. Anaphylaxis ii. Discordant hx/ skin prick test iii. Non-IgE mediated syndromes iv. Not responding to exclusion diet f. Introduction into diet via baking = not if previous severe reaction, previous reaction to trace amount, asthma or multiple food allergies 9. Prevention of food allergy a. Exclusive breast feeding for 4-6 mo b. Introduce solid (complementary) foods after 4-6 mo of exclusive breast feeding c. Introduce low-risk complementary foods 1 at a time d. Introduce potentially highly allergenic foods (fish, eggs, peanut products, milk, wheat) soon after the lower-risk foods (no need to avoid or delay) e. Don’t avoid allergenic foods during pregnancy or nursing f. Soy-based formulas do not prevent allergic disease

Answer 107

• Gastrointestinal inflammatory reaction and thus presenting with GIT symptoms + signs o Vomiting and/or diarrhoea – may be bloody o Abdominal pain/bloating o Growth impairment in some non-IgE conditions • Can have associated eczema flare • Usually does NOT occur in exclusively breasted infants (exception is allergic Proctocolitis; and some cases FIIPES) • Unlike IgE food allergy o No urticaria/ angioedema/ respiratory difficulty o ssIgE/SPT usually negative/ low positive o No fatalities Conditions 1. Eosinophilic oesophagitis – also classified as mixed IgE and non-IgE 2. Allergic eosinophilic esophagitis – also classified as mixed IgE and non-IgE 3. Allergic proctocolitis 4. FPIES 5. Dietary protein-induced enteropathy 6. Celiac disease (gluten sensitive enteropathy) 7. Contact dermatitis 8. Dermatitis herpetiformis 9. Pulmonary haemosiderosis

Answer 108

1. Key points a. Also called food protein-induced allergic proctocolitis (FPIAP) b. Common cause of rectal bleeding c. Characterised by inflammation of distal colon in response to one or more food proteins d. Most common triggers i. Cow’s milk protein – 75% 1. Can be exposed through breastmilk or infant formula ii. Egg – 16% iii. Soy protein – 6% iv. Corn – 2% 2. Pathogenesis a. Characterised by inflammation of distal colon in response to one or more food proteins 3. Clinical manifestations a. Healthy, non-febrile baby b. Usually 2-8 weeks of age; resolves by late infancy c. Usually breastfed (or started cow milk/ soy formula) – 60% occur in breastfed infants d. Gradual onset fresh blood specks/ clots in stool (frank blood uncommon) e. Diarrhoea uncommon (<5%) f. Features NOT consistent with allergic proctocolitis = fever, FTT, frank diarrhoea, forceful vomiting and/or abdominal distension 4. Investigations a. Clinical diagnosis b. SPT/ssIgE not require c. Rectal biopsy – (NOT DONE) – eosinophilic infiltration 5. Management a. Remove cow’s milk +/- soy from maternal diet if BF b. Remove corn/egg from maternal diet if BF (if fail to respond to removing milk/soy) c. Extensively hydroylsed formula d. Amino acid formula e. Usually resolves by 12 months of age – re-introduce food triggers after 12 months of age

Answer 109

1. Key points a. Infantile food protein enteropathy b. Note this is the same pathology as celiac disease c. Triggers i. Cow’s milk – most common ii. Soy, egg, wheat – other common triggers 2. Pathogenesis a. T cell activation b. Villous atrophy with loss of lactase function at tips of villi – lactose intolerance c. Chronic diarrhoea – osmotic, fat malabsorption, protein loosing enteropathy 3. Clinical manifestations a. Usually present within first 12 months b. Chronic, non-bloody diarrhoea within weeks after introduction of food c. Often have FTT d. Other features i. Vomiting ii. Abdominal distension iii. Early satiety iv. Malabsorption 4. Investigations a. Anaemia b. Hypoalbuminaemia c. +/- endoscopy 5. Management a. Allergen avoidance in most cases i. Improvement 6-12weeks ii. Increase appetite 2-4weeks iii. Weight gain 8-12weeks b. Remove cow’s milk and soy c. EHF if no FTT -> if no response then try amino acid d. If presenting with FTT -> amino acid e. Resolves by 24-36 months of age

Answer 110

1. Key points a. Oesophageal eosinophilic inflammation (+/- gastrointestinal eosinophilc inflammation) b. Increased prevalence with time – 22x per 100,000 c. Triggers – 6 implicated i. Cow milk, soy, wheat, egg ? Nuts ? Seafood ii. ? Aeroallergens 2. Clinical manifestations a. Infant i. Vomiting/gagging with meals ii. Food refusal/ aversion iii. Persistently irritable baby iv. Lack PPI response v. +/- poor growth (food refusal; ? more extensive GIT eosinophilia) b. Child/adolescent i. Vomiting/gagging with meals (gag = cough with meal) ii. ‘Fussy eaters’ iii. Food bolus obstruction + atopic child = eosinophilc oesophagitis until proven otherwise iv. Abdominal pain v. GER symptoms 3. Investigations a. Endoscopy = trachealisation, furrowing b. No role for ssIgE/SPT in predicting food trigger c. Current only way to ascertain food trigger is elimination and then re-introduction with repeat scope 4. Management a. Initially if diagnosis, try high dose PPI (2 mg/kg) for 6-8 weeks and re-scope – 25% remission rate b. If PPI un-responsive, then management options i. Amino acid formula alone (young children) ii. Dietary elimination (4-6 food triggers); need dietician 1. ‘Melbourne diet’ – no dairy, soy, wheat, egg 2. Other centres – may also eliminate nuts and seafood iii. Swallowed flixotide inhaler or budesonide slurry 1. Higher risk of adrenal suppression with flixotide than budesonide 2. Slurry budesonide made with Splenda c. Re-scope once therapy instituted d. If-reintroducing new food trigger, repeat scope to determine success

Answer 111

1. Key points a. Occurs at any age 2. Clinical manifestations a. Chronic/ intermittent abdominal pain b. Emesis c. Irritability d. Poor appetite e. FTT f. Weight loss g. Anaemia h. Protein losing enteropathy i. Gastroenteropathy 3. Diagnosis a. History b. Positive SPT c. Serum specific IgE d. Biopsy – conclusive diagnosis 4. Treatment a. Not well established b. Elimination diet c. Elemental diet

Answer 112

Food protein induced enterocolitis syndrome 1. Key points a. 15 per 10,000 infants <2 years old in Australia b. Innate immune system activation and remains a clinical diagnosis i. Often mistaken for sepsis/ gastroenteritis ii. +/- OFC if unsure of diagnosis c. No fatalities d. Trigger i. Rice commonest trigger – 75% react only to one food ii. Other common triggers – cow’s milk, soy iii. Rare to be triggered by food proteins through breastmilk 2. Clinical manifestations a. Usually present <12 months of age b. Typically present 2-4 hours after eating a newly introduced food c. Acute i. Profuse vomiting every 10-15 minutes (approximately 1-3 hours after ingestion) ii. Diarrhoea (approximately 5 hours after ingestion) – some develop diarrhoea (blood +) iii. Floppy, pale iv. Appear shocked and dehydrated v. Hypothermic, hypotensive vi. Abdominal distension vii. No cutaneous or respiratory features d. Chronic i. Vomiting ii. Diarrhoea iii. Lethargy iv. Dehydration v. Abdo distension vi. Weight loss, faltering growth 4. Natural history a. Symptoms resolve with removal of allergen from diet b. Usually presents with neonates or infants, ‘outgrown’ by 3 years i. Cow’s milk = 90% ii. Soy = 25-90% iii. Vegetables = 67% iv. Oats = 66% v. Rice = 40% c. 30% go on to develop atopy (cf. allergic proctocolitis where no risk) d. Positive IgE predicts protracted course

Answer 113

Food protein induced enterocolitis syndrome 3. Investigations a. Neutrophilia, thrombocytopaenic b. Normal ESR/CRP c. Hypoalbuminaemia d. Gas = metabolic acidosis, methaemoglobinaemia (1/3rd of patients with severe reactions – may be caused by severe intestinal inflammation and reduced catalase activity resulting in increased nitrites) e. Stool = faecal leukocytes and eosinophils, frank/occult blood f. Negative IgE test to trigger food in most cases 5. Management a. Repeat SPT (especially to egg/ cow milk) prior to challenge due to risk of IgE mediated transformation (ie. negative SPT to positive SPT and IgE food allergy) i. Big difference between OFC for IgE mediated allergy and FPIES challenge b. FPIES only non-IgE mediated FA where challenges recommended in hospital i. +/- IV inserted ii. Usually single dose given iii. Observed for 4 hours post dose iv. If reaction – IV fluids, oral/IV ondansetron c. Good prognosis in majority – usually re-challenge in hospital 12 months post-last reaction 6. Dietary management a. Cow’s milk FPIES i. Try soy (30-60% cross reaction) but with OFC ii. EHF safer b. Fish/shellfish FPIES – introduce other fish/shellfish under OFC c. Chicken FPIES – avoid all poultry; usually single FPIES d. Rice FPIES – wheat corn usually safe, high risk reaction to oats e. Some children react to most

