THE IMMUNE SYSTEM

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THE IMMUNE SYSTEM

• Prepared by Dr Amal Damrah
• Directed by Dr Anan Al Faqeh

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The Immune System

• A. Humoral Mediated
• (B-Cell immunity Free Igs)
• Antibodies react to bacteria by1. Binding
  directly with bacterial toxins to neutralize them
• 2. Coat bacteria to enhance the phagocytosis
  be non-specifics components (monocytes, etc.,)

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The Immune System

• B. Cell Mediated ( T-cell immunity membrane
  receptors)
• Viruses, parasites, fungi, etc., are reacted by
• 1. Helper - T
• 2. Cytotoxic - Tcells
• 3. Macrophages
• 4. Tranfer factor
• 5. Cytokines (lymphokines/interleukin)

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Immunodeficiency Diseases
Primary The deficiency is the cause of disease.
Primary immunodeficiencies are usually
congenital, resulting from genetic defects in
some component of the immune system.

• Secondary deficiency is acquired as a result of
  other diseases or conditions
• HIV infection
• malnutrition
• immunosuppression

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Primary Immunodeficiencies






Class Relative Susceptibilities
Treatment Frequency B lymphocytes
50 bacterial infections
immunoglobulin injections T
and B combined 20 viral, fungal, bacterial
bone marrow and
protozoal infections transplant T lymphocytes
10 viral, fungal, and bone
marrow protozoal infections
transplant Phagocytes 18 bacterial
infections antibiotics,
cytokines Complement 2 bacterial
infections, infusions of
autoimmunity complement
components
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Development of the Immune System
Yolk sac/Bone
Hematopoietic stem cells
Etrythrocytes Granulocytes
Monocytes Megokaryocytes
Lymphoid stem cells
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Primary Immunodeficiency Diseases occur when
there is a defect in any one of the many steps
during lymphocyte development
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Immunology Review
Antigen
macrophage
Immune System
Immunoglobulins (immediate hypersensitivity)
Transfer factor Delayed hypersensitivity
B-cells Humoral Bone (Gut associated lymphoid
tissue)
T-cells Cellular thymus
Advanced lymphcytes
Plasma Cells
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• Adaptive immunity distinguishes self from
  nonself.
• Molecules called the Major Histocompatibility
  Complex (MHC) identify a cell as self and are
  genetically determined.
• Anything with something different is identified
  as foreign.
• Foreign invaders are vigorously attacked.
• The system REMEMBERS.

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• All WBCs are produced in bone marrow.
• Monocytes enter bloodstream, then exit enlarge
  to form macrophages.
• Most lymphocytes enter bloodstream travel to
  thymus gland (develop into T cells).
• In thymus, each T cell is genetically programmed
  to respond to one specific kind of foreign
  antigen.

T cell antigen receptors
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Types of T-Lymphocyte

• Helper cells (T4 cells)
• Cytotoxic cells (Killer T cells)
• Suppressor cells
• Memory cells

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Helper T-Cells

• Master on-switch of immune system
• Recognize antigens
• Secrete lymphokines that activate all other
  immune system cells
• Stimulate B-cells to begin antibody production

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• cytotoxic T cells (CD8 / T8 cells)
• activated by interleukin-2
• bind to body cells displaying foreign antigens
  (virus- or bacteria-infected cells, cancer cells,
  transplanted or transfused cells)
• release perforin (causes cell lysis)

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Helper T-cell
Killer T-cell
T-cell receptor
Foreign antigen
CD4 coreceptor
CD8 coreceptor
Class-2 MHC molecule
Class-1 MHC molecule
Antigen presenting cell
Target cell
Figure 15.18 Coreceptors on helper and killer T
cells . A foreign antigen is presented to T
lymphocytes in association with MHC Molecules.
The CD4, on helper T cells and CD8 corecepters on
killer T cells, permit each type of T cell to
interact only with a specific class of MHC
molecule
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Suppressor T-Cells

• Produce lymphokines that inhibit proliferation of
  B and T cells
• Downregulate or dampen immune response

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Memory T-Cells

• Have previously encountered specific antigens
• Respond in enhanced fashion on subsequent
  exposures
• Induce secondary immune response

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Index of Suspicion

• gt10 episodes acute otitis media per year (infants
  and children).
• gt2 episodes consolidated pneumonia per year.
• gt2 life-threatening infections per lifetime.
• Two or more serious sinus infections within 1
  year.
• Unusual organisms.
• Unusual response to organism.