Answer 114

IgE Anaphylaxis • Breastfeeding = continue o Anaphylaxis to CMP via breast milk rare • First line = amino acid • Fail to tolerate due to taste -> try under medical supervision o Extensively hydrolysed o Soy Non-Anaphylaxis • Breastfeeding = continue – do not usually need to restrict CMP unless residual symptoms (eg. eczema) • First line = soy or novalac rice formula • Second line = extensively hydrolysed • Third line = amino acid • Baked products o 60-70% of children with egg/cow milk allergy tolerate it in baked form o Insufficient evidence that exposure results in acceleration to tolerance o Evidence that improves quality of life o Unpredictable reaction – challenge done under medical observation • Use of soy formula o Soy not recommended until >6 months  Higher rate of concurrent soy allergy (25% <6 months vs 5% >6 months)  Nutritional concerns Non-IgE Mediated • Breastfeeding = soy and cow’s milk exclusion • First line = extensively hydrolysed (per lecture) • Second line = AAF (per guidelines)

Answer 115

``` • Pathophysiology unclear • Often unsettled infants whilst breastfeeding but worsened on solid food • Need to exclude o GIT o Metabolic o EOIBD if blood ins tools/FTT • Symptoms settle on amino acid formula • Children outgrow condition over time (3 years+) ```

Answer 116

1. Epidemiology a. Acquired immune deficiency more common – malnutrition, HIV, chemotherapy b. Primary immune deficiency is rare i. Overall Australian prevalence 1/10,000 (Excludes IgA 1/500) ii. XLA 1/103,000 iii. DiGeorge 1/66,000 iv. SCID 1/66,000 v. CVID 1/83,000 vi. CGD1/181,000 c. Most disorders are autosomal recessive 2. Indications to consider PID a. 2 or more serious respiratory/ bacterial infections within 1 year b. >1 episode of sepsis c. 8/more ear infections within a year d. 2/more months with antibiotics with little effect e. 2/more deep seated infection f. Recurrent deep skin /organ abscesses g. Persistent thrush > 1 year h. Need for IV ABX i. Infections with unusual pathogens: PJP, Aspergillus, Serratia, j. FTT k. Chronic diarrhoea, monoliasis, persistent infections after live vaccines 3. Clinical manifestations - B cell: BACTERIAL (esp polysaccharide organisms e.g. Strep, Hib) - T cell: VIRAL, fungal (e.g. chronic candidiasis) - Phagocytic: poor wound healing, delayed umbi separation - Complement: angioedema, Neiserria meningitidis

Answer 117

COMPLETE BLOOD COUNT, MANUAL DIFFERENTIAL, AND ERYTHROCYTE SEDIMENTATION RATE • Absolute lymphocyte count (normal result rules against T-cell defect) • Absolute neutrophil count (normal result rules against congenital or acquired neutropenia and [usually] both forms of leukocyte adhesion deficiency, in which elevated counts are present even between infections) • Platelet count (normal result excludes Wiskott-Aldrich syndrome) • Howell-Jolly bodies (absence rules against asplenia) • Erythrocyte sedimentation rate (normal result indicates chronic bacterial or fungal infection unlikely) SCREENING TESTS FOR B-CELL DEFECTS • Immunoglobulin (Ig) A measurement; if abnormal, IgG and IgM measurement • Isohemagglutinins • Antibody titers to blood group substances, tetanus, diphtheria, Haemophilus influenzae, and pneumococcus SCREENING TESTS FOR T-CELL DEFECTS • Absolute lymphocyte count (normal result indicates T-cell defect unlikely) • Flow cytometry to examine for the presence of naïve T cells (CD3+CD45RA+ cells) SCREENING TESTS FOR PHAGOCYTIC CELL DEFECTS • Absolute neutrophil count • Respiratory burst assay SCREENING TEST FOR COMPLEMENT DEFICIENCY

Answer 118

Age at onset • Early onset • Usually 2-6 mo of age ``` Affected organs • Any type of infection • Extensive mucocutaneous candidiasis • Respiratory infections • Protracted diarrhea • FTT ``` Pathogen • Bacteria: common GP and GN bacteria and mycobacteria • Viruses: CMV, EBV, adenovirus, parainfluenza 3, varicella, enterovirus • Fungi: Candida, PJP Special features • GVHD caused by maternal engraftment or nonirradiated blood transfusion • Postvaccination disseminated BCG or varicella • Hypocalcaemic tetany in infancy (?DiGeorge) Investigations • Lymphocyte count • Delayed hypersensitivity skin tests • Flow cytometry

Answer 119

1. Key points a. The most common type of immunodeficiency b. Onset 3-6 months after maternal IgG wanes c. Common features i. Recurrent infections with encapsulated bacteria/ enterovirus ii. Sinopulmonary / respiratory infections / otitis media/ conjunctivitis/ diarrhoea Age at onset • Onset after maternal antibodies diminish, • Usually after 5-7 mo of age, later childhood to adulthood ``` Affected organs • Recurrent sinopulmonary infections/ bronchiectasis • Chronic gastrointestinal symptoms • Malabsorption • Arthritis • Enteroviral meningoencephalitis • Usually NO growth impairment ``` Pathogen • Bacteria: pneumococci, streptococci, staphylococci, Haemophilus, Campylobacter, Mycoplasma [encapsulated organisms] • Viruses: enterovirus (X-linked agamma), poliovirus • Fungi and parasites: giardia, cryptosporidia Special features • Autoimmunity • Lymphoreticular malignancy: lymphoma, thymoma • Postvaccination paralytic polio ``` Investigations • Ig levels • Protein antigens • Protein-conjugated antigens – Hib • Polysaccharide • Flow cytometry ``` 5. Management a. Antibiotics b. IV / SC immunoglobulin i. Aim is to provide missing antibodies, not to raise IgG levels ii. Options 1. IVIG (Intragram P) Q3-4H 2. SCIG (Evogram) weekly iii. Dose = 300-600 mg/kg/month iv. Aim for IgG trough or steady state 7-8 g/L v. Does not correct IgA deficiency vi. Reactions = anaphylaxis (esp if IgA deficiency and have antibodies to IgA) c. SCT – more for combined (CD40ligand/ X linked lymphoproliferative)

Answer 120

Age at onset • Early onset ``` Affected organs • Skin: abscesses, impetigo, cellulitis • Lymph nodes: suppurative adenitis • Oral cavity: gingivitis, mouth ulcers • Internal organs: abscesses, osteomyelitis ``` Pathogens • Bacteria: staphylococci, Pseudomonas, Serratia, Klebsiella, Salmonella • Fungi and parasites: Candida, Nocardia, Aspergillus Special features • Prolonged attachment of umbilical cord • Poor wound healing ``` Investigations • Neutrophil counts • BT die test • Chemotaxis assay • Myeloperoxidase stain ```

Answer 121

Age of onset • Onset at any age ``` Affected organs • Meningitis • Arthritis • Septicaemia • Recurrent sinopulmonary infections ``` Pathogens • Bacteria: pneumococci, Neisseria [encapsulated organisms] • No virus/ parasites Special features • Autoimmune disorders: SLE, vasculitis, dermatomyositis, scleroderma, GN, angioedema Investigations • CH50 • AH50 • C1- inhibitor level and function

Answer 122

AKA Bruton agammaglobulinaemia 1. Genetics + pathogenesis a. Xq22 – XLA gene = codes for B-cell protein tyrosine kinase (Bruton tyrosine kinase) b. BTK = necessary for pre-B-cell expansion and maturation (probably has roles at all stage of B -cell development) c. Expression of Btk in cells of myeloid linage is important – boys with XLA often have neutropenia at the height of an acute infection d. >500 different mutations have been identified 3. Investigations a. Neutropenia at height of infection b. Flow cytometry i. Peripheral blood B lymphocytes < 1% (demonstrated on flow cytometry), pre B cells present in bone marrow ii. ↑ T cell percentage, normal T cell subset ratios, normal T cell function and thymus c. Immunoglobulin levels i. IgG, IgA, IgM, IgE <95% centile for age and race ii. <100 mg/dL iii. Isohaemagluttinins (natural Ab to type A and B polysaccharide antigens) absent iv. Antibodies to vaccines absent d. Intestinal biopsy: absence of plasma cells e. Prenatal testing – can be performed on male fetuses if family has known mutation 4. Management a. Lifelong IVIG (IV/ Subcut) b. ABX

Answer 123

AKA Bruton agammaglobulinaemia 1. Clinical manifestations a. Well until 6-9 months of life (maternally IgG antibodies) b. Lymphoid hypoplasia on examination – no palpable lymph nodes c. Improve with ABX/ immunoglobulin therapy d. Neutropenia responsive to GCSF e. Pathogens i. Recurrent infections with extracellular pyogenic organisms – Streptococcus pneumoniae, Haemophilus influenzae ii. Viral infection normally handled EXCEPT hepatitis + enterovirus 1. CNS infections with echovirus and coxsackie virus 2. Echovirus associated myositis iii. Mycoplasma infections iv. Chronic fungal infections v. Paralysis with poliovirus f. Type of infection i. Sinusitis ii. Otitis media iii. Pneumonia iv. Sepsis or meningitis g. Counterintuitive association with autoimmunity i. Rheumatoid arthritis ii. Sarcoid iii. Lymphoreticular malignancy

Answer 124

Uptodate: Common variable immunodeficiency (CVID) is a heterogeneous disorder involving immune dysfunction of B and T cells and dendritic cells. The characteristic immunologic defect is the inability of B cells to differentiate into plasma cells capable of secreting all immunoglobulin types. Definition — CVID is defined by the following: ●Age-specific reduction in serum concentrations of immunoglobulin (Ig)G, in combination with low levels of IgA and/or IgM (at least two standard deviations below mean for age) ●Poor or absent response to immunizations and/or absent isohemagglutinins and/or low switched B cells (<70 percent of age-related normal value) ●Absence of profound T cell immunodeficiency ●Absence of any other defined immunodeficiency state 1. Key points a. Syndrome characterised by hypogammaglobulinaemia with phenotypically NORMAL B cells b. Also called ‘acquired hypogammaglobulinaemia’ due to the generally later age of onset of infections c. Experience similar infections as XLA however echovirus and meningoencephalitis is RARE e. Normal numbers of circulating lymphocytes - do not differentiate into Ig producing cells when stimulated

Answer 125

a. Looks similar to XLA except echovirus/ meningoencephalitis is rare b. Onset is later – late childhood/ adulthood c. FHX autoimmunity, immunodeficiency, malignancy d. Normal tonsils/ lymph nodes e. Splenomegaly in 25% f. Recurrent infection i. Pathogens 1. Encapsulated bacteria ii. Type of infection 1. Pneumonia – can develop bronchiectasis 2. Sinusitis 3. Otitis media 4. Diarrhoea – bacterial, giardiais 5. Meningitis with encapsulated organisms g. Pulmonary manifestations = 85% i. Pulmonary airway obstructive disease h. Lymphoproliferative and granulomatous manifestations i. Granulomatous interstitial lung disease (GILD) ii. Lymphadenopathy iii. Splenomegaly i. Autoimmune disease = 25% i. Examples = alopecia areata, haemolytic anaemia, gastric atrophy, thrombocytopaenia, pernicious anaemia, scleroderma, vasculitis, thymoma j. Risk of malignancy i. Increased risk of lymphoreticular malignancy - 8% k. Malabsorption i. Sprue like syndrome: steatorrhoea, malabsorption, PLE ii. Nodular follicular lymphoid hyperplasia iii. Giardia l. Other i. Asthma/ rhinitis ii. IgA deficiency – often in first degree relatives ?common genetic basis

Answer 126

1. Investigations (variable spectrum) a. Normal B cell levels (can be reduced) b. Immunoglobulins – marked decrease of IgG and IgA +/- low IgM c. Poor Ab response to vaccines and/or absent isohaemagglutinins d. Low switched memory B cells (<70% of age-related normal values) e. Normal T cell numbers, reversed CD4:8 ratio f. Normal T cell proliferative responses in most (can decline with time) 2. Management a. IVIG – will not reverse chronic lung disease b. ABX c. Physiotherapy/ drainage

Answer 127

Uptodate: Selective immunoglobulin A (IgA) deficiency (sIgAD) (MIM 137100) may be defined as the isolated deficiency of serum IgA (ie, in the setting of normal serum levels of immunoglobulin G [IgG] and immunoglobulin M [IgM]) in an individual older than four years of age in whom other causes of hypogammaglobulinemia have been excluded. 1. Key points a. <10 mg/dL of serum and secretory IgA b. The most common immunodeficiency disorder, up to 0.33% (1/500) c. Other causes i. Drugs – phenytoin / carbamazepine, valproic acid, d-penicillamine, gold, sulfasalazine, hydroxychloroquine, NSAIDs ii. Congenital rubella/ CMV iii. Association with other immunodeficiency – ataxia telangiectasia/ DiGeorge/ CVID d. Associations i. Allergic disease ii. Coeliac disease iii. Autoimmune disease – SLE/ RA/ Thyroiditis/ Addison’s iv. Anti-IgA antibodies in 33% 2. Genetics + pathogenesis a. Basic defect unknown b. Phenotypically normal B cells d. Familial clusters of IgA deficiency and CVID

Answer 128

3. Clinical manifestations a. MOST are asymptomatic b. Type of infections i. Respiratory ii. Gastrointestinal iii. Urological c. Pathogens = as for other Ab deficiency syndromes i. Intestinal giardiasis is common d. Other features i. Coeliac like syndrome – may or may not respond to gluten free diet ii. Increased risk of autoimmune disease + malignancy e. ↑ autoantibodies, autoimmune disease and malignancy f. Can have anaphylactic reactions to IgA products – need washed blood 4. Investigations a. Immunoglobulin levels i. IgA < 0.07 g/L in patient over 4 (NOT detectable) ii. High incidence of IgG2 deficiency iii. Other immunoglobulin levels normal b. Serum antibodies to IgA in 45% c. Worth checking ab function 5. Management a. IVIG NOT indicated for isolated IgA deficiency (not useful and may have risk of anaphylaxis) b. Transfusion i. Serum antibodies to IgA in 45% 1. If IgE subtype – can cause fatal anaphylactic reaction following administration of blood products containing IgA 2. 5-10x washed donor erythrocytes or blood products from IgA deficient individuals should be transfused ii. Many IVIG preparations contain enough IgA to cause anaphylactic reaction 1. Should use >99% IgG IVIG

Answer 129

``` • Key points o Normal total IgG serum concentration but deficient subclass o IgG2 deficiency may be associated with IgA/ CVID o Most patients with absent/ very low IgG2 have IgA deficiency o Some patients go on to develop CVID • Clinical manifestations o Biologic significance unclear – some individuals with normal IgG subclasses are clinically unaffected o May not make specific antibodies to protein and polysaccharide antigens o IVIG should not be administered unless shown to have a deficiency of Ab to a broad array of Ag ```

Answer 130

1. Key points a. Persistence of normal nadir of Ig seen at birth b. Features i. Normal Ab production to challenge ii. Normal growth patterns iii. Lack of opportunistic infections – may have recurrent respiratory viral infections c. Delayed synthesis of immunoglobulins until after maternal IgG catabolized d. Resolves spontaneously after 4 years (by definition) e. Specific antibody production is normal f. Serious infections rare, can be seen in FHx of SCID g. More common in males 60%, associated with atopy 2. Treatment a. Ab prophylaxis b. Rarely IVIG 3-6 months c. Monitor IgG, tends to increase with time

Answer 131

``` • Protein loss o Protein losing enteropathy o Intestinal lymphangiectasia o Chylothorax o Nephrotic syndrome ``` • Drugs o Steroid o Rituximab

Answer 132

Specific antibody deficiency (SAD) describes an inadequate antibody response to polysaccharide antigens in an individual with normal responses to protein antigens, normal serum levels of immunoglobulins (Ig), and normal IgG subclass concentrations. It is believed to be the most common form of antibody disorder in older children and adults with recurrent rhinosinusitis and/or bronchopulmonary infections. Pathogenesis unclear. Recurrent or severe rhinosinusitis and/or bronchopulmonary infections are the primary presenting disorder. The diagnosis of SAD is made in a patient older than two years of age with recurrent or severe sinopulmonary infections, in whom the only identifiable abnormality is a deficient response to polysaccharide vaccines. Other measurements of immunologic function, including serum levels of IgG, IgG subclasses, IgA, IgM, and IgE, should be normal, and responses to protein vaccines should be normal. In addition, no other primary or secondary immune disorders should be present. The diagnosis is not appropriate in a child younger than two years, because deficient polysaccharide responses are commonly seen and not considered abnormal. Treatment of patients with SAD includes the following: ●Immunization with conjugate vaccines ●Aggressive management of other conditions predisposing to recurrent sinopulmonary infections (eg, asthma, allergic rhinitis, chronic rhinosinusitis) ●Increased vigilance and appropriate antibiotic therapy for infections ●Prophylactic antibiotics ●Intravenous or subcutaneous immunoglobulin replacement

Answer 133

AKA Duncan disease 1. Key points a. Rare, severe dysregulation of the immune system b. Usually occurs in response to EBV c. Rare, 1 in 3 million males 2. Clinical presentation a. Presentation is usually with the first exposure to EBV, usually <5yrs (2.5yrs most common) b. Well prior to then c. Outcomes i. HLH ii. Lymphoma iii. Dysgammaglobulinaemia 3. Genetics + pathogenesis a. XLR trait with clinical hallmark of inadequate response to EBV b. Defect in SLAM associated protein (SAP) in 60% - acts on particularly T and NK cells, but also B cells to mobilize cellular and humoral defenses

Answer 134

5. Clinical picture (3 types) a. Fulminant EBV infection (often fatal) – 60% i. Thrombocytopenia, anaemia, hepatic dysfunction, meningoencephalitis ii. Secondary HLH (Haemophagocytic lymphiohistiocytosis) can also be triggered by EBV iii. Coinciding XLD and HLH is a poor prognostic feature b. Lymphomas (especially B cell lineage) – 30% i. Impaired immune surveillance by T cells ii. Often extranodal disease, especially ileocaecal c. Acquired hypogammaglobulinaemia/ Dysgammaglobulinaemia – 20-30% i. Best prognosis ii. low IgG, high IgA and high IgM iii. Other: vasculitis, aplastic anaemia, lymphoid granulomatosis 6. Investigations a. Diagnosis difficult due to variable clinical picture b. B and T cell numbers normal but function is impaired c. IgG low, IgM, IgA may be high d. Anaemia, thrombocytopaenia, abnormal LFTs e. Dx: gene testing (FISH for SAP) 7. Treatment a. Avoid infections b. Manage EBV infection: anti-viral, IVIG, rituximab c. HLH = need BMT d. Lymphoma = chemo +/- RTx e. Prevention = rituximab (anti-CD20) wipes out B cells can control primary infection / prevent infection pre BMT f. Curative = BMT 8. Prognosis a. In 1995; 70% die by 10yrs, 100% by 40yrs b. Now, overall survival ~70%

Answer 135

* More severe than antibody disorders * Rarely survive beyond infancy * Thymic transplantation or HSCT treatment of choice

Answer 136

1. Classification a. Partial DiGeorge = variable hypoplasia of the thymus and parathyroid glands b. Complete DiGeorge = total aplasia i. <1% of patients with DiGeorge syndrome ii. 1/3 have associated CHARGE syndrome – mutations in CHD7 gene found in 60-65% of individuals with CHARGE syndrome 2. Genetics + Pathogenesis a. Microdeletion of sequences from 22q11 - main problem is error in T box transcription factor TBX1 b. Dysmorphogenesis of 3rd + 4th pharyngeal pouches -> hypoplasia/ aplasia of the thymus + parathyroid glands 3. Clinical manifestations (immune) a. Complete DiGeorge i. Resembles SCID – opportunistic infections including PJP, GVHD from nonirradiated blood transfusions b. Partial DiGeorge – few infections, normal growth c. Associated defects – R sided aortic arch, oesophageal atresia, bifid uvula, congenital heart disease (conotruncal/ atrial + ventricular septal defects), short philtrum 4. Investigations a. Absolute lymphocytes – moderately low for age b. T cell counts decreased – correlate with the degree of thymic hypoplasia c. Mitogen stimulation – reduced response d. Immunoglobulin levels usually normal i. IgA may be reduced ii. IgE may be elevated e. All children with primary hypoparathyroidism, CHARGE, truncus/ interrupted aortic arch should be investigated 5. Treatment a. Non SCID patients: prophylactic abx +/- immunoglobulin replacement b. Thymic transplantation c. OR bone marrow transplantation

Answer 137

• Syndrome characterised by impaired immune responsiveness to Candida ``` • Conditions o APECED/ APS 1 o CARD9 mutation o HyperIgE syndrome o Autosomal recessive deficiency of IL-17 receptor A (IL17RA) chain ``` • Clinical manifestations o Symptoms begin in the first month of life or as late as the 2nd decade of life o Chronic severe Candida skin and mucous membrane infection o Rarely develop systemic Candida disease • Treatment o Systemic azoles

Answer 138

= autoimmune polyendocrinopathy candidiasis ecto- dermal dystrophy OR autoimmune polyglandular syndrome 1 1. Genetics a. Mutation in Autoimmune Regulator (AIRE) gene 2. Pathogenesis - AIRE allows expression of autoantigens during T cell development/in thymus -> mutation prevents this, leading to propagation of auto-reactive T cells (would normally be eliminated) 3. Clinical manifestations a. Mucocutaneous candidiasis  hypoparathyroidism  adrenal failure b. Classic triad i. Chronic mucocutaneous candidiasis 1. Oral cavity, nails, skin, less frequently esophagus, vagina and gastrointestinal tract 2. Presenting features in 60%, present in all patients by age 40 3. Candida albicans most common infection ii. Hypoparathyroidism 1. Most common endocrine abnormality and second most common feature of AIRE 2. Presenting feature in 30%, >80% eventually affected 3. Results in hypocalcaemia and hypoMg – can result in seizures iii. Adrenal failure 1. Third most common features 2. Occurs in 5% at presentation, but >60% by age 115 c. Other manifestations i. Other endocrinopathies ii. Other autoimmune manifestations iii. Complications due to chronic Candida infection iv. Antibody deficiency to polysaccharide antigens v. Other oral and gastrointestinal manifestations vi. Other ocular features vii. Pulmonary disease, interstitial nephritis, encephalopathy

Answer 139

1. Key points a. Combined immunodeficiency syndrome = disturbance in the development and function of T and B cells b. Termed ‘severe’ if result in early death from overwhelming infection, particularly in the first year of life c. Various mutations that lead to absence of adaptive immune function +/- lack of NK cells 2. Pathogenesis a. Mutation in 1 of 13 known genes that encode components of immune system for lymphoid development b. In some cases, results in only T cell deficiency; however, T cell dysfunction precludes effective humoral immunity as B cells require T cells to produce antibodies c. NK cells develop via a pathway distinct from B an T cells; present in 50% of patients with SCID and may provide a degree of protection against bacterial and viral infections 3. Genetics a. X-linked i. Majority of cases X-linked ii. Most common mutation IL2RG – encodes IL-2 receptor (common cytokine receptor) b. Autosomal recessive i. Mutations include 1. JAK3 2. IL-7RA 3. RAG1 and RAG2 4. DCLRE1C 5. ADA c. Unknown mutation in 25% of cases

Answer 140

6. Clinical manifestations a. Clinical presentation i. Severe infections ii. Chronic diarrhoea iii. FTT b. Infections i. Persistent mucocutaneous candidiasis ii. Infections with common viral pathogens – adenovirus, CMV, EBV, rotavirus, norovirus, RSV, VZV iii. Opportunistic infections with non-pathogenic organisms – PJP iv. Attenuated vaccine organisms – polio vaccine virus, rotavirus, varicella, BCG c. GVHD i. Transfusions of blood products containing viable lymphocytes ii. Transplacental passage of alloreactive maternal T cells 5. Classification ``` Classic SCID • Present in infancy • Persistent viral respiratory +/- gastrointestinal infection • PJP • Disseminated BCG • FTT • Superficial candidiasis • Absent lymphoid tissue • Absent Ig • Absent T lymphocytes ``` ``` Omenn Syndrome i. Most commonly caused by RAG1/ RAG2 mutations ii. Due to abnormal T cells proliferating and accumulating in skin • Present in infancy • Erythroderma • Alopecia • Hepatosplenomegaly • Massive lymphadenopathy • Inflammatory pneumonitis/ enteritis • Raised IgE • Eosinophilia • Lymphocytosis - recurrent skin infections ``` ``` Atypical SCID • Present >12 months • Recurrent, severe, prolonged viral infections • Bronchiectasis • Autoimmune cytopenias • FTT • Granulomatous cutaneous lesions • EBV-associated lymphoproliferation • Partial or restricted antigen specific Ab responses • Lymphopaenia ```

Answer 141

a. Screening = TREC i. T cell receptor excision circle – biomarker of naïve T cells; ii. Formation of TREC from excised DNA occurs during the VDJ recombination of TCR in the thymus - will be low in SCID (low numbers circulating T cells) but also low in other disorders of T cells e.g. DiGeorge b. Imaging = Absence of thymic shadow on CXR c. Bloods i. Low absolute lymphocyte count ii. Abnormalities of lymphocyte subpopulations iii. T cell mitogen response extremely low (PHA test) d. Histological features i. Small thymuses – fail to descend, have no thymocytes, no corticomedullary distinction of Hassal corpuscles ii. Follicular and paracortical areas of spleen depleted of lymphocytes iii. Lymph nodes, tonsils, adenoids and Peyer patches absent or underdeveloped e. Antenatal diagnosis i. Lymphocyte count of cord blood ii. Do NOT do specific gene testing unless know specific mutation

Answer 142

8. Treatment a. Protective measures i. Mother should receive booster vaccine ii. Protective isolation iii. Prophylaxis – PJP, fungus iv. IVIG replacement v. Avoidance of live vaccines vi. Blood products – irradiated, leukodepleted and CMV negative vii. No breast feeding viii. Nutrition ix. Aggressive treatment of infection eg. CMV b. HSCT 9. Prognosis = Fatal in first year of life unless HSCT

Answer 143

1. Key points a. Distinguished from SCID by presence of low but NOT absent T cell function b. Usually survive longer than infants with SCID – but still FTT and die early in life c. Diverse genetic causes 2. Clinical manifestations a. Recurrent or chronic pulmonary infections b. FTT c. Oral or cutaneous candidiasis d. Chronic diarrhoea e. Recurrent skin infections f. GN bacterial sepsis g. UTI h. Severe varicella in infancy 3. Investigations a. Neutropenia + eosinophilia common b. Serum Ig may be normal or elevated ``` Conditions • Hyper IgM syndrome • Wiskott-Aldrich • Ataxia-telangiectasia • DiGeorge syndrome • Nijmegen breakage syndrome • PNP deficiency • MHC I and II deficiency • STAT 1 deficiency • Cartilage hair hypoplasia ```

Answer 144

1. Key points a. Genetically heterogenous b. Characterised by normal or elevated serum IgM levels, low or absent IgG, IgA and IgE serum levels c. Defect in class switching recombination (CSR) process 2. Genetics - Multiple (CD40/CD40L, NEMO, AID, UNG) b. Clinical manifestations (variable between different types above) i. Small tonsils, no palpable lymph nodes ii. Profound neutropenia iii. Infection 1. Recurrent pyogenic infections by 1-2 years of life – otitis media, sinusitis, pneumonia, tonsillitis 2. Impaired T cell interactions with monocytes/ macrophages -> PJP, cryptosporidiosis, CMV a. Marked susceptibility to PJP iv. Malignancy + autoimmunity d. Management i. Very poor prognosis without treatment ii. Avoidance of live vaccines iii. Avoidance of cryptosporidium iv. Stem cell transplant early v. Monthly infusion with IVIG / use of G-CSF for those who are neutropenic

Answer 145

Purine nucleoside phosphorylase (PNP) deficiency (MIM #613179) is a rare, autosomal-recessive immunodeficiency. It is characterized by progressive immune abnormalities ranging from severe to nonsevere combined immunodeficiency (table 1) and neurologic symptomatology that includes ataxia, developmental delay, and spasticity. Autoimmunity, especially autoimmune hemolytic anemia, is also frequently present. • Point mutation in PNP gene 14q13 • Like ADA deficiency but no physical / skeletal abnormalities • Clinical manifestations o Usually less severe but can present as SCID o 2/3 have neurologic abnormalities o 1/3 have autoimmune disease o Death from generalised vaccinia, varicella, lymphosarcoma, or GVHD • Investigations o Serum and urinary urate DEFICIENT o Lymphopenia with normal NK cells o B cell function may be near normal

Answer 146

1. Key points a. Unusual form of short-limbed dwarfism + frequent infections b. Predominantly occurs in Amish population c. Associated conditions i. Deficient erythrogenesis ii. Hirschsprung disease iii. Malignancy 2. Genetics + pathogenesis a. AR d. Decreased number of T cell and defective T cell proliferation 3. Clinical manifestations a. Physical i. Short pudgy hands, redundant skin ii. Hyperextensible joins iii. Fine/ light hair and eyebrows iv. Bones – scalloping, sclerotic or cystic changes b. Immune dysfunction -> frequent infections i. Defective Ab mediate immunity ii. CID = most common iii. SCID 4. Investigations a. Cytopenias

Answer 147

• AR • Mutation in SMARCAL1 – involved in chromatin remodeling • Features o Short stature, spondilo-epiphyseal dysplasia o Typical facies o Hx of IUGR o Nephropathy with steroid resistant nephrotic syndrome o Cerebral ischaemic o Develop bacterial, viral and fungal infections

Answer 148

MHC I Antigen Deficiency = Bare Lymphocyte Syndrome • Rare • Clinical manifestations o Milder phenotype than SCID o Sera contains normal quantities of MHC class I antigens + beta-2 microglobulin  BUT MHC I not detected on any cells in the body  Deficiency of CD8 but NOT CD4 T cells MHC II Antigen Deficiency • Often North African descent • Not as severe as SCID • Clinical manifestations o Present in early infancy o Persistent diarrhoea – cryptosporidiosis, enterovirus o Oral candidiasis o Bacterial pneumonia o PJP o Septicaemia • Investigations o Low CD4 T cells, normal/ elevated CD 8 cells o Hypogammaglobulinemic  impaired antigen specific responses due to absence of APC molecules o Lymphocytes have normal response to mitogen, no response to antigen

Answer 149

1. Genetics + pathogenesis a. X linked c. Codes for WASP protein d. Impaired humoral responses to polysaccharide antigens – diminished isohaemagglutinins, poor or absent Ab response after immunisation with polysaccharide vaccines 2. Clinical manifestations (TIME = thrombocytopenia, inmmunodeficiency, malignancy, eczema) a. Immune deficiency i. Otitis media, pneumonia meningitis and sepsis – polysaccharide capsules eg. strep pnuemo ii. PJP iii. Herpesviruses b. Bleeding diathesis i. Thrombocytopenic purpura, with normal appearing megakarocytes but small defective platelets ii. Prolonged bleeding from circumcision or bloody diarrhoea c. Malignancy d. Eczema 3. Natural history a. Present in first year of life b. Survival beyond teens is rare c. Infections, bleeding and EBV-associated malignancies major cause of death 4. Investigations a. IgG2 normal b. Highly variable concentration of albumin, IgG, IgA and IgM c. % T cells moderately reduced d. Lymphocyte response to mitogens variably depressed 5. Treatment a. Monthly IVIG

Answer 150

1. Genetics + pathogenesis a. Autosomal b. ATM gene defect (ataxia telangiectasia mutation) 2. Clinical features a. Cerebella ataxia i. Evident soon after children start to walk ii. Progresses until confined to wheelchair by age 10-12 years b. Oculocutaneous telangiectasias i. Develop age 3-6 years c. Chronic sinuopulmonary disease d. High incidence of malignancy e. Variable humoral and cellular immunodeficiency i. Selective IgA deficiency most common 3. Investigations a. Depressed response to T / B cell mitogens b. Low CD 3 and CD4 T cells c. Low IgA, IgE and IgM d. Low IgG2 or total IgG e. Progressive lymphopenia with antibody deficiency f. Hypoplastic thymus with poor organization, lacks Hassal corpuscles 4. Natural history a. Death normally early adulthood

Answer 151

1. Pathogenesis a. Abnormal lymphocyte apoptosis resulting in polyclonal population of T cells (double-negative T cells) i. Express CD3 and alpha/beta antigen receptors ii. Do NOT have CD4 or CD8 receptors b. Respond poorly to antigens or mitogens c. Do not produce growth or survival factors (IL-2) d. Caused by mutations in the Fas pathway 2. Genetics a. Fas gene most common, usually produces a cell surface receptor which induces apoptosis when stimulated -> mutation causes persistent survival and immune dysregulation 7. Treatment a. Immunosuppression b. Splenectomy if hypersplenism c. Treatment of malignancy d. SCT

Answer 152

3. Diagnostic features a. Required i. Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly) ii. Elevated peripheral blood double-negative T cells b. Accessory i. Primary 1. Defective in vitro Fas-mediated apoptosis 2. Somatic or germline mutations in ALPS causative genes – FAS, FASL, CASP10 ii. Secondary 1. Elevated biomarkers a. Plasma soluble FASL > 200 pg/ml b. Plasma IL-10 >20 pg/ml c. Plasma or serum vitamin B12 >1500 ng/L d. Plasma IL-18 >500 pg/ml 2. Immunohistochemical findings consistent with ALPS as determined by an experienced histopathologist 3. Autoimmune cytopaenias and polyclonal hypergammaglobulinaemia 4. Family history of ALPS or non-malignant lymphoproliferation 4. Clinical manifestations a. Autoimmunity i. Anaemia Coombs-positive haemolytic anaemia, thrombocytopaenia, neutropenia ii. Other autoimmune features – urticaria, uveitis, GN, hepatitis, vasculitis, GN, panniculitis, arthritis, CNS involvement b. Chronic persistent or recurrent lymphadenopathy c. Splenomegaly + hepatomegaly (50%) i. May result in hypersplenism with cytopaenias d. Hypergammaglobulinaemia (IgG, IgA) e. Malignancy i. Hodgkin + NHL ii. Solid tissue tumours 5. Natural history a. Most patients present in the first year of life b. Usually symptomatic by age 5

Answer 153

= Immunodysregulation polyendocrinopathy enteropathy X-linked 1. Key points a. Rare, often fatal, X linked syndrome b. Typically presents in infancy with classic triad i. Enteropathy = results in life-threatening chronic diarrhoea ii. Autoimmune endocrinopathy = neonatal type 1 diabetes or thyroiditis iii. Dermatitis = usually eczematous 2. Genetics + pathogenesis a. Mutations in the gene for transcription factor FOXP3 – fundamental to the function of Tregs 3. Clinical manifestations a. Autoimmune i. Endocrine 1. Type 1 diabetes mellitus – most common with onset generally during first year of life 2. Hypo or hyperthyroidism ii. Chronic diarrhoea due to autoimmune enteropathy iii. Immune-mediated cytopaenias b. Dermatitis – usually eczematous c. Infection – severe bacterial infections (meningitis, sepsis, pneumonia, osteomyelitis) d. Other i. Lymphadenopathy and splenomegaly ii. Severe food allergies iii. Nephritis iv. Failure to thrive v. Developmental delay 4. Investigations a. Diagnosis established by mutational analysis of FOXP3 gene 5. Management a. Immune suppression b. Dietary modification to avoid food allergies c. HSCT – only curative therapy 6. Prognosis a. Untreated – infants with IPEX usually die in early childhood

Answer 154

1. Key points a. Interaction with pathogen i. Direct ii. Indirect = opsonized microbes by Fc receptors or complement receptors b. Phagosome develops from fusion of neutrophil granules c. Results in targeted delivery of antimicrobial molecules + ROS d. Neutrophils also produce NETS – release protease components to trap pathogens 2. Classification a. Reduced number of neutrophils i. Increased neutrophil destruction 1. Drug induced – PTU/ penicillin/quinine 2. Immune neutropenia ii. Defects of neutrophil differentiation/ production 1. Cyclical neutropenia = ELANE mutation 2. Kostmann syndrome = HAX1 mutation 3. Glycogen storage disease b. Defects of motility i. LAD 1-3 ii. Shwachman Diamond syndrome c. Defects of respiratory burst i. Chronic granulomatous disease ii. Chediak – Higashi syndrome iii. Specific granule deficiency iv. Myeloperoxidase deficiency

Answer 155

3. Clinical manifestations a. Recurrent deep tissue infections i. Lymphadenitis ii. Pneumonia iii. Osteomyelitis iv. Liver abscesses b. Unusual or resistant infections i. Staphylococcus aureus ii. Pseudomonas iii. Klebsiella iv. Aspergillus v. Burkholderia vi. Candida vii. Nocardia c. Periodontal disease or tooth loss d. Omphalitis 4. History + examination a. Family history of recurrent infection b. Gingivitis c. Chronic diarrhoea d. Infections with absence of neutrophilic infiltration e. Elevated CRP/ESR f. Splenomegaly or hepatomegaly g. Moderate lymphadenopathy h. Inflammatory anaemia 5. Investigations a. FBE, ESR – exclude lymphopaenia b. Immunoglobulins c. T+ B cell quantification + subsets d. PHA stimulation e. Response to tetanus immunisation f. Neutrophil evaluation i. NBT slide test for ii. Tests of oxidative metabolism iii. Adhesion molecule expression iv. Other – chemotaxis, phagocytosis, bactericidal assays

Answer 156

• Neutrophils arrive at site of inflammation within 2-4 hours after microbial invasion • All autosomal recessive disorders of leukocyte dysfunction • Three forms: LAD-1, LAD-2, LAD-3 Constellation of: leukocytosis/neutrophilia, recurrent bacterial infections, absent pus/poor wound healing, delayed separation of umbi/omphalitis 2. Clinical manifestations (general) a. Recurrent, indolent bacterial infections – staph, enteric gram negative , candida, aspergillus b. Delayed umbilical separation (>21d), omphalitis c. Skin/ mouth / respiratory tract/ lower GI/ genital mucosa infection (but pus does not form) 3. Investigations a. Leukocytosis ++++ b. Decreased chemotaxis c. Flow cytometry = measurements of CD11b/CD18 expression in stimulated and unstimulated neutrophils d. LAD-2 = looking for C15 on neutrophils 4. Treatment a. Allogeneic HSCT if severe LAD-1/ LAD-3 i. Complicated by graft rejection b. Bactrim prophylaxis c. Some LAD-2 patients respond to fucose (spelt correctly!) supplementation d. Ustekinumab – blockade of IL-23 and IL-12 reduced gingivitis + ulcers 5. Prognosis a. Severe deficiency results in death in infancy b. Lifelong susceptibility to severe infection

Answer 157

Constellation: defective degranulation, albinism, neuropathy, bleeding diathesis 1. Key points a. Rare disorder b. Defect in granule morphogenesis – results in large granules in multiple tissues c. All cells have oversized/ dysmorphic lysosomes/ granules (neutrophils, melanosomes, neurologic cells) 3. Clinical manifestations a. Light hair b. Photophobia with rotary nystagmus c. Frequent infections (S aureus most common) d. Neuropathy (in teens) e. Bleeding diathesis (impaired platelet function) f. Short stature 4. Key complication = HLH (‘accelerated phase’) a. Pancytopenia, high fever and lymphohistiocytic infiltration of liver/ spleen and lymph nodes b. Neutropenia c. Associated with secondary bacterial + viral infections d. Occurs in 85% of patients – usually results in death 5. Investigations a. Large inclusions on nucleated blood cells (Wright stain/ peroxidase stain) i. May need to do BMA – can be missed on peripheral smear b. Progressive neutropenia c. Abnormal platelet, neutrophil and NK function 6. Treatment a. High dose ascorbic acid – improves clinical status of children in stable phase b. HSCT only curative treatment c. If accelerated phase (HLS) -> HSCT required to fix haematopoietic and immunologic function

Answer 158

1. Key points a. One of the most common inherited disorders of phagocytes b. 1/2000 individuals 2. Genetics + Pathogenesis a. AR b. Defect in MPO gene c. MPO = green heme protein in lysozymes of neutrophils and monocytes (makes pus green!) 3. Clinical manifestations a. Usually clinically silent 5. Treatment a. No specific therapy required b. Antifungal treatment only – for candida cover (can rarely result in disseminated candida) c. Excellent prognosis

Answer 159

1. Key points a. Neutrophils and monocytes have defect in microbicidal oxygen metabolism (NADPH oxidase burst) b. Incidence 1/250,000 2. Genetics + pathogenesis a. Mostly X linked but multiple mutations b. Leads to defect in generation of microbicidal oxygen metabolites – NADPH oxidase complex, required for oxygen dependent intracellular killing mechanism i. Results in the ability of phagocytes (neutrophils, macrophages, monocytes) to destroy certain microbes 3. Clinical manifestations a. Onset can be from early infancy to young adulthood (less common) b. Infection i. Pathogens 1. Any catalase +ve organism – most commonly Staph aureus (note all fungi and most bacteria are catalase positive) 2. Bacteria = S aureus, Burkholderia, Serratia, Nocardia, Salmonella 3. Fungi = Aspergillus (most common) – particularly Nidulans a. Aspergillus responsible for leading cause of mortality 4. Susceptibility to MTB, including BCG vaccine ii. Sites of infection 1. Focal infections more common than systemic disease 2. Recurrent pneumonia, lymphadenitis, hepatic / other abscesses, osteomyelitis a. Liver abscess rare in children - if present should be Ix for CGD 3. Colitis 4. Gingivitis c. Sequelae of chronic infection i. Granuloma formation - can cause GI/GU obstruction – hallmark of CGD ii. Anaemia of chronic disease, poor growth, lymphadenopathy, hepatosplenomegaly, chronic purulent dermatitis, restrictive lung disease, gingivitis, hydronephrosis, esophageal dysmotility, pyloric outlet narrowing iii. Note >80% of CGD patients have serology for Crohn disease

Answer 160

4. Investigations a. Pigment laden macrophages b. Nitroblue tetrazolium (NBT) dye test (normally yellow die reduced to blue/black, CGD unable to do) c. Diagnostic test = DHR assay i. DHR taken up by phagocytes ii. Phagocytes activated + super oxide production leads to oxidation of DHR and generation of fluorescence that can be detected by flow cytometry 5. Management a. Prophylaxis i. Bactrim ii. Antifungal = itraconazole b. Aggressive treatment of infections (eg. pneumonia requires 6-8 weeks IV antibiotics) i. At risk of deep-seated indolent bacterial infections which can become widespread – need drainage ii. ESR can be helpful c. Monitoring for disease complications d. Granulocyte transfusions if antibiotics ineffective e. Interferon gamma = unclear mechanism but reduces infections/ hospitalizations by 7% f. Stem cell transplant = curative, long term survival 90%

Answer 161

1. Key points a. Most cases acquired b. Absolute neutrophil count (ANC) = total WBC x percentage of segmented neutrophils + bands c. Neutrophils predominate at birth but rapidly decrease, then increase again throughout childhood e. Acute neutropenia = rapid neutrophil use and/or compromised neutrophil production f. Chronic neutropenia = lasts >3 months and arises from reduced production, increase destruction or increased splenic sequestration 2. Classification a. Decreased production b. Infective granulopoiesis c. Shift of circulating PMNs to vascular endothelium or tissue d. Enhanced peripheral destruction 5. Clinical manifestations a. Fever b. Aphthous stomatitis – almost always present by 1 year of age c. Gingivitis d. Infections i. Cellulitis, furunculosis, perirectal inflammation ii. Colitis, sinusitis, otitis media iii. Pneumonia, deep abscesses, sepsis e. Pathogen (many, viral/bacterial/fungal, S aureus most common) 6. Investigations a. Neutropenia = 2-3 times per week for 4-8 weeks – to investigate for cyclical neutropenia b. Bone marrow aspirate + trephine c. Glucocortoid mobilisation

Answer 162

a. Acquired i. Post-infectious ii. Collagen vascular disease – Felty’s syndrome, SLE iii. Drug-induced – clozapine, thionamides, sulfasalazine iv. Nutritional v. Primary autoimmune disorders 1. Immune neonatal neutropenia 2. Chronic autoimmune neutropenia 3. Chronic idiopathic/benign neutropenia 4. Pure white cell aplasia vi. Complement activation vii. Hypersplenism viii. Bone marrow disorders ix. Hypoplasia – aplastic anaemia, Fanconi anaemia x. Leukaemia b. Congenital i. Disorders of granulopoesis 1. Severe congenital neutropenia 2. Cyclical neutropenia ii. Disorders of molecular processing 1. Shwachman diamond 2. Dyskeratosis congenital iii. Disorders of vesicular trafficking 1. Chediak-Higashi 2. Griscelli Syndrome type II iv. Disorders of metabolism 1. Glycogen storage disease type Ib v. Other 1. Chronic benign neutropenia 2. Idiopathic chronic neutropenia 3. Myelokathexis 4. Reticular dysgenesis

Answer 163

= Kostmann syndrome a. 2-3 cases per million b. Genetics i. ELANE (most), HAX1, G6PC3 iv. Arrest in myeloid maturation at the promyelocyte stage in the bone marrow c. Investigations i. Neutropenia +/- Monocytosis, eosinophilia d. Clinical presentation i. Presents in infancy with severe neutropenia –typically in first months of life ii. No dysmorphic features iii. Propensity to infection 1. Skin infections – including omphalitis 2. Pneumonia 3. Perirectal abscesses iv. Oral ulcers, gingivitis e. Treatment i. GCSF ii. HSCT f. Prognosis i. Previously died within 1-2 years of life ii. Long-term risks = myelodysplastic syndrome, AML

Answer 164

a. Key points i. Rare, autosomal dominant ii. 0.5-1 case per 1 million individuals iii. Tends to be less severe than congenital neutropenia b. Genetics + pathogenesis i. Regulatory abnormality involving early haematopoietic precursor cells ii. Mutations in ELANE gene most common c. Clinical manifestations i. Characterised by neutropenia that recurs every 14 to 35 days – over 90% of patients exhibit a cycle period of 21 days ii. Symptoms during neutropenic nadir 1. Malaise, fever 2. Oral and genital ulcers 3. Gingivitis, periodontitis 4. Pharyngitis 5. LN enlargement iii. May have more serious infections – pneumonia, mastoiditis, intestinal perforation resulting in clostridial sepsis d. Investigations i. FBE 3 times per week for 6-8 weeks = demonstrating oscillation, or lack indicates those at risk of MDS/AML (only associated with severe congenital neutropenia) ii. ELANE mutation testing e. Treatment i. GCSF – reduce cycle to 9-11 days with 1 day or less of profound neutropenia iii. Cycles less noticeable in older patients

Answer 165

a. Genetics + pathogenesis i. AR disorder ii. Mutation in SBDS gene - protein involved in ribosome biogenesis/ RNA processing b. Clinical manifestations i. Key triad 1. Neutropenia 2. Metaphyseal dysplasia 3. Pancreatic insufficiency c. Treatment i. Many patients do not require GCSF ii. May progress to MDS – bone marrow monitoring warranted (associated with monosomy 7) iii. Pancreatic enzyme replacement

Answer 166

a. Disorders of telomerase activity b. Present with bone marrow failure rather than isolated neutropenia c. Classic phenotype i. Nail dystrophy ii. Leukoplakia iii. Malformed teeth iv. Reticulated hyperpigmentation

Answer 167

* Autosomal recessive defects in biogenesis or trafficking of lysosomes and related endosomal organelles * All syndromes share phenotype characteristics including defects in melanosomes contributing to partial albinism, abnormal platelet function, immunological defects (neutrophil, B lymphocyte, NK cell and CTL) 1. Chediak-Higashi a. Rare inherited disorders b. Best known for giant cytoplasmic granules in neutrophils, monocytes and lymphocytes c. LYST gene mutation d. Key features i. Oculocutaneous albinism ii. Progressive peripheral neuropathy iii. Frequent neutropenia iv. Tendency to develop HLH e. Treatment = BMT 2. Griscelli Syndrome type II b. Peripheral blood granulocytes do NOT show giant granules c. Key features i. Neutropenia ii. Partial albinism iii. High risk of HLH iv. Hypogammaglobulinaemia

Answer 168

a. Mutation in G6PT1 – glucose 6 phosphate transport b. Inhibit glucose transport resulting in defective neutrophil motility + increased apoptosis c. Key manifestations i. Massive hepatomegaly ii. Severe growth retardation iii. Neutropenia with recurrent infections d. Treatment i. GCSF – improves neutropenia but does not correct underlying functional neutrophil defect

Answer 169

a. Mild to moderate neutropenia that does not lead to increased risk of infection b. Sporadic or inherited – dominant or recessive c. Low risk of serious infection – no treatment

Answer 170

a. Onset of neutropenia after 2 years of age with no identifiable cause b. May have recurrent pyogenic infections c. Bone marrow shows variable patterns of myeloid formation with arrest generally occurring between myelocyte and band forms

Answer 171

1. Key points a. Transient neutropenia often accompanies or follows viral infections b. Most frequent cause of neutropenia in childhood - usually benign (short lived) 2. Aetiology a. Viruses i. Influenza A and B ii. Adenovirus iii. RSV, enteroviruses, HHV6 iv. Measles, rubella, varicella v. Parvovirus B19 + Hep A/B – can cause neutropenia but more commonly associated with pure red cell aplasia or multiple cytopaenias (respectively) vi. EBV, CMV, HIV – chronic neutropenia b. Bacterial c. Protozoal d. Fungal e. Rickettsia 3. Pathogenesis a. Related to virus-induced redistribution of neutrophils from the circulating to the marginating pool b. Neutrophil sequestration in virus-induced tissue damage or splenomegaly 4. Clinical manifestations a. First 24-48 hours of illness and persists for 3-8 days – corresponds to period of viraemia

Answer 172

IMMUNOLOGIC • Aminopyrine • Propylthiouracil • Penicillins TOXIC • Phenothiazines • Clozapine HYPERSENSITIVITY • Phenytoin • Phenobarbital

Answer 173

• Presence of circulating anti-neutrophil antibodies  destruction by complement-mediated lysis or splenic phagocytosis of opsonized neutrophils 1. Alloimmune neonatal neutropenia a. Transfer of maternal alloantibodies directed to infant neutrophils – analogous to Rh haemolytic disease i. Prenatal sensitisation induces maternal IgG antibodies to neutrophil Ag b. Clinical manifestations i. Severe neutropenia ii. Usually present in first 2 weeks of life 1. Skin or umbilical infections 2. Fever 3. Pneumonia c. Natural history i. Neutrophil count recovers by 8 weeks d. Treatment i. Supportive ii. Antibiotics 2. Autoimmune neutropenia of infancy a. Benign condition b. Usually presents 8-11 months of age c. Clinical manifestations i. Severe neutropenia, normal total WCC ii. Usually diagnosed due to neutropenia with a minor infection – occasionally more severe infection iii. No associated autoimmune diseases iv. Lasts up to 2 years, resolves spontaneously d. Investigations i. Anti-neutrophil Ab in serum – although note frequent FP and FN results e. Treatment i. Not usually necessary ii. May give GCSF

Answer 174

The conditions grouped together under Mendelian susceptibility to mycobacterial diseases are caused by genetic defects affecting the interactions of mononuclear phagocytes and T helper cells around the synthesis and response to interferon (IFN) gamma, often referred to as the type 1 (Th1) pathway. The majority of these diseases were recognized through adverse effects related to the administration of Bacillus Calmette-Guérin (BCG). 1. Pathogenesis a. Defect in mononuclear phagocytic/ T helper 1 cell pathway b. IFN -gamma- IL12 pathway = required for control of bacterial/ parasitic/ viral infections i. Macrophages infected with mycobacterium -> IL-12 production -> stimulates Th1 cells and NK cells -> IFN-g -> stimulates macrophage receptors to induce killing of intracellular pathogens c. Heterogenous genetic defects in pathway 2. Clinical manifestations a. Typically present with infections with BCG or environmental NTM b. Infections = intracellular i. Non TB mycobacteria ii. BCG iii. Salmonella/ listeria/ Leishmania iv. Candida/ moulds/ viruses STAT1 defects 3. Investigations a. IFN gamma pathway b. IFN gamma production after cell stimulation c. STAT1 phosphorylation d. Cell surface receptor evaluation e. Genetic diagnosis 4. Management a. Prolonged course of abx, prophylaxis b. IFN gamma (often require high dose) c. HSCT

Answer 175

AKA Jobs syndrome 1. Key points a. Autosomal recessive forms of HyperIgE also exist 2. Genetics + pathogenesis a. Mutation in STAT3 mutation -> impaired Th17 differentiation and function 3. Clinical manifestations a. Infections i. Recurrent staphylococcal skin infections 1. Begin in infancy 2. Include abscesses, furuncles, and cellulitis 3. Frequently results in lymphadenitis ii. Sinopulmonary infections 1. Most commonly due to S. aureus b. Severe eczema i. Begins in first week of life – papulopustular, often crusted rash ii. Begins on the face and scalp and spreads to the upper trunk/ shoulders and buttocks iii. Similar to appearance of atopic dermatitis iv. Associated with intense pruritis c. Facial features i. Coarse facial features – thickening of soft tissue of face, ears and nose, resulting in a doughy appearance, present in 80-100%, occurs after puberty ii. Increased alar width (broad nasal base) and broad nasal bridge iii. Frontal bossing, wider outer canthal distances and deep-set eyes iv. Dysmorphia increases with age d. Skeletal i. Retain primary teeth – require extraction ii. Scoliosis and osteoporosis iii. Bone fractures with minor trauma e. Other i. Risk of NHL ii. Neurological abnormalities iii. Vascular abnormalities 4. Investigations a. Elevated IgE – usually > 2000 IU/ml b. Peripheral eosinophilia 5. DDx a. Atopic dermatitis i. May have extremely high IgE and recurrent superficial S aureus ii. Do NOT have deep-seated abscesses or pneumonia iii. Do NOT have facial or bone features b. Wiskott-Aldrich syndrome – may have eczema and elevated IgE, however should also have thrombocytopaenia, small platelets and bruising; abscesses less common c. SCID 6. Treatment a. Treatment of eczema b. Antimicrobial prophylaxis – Bactrim c. Treatment of infections

Answer 176

1. Key points a. Predispose to bacterial infections and/or SLE b. Classification i. Integral component defects ii. Regulatory component defects c. Revision of complement i. Almost 60 plasma and membrane proteins ii. 3 distinct pathways iii. Common terminal lytic cascade iv. Potent regulators d. Key functions i. Opsonisation = C3b (or C4b) ii. Stimulate inflammatory reactions = C5a (or C3a) iii. Complement mediated cytolysis 2. SUMMARY a. Classical pathway i. Deficiency of components of classical pathway (C1, C2, C4) predisposes to autoimmune disease ii. Deficiency of control proteins (eg. C1 esterase inhibitor) leads to uncontrolled activation of classical pathway b. Alternative i. Deficiency of components predisposes to infections with encapsulated organisms (eg. Pneumocococcus, Neisseria) ii. Deficiency of control proteins leads to uncontrolled activation of alternative pathway c. Lectin pathway i. ? MBL deficiency may increase risk of encapsulated organism infection (contentious)

Answer 177

a. Deficiency in an integral component i. Infections 1. Site a. Sinuopulmonary b. Bacteraemia c. Meningitis 2. Pathogens = encapsulated a. Streptococcus pneumoniae b. Hib c. Neisseria meningitidis ii. Autoimmunity 1. SLE – commonly develops in individuals deficient in an early component of classical pathway (C1q, C1r, C1s, C4 an C2) b. Deficiency in regulatory protein i. Specific disorders from undesirable complement activation ii. Examples 1. Heterozygous deficiency of C1 inhibitor  hereditary angioedema 2. Haploinsufficiency of factor H  predisposes to atypical HUS and AMD 3. Homozygous deficiency of factor H  alternative pathway activation, cleavage and consumption of C3 and factor B = susceptibility to pyogenic infections

Answer 178

a. C3/C4 b. Complement function i. CH50/AP50 (classic/alternate) ii. CH100/AP11 c. For HAE = C1 esterase inhibitor level/function Low A normal C = alternate pathway defect Normal A low C = classic pathway defect (pre-C3 -> C1/2/4) Both low = C3 deficiency or MAC component defect Both normal = properdin deficiency C1 inhibitor defect = reduced C1 inhibitor function assay = hereditary angioedema C4 = key component of classical pathway -> if low think classical, if normal think alternative 5. Treatment a. Aggressive treatment of serious infection b. Vaccination i. ALL routine vaccinations ii. Not at increased risk for adverse effects iii. Conjugate vaccines preferred over pure polysaccharide vaccines c. Antibiotic prophylaxis d. Replacement therapy – not currently routine

Answer 179

1. SUMMARY (Lupus + Neisseria) a. Deficiency of components of classical pathway (C1, C2, C4) predisposes to autoimmune disease i. Predisposes to SLE – impaired clearance of immune complexes, apoptotic cell debris, development of autoantibodies to nuclear proteins b. Deficiency of control proteins (eg. C1 esterase inhibitor) leads to uncontrolled activation of classical pathway i. Hereditary angioedema 1. Uncontrolled activation of classical pathway leads to increased activation of FXII and production of bradykinins -> increased vascular permeability + angioedema (no urticaria as not mast cell driven) 2. Genetics + pathogenesis a. Usually AR – two abnormal alleles required to yield complete deficiency, heterozygotes asymptomatic c. Note properdin deficiency autosomal dominant 3. Indications for screening a. Recurrent, unexplained pyogenic infections in the setting of normal WBC and Ig levels b. Recurrent Neisserial infections at any age c. Multiple family members with Neisserial infections 4. Screening + interpretation a. Total haemolytic complement (THC = CH50) b. Genetic screening 5. Specific disorders a. C1 deficiency (C1q, C1r, C1s) i. Most common inherited deficiency is C1q ii. >90% of C1q deficient individuals develop SLE, may also have recurrent bacterial infections iii. Deficiency of C1r or C1s also results in SLE with prominent renal and cutaneous involvement b. C4 deficiency i. Rare ii. 80% present with SLE – severe and at an early age iii. Note interpretation of C4 in patients with SLE can be complicated – may be low due to consumption OR deficiency iv. Consumption more likely with reduction in multiple complement components c. C2 deficiency i. Manifestations 1. 10-30% present with SLE 2. Recurrent pyogenic infections with encapsulated bacteria ii. Sometimes associated with IgG subclass deficiency iii. Other associated diseases = discoid lupus, polymyositis, GN, Hodgkin lymphoma, vasculitis iv. Tests for ANA may be positive in low titre and show speckled pattern d. C3 deficiency i. Major opsonin of the complement system ii. Results in severe, recurrent infections with encapsulated bacteria iii. Presents shortly after birth iv. Particularly prone to infections with pneumococcus v. Subsequent problems due to excess immune complexes – especially GN e. C5-C9 deficiency i. Associated with Neisseria species infections – characteristically an unusual serotype ii. Tend to be recurrent and clinically mild-to-moderate

Answer 180

* Rare * Alternative pathway (AH50) screen for deficiency • Summary o Deficiency of components predisposes to infections with encapsulated organisms (Strep, Neisseria) - Factor B deficiency • Increased susceptibility to Strep + Neisseria - Properdin deficiency • X-linked inheritance • Increased susceptibility to Strep + Neisseria o Deficiency of control proteins leads to uncontrolled activation of alternative pathway - Factor H (defect or deficiency) = aHUS – uncontrolled lysis of normal (host) cells - Factor I = aHUS

Answer 181

1. Key points a. More common than inherited complement disorders b. Usually only partial and affect several components at once c. Most common – SLE – reduction in C4 and C3 d. Commonly occur in associated with diseases with autoantibodies 2. Mechanism a. Accelerated consumption by immune complexes – common i. SLE ii. Antiphospholipid syndrome iii. Cryoglobulinaemia iv. Vasculitic syndromes v. Renal disease vi. Autoimmune haemolytic anaemia b. Reduced hepatic synthesis – uncommon c. Loss of components in the urine – rare

Answer 182

1. Function a. Type 1 transmembrane receptors b. Extracellular domain recognizes microbial product c. Cytoplasmic TIR domain recruits signaling molecules d. Activate gene transcription for inflammation + antimicrobial defenses 2. Types - many 3. Defects a. Susceptibility to bacterial infections i. Myd88 and IRAK 4 mutations 6. Investigations = CD62L shedding ii. Anhidrotic ectodermal dysplasia 1. NEMO (XL) or IKBA (AD) gain of function mutation 5. Investigations = investigations of T and B cells b. Susceptibility to candida infections i. Many = STAT1 gain of function ii. Chronic mucocutaneous candidiasis iii. CARD9 deficiency c. Susceptibility to virus infection - STAT1/2 important again

Answer 183

1. Classification + Aetiology - cervical vs generalised - acute vs chronic a. Generalised i. Acute = viral/post-viral ii. Chronic 1. Infective = EBV, CMV, toxoplasmosis 2. Malignancy = leukaemia, lymphoma 3. Inflammatory = JCA, SLE, HIV b. Cervical i. Acute 1. Infective = URTI, tonsillitis, EBV, bacterial infection, dental infection 2. Kawasaki disease ii. Chronic 1. Infective = EBV, TB, atypical mycobacterial, cat scratch 2. As for generalised

Answer 184

i. Acute bilateral lymphadenitis 1. Viral URTI 2. Systemic viral infections eg. EBV, CMV 3. Kawasaki disease – may present initially as cervical lymphadenitis alone ii. Acute unilateral lymphadenitis 1. Gp A strep or Staph Aureus = 40-80% of acute unilateral lymphadenitis, occurs 1-4 years of age a. Fever, tenderness, overlying erythema b. May be associated with cellulitis 2. Anaerobic bacteria – older children with dental caries ore periodontal disease 3. Group B strep (neonates) iii. Subacute/chronic unilateral lymphadenitis 1. Atopic eczema 2. Infectious a. Bartonella henselae (cat-scratch disease) i. Occurs about 2 weeks after a scratch or lick from kitten or dog ii. Usually involves axillary nodes, tender nodes iii. Papule at infection side b. MAC i. Patients usually 1-4 years of age ii. Afebrile, systemically well and not immunocomprimised iii. Node usually unilateral, slightly fluctuant, non-tender, sometimes tethered to underlying structures and violaceous hue to overlying skin c. Toxoplasma gondii i. Systemic features (fatigue, myalgia) ii. There may be generalised lymphadenopathy d. Mycobacterium tuberculosis i. Usually a contact history ii. Affects older children iii. Systemic symptoms (eg. fever, malaise, weight loss, non-tender nodes) e. HIV 3. Malignancy a. Lymphoma = Hodgkin, NHL b. Leukaemia 4. Rheumatological a. Juvenile chronic arthritis b. SLE