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History Our Guide

• Important historical points
• Frequency, duration, severity, complications,
  response to treatment
• Risk factors
• Family history
• Infection with low-virulence or unusual organisms
• Age of onset

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History Our Guide

• Predominant T-Cell Defects
• Early onset, usually 2-6 mos
• Bacteria, mycobacteria, viruses CMV, EBV,
  varicella fungi, parasites, PCP, mycobacterium
  avium-intracellulare
• FTT, protracted diarrhea, extensive mucocutaneous
  candidiasis
• GVHD caused by maternal engrafment, nonirradiated
  blood
• Hypocalcemic tetany in infancy

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Physical Exam

• A benign physical exam does not rule out
  immunodeficiency.
• Look for
• General appearance, weight, overall health
• Hair, connective tissue
• Dysmorphic features
• Gingivitis, dental erosions, signs of sinusitis
• Tonsillar tissue, adenopathy, splenomegaly
• Arthritis, ataxia, neuro deficits

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Disease Specific Skin Findings

• Eczema and petechiae Wiskott-Aldrich Syndrome
• Telangiectasia Ataxia-Telangiectasia
• Oculocutaneous albinism Chediak-Higashi
• Dermatomyositis-like rash XLA
• Chronic dermatitis Hyper-IgE
• Extensive warts, candidiasis T-Cell defects

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From the CBC

• Normal Absolute Lymphocyte Count (ALC)
• excludes T cell defects, AIDS
• excludes congenital and acquired neutropenias and
  LAD (increased ANC)
• Normal platelets
• excludes Wiscott Aldrich Syndrome (WAS)

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Laboratory Evaluation

• T-Cell Immunity
• Delayed-hypersensitivity skin tests
• Intradermal injection of antigens Candida,
  tetanus, trichophyton.
• Should produce redness and induration of gt 5mm by
  48-72 hours.
• Severe illness, or steroids can cause diminished
  responses. (anergy)
• Mitogen testing
• In vitro proliferative responses to concanvalin
  A, phytohemagglutinin

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Primary defects of cellular immunity

• DiGeorge Syndrom.
• Defective expression of the T-cell receptor
• Defective cytokine production.

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DiGeorge Anomaly

• Variable hypoplasia of thymus and parathyroid.
• Hypocalcemia ? seizures
• Susceptability to fungi, viruses, PCP.
• T-Cells variable in number, abnormal mitogen
  studies
• Normal to increased B-Cells, normal antibody
  levels.
• Microdeletion of 22q11.2
• Associated heart defects, facial anomalies,
  esophageal atresia.

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Immunodeficiency Disorders Associated with
T-cells- DiGeorge Syndrome (Congenital Thymic
Aplasia)
Cardiovascular abnormalities Hypoparathroidism

• 3rd 4th pharangeal pouches do not develop or
  are underdeveloped
• Absence of thymus
• (NO T-CELLS)
• Increased viral, fungal protozoan infections
• Facial features
• short philtrum of upper lip, hypertelorism,
  mandibular hypoplasia and low-set ears.
• Congenital heart dis.

Characteristic facial features
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Types of DGS

• There are two DGS subtypes, partial and complete,
  which differ in the severity of the T cell
  defect.
• With complete DGS, the thymus is completely
  absent and peripheral blood CD3 cells typically
  comprise lt1 to 2 percent of the circulating
  lymphocytes.
• Infants with partial DGS demonstrate variable T
  lymphocyte counts and function.

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EVALUATION

• Neonates  Evaluation for DGS should be
  considered for any neonate with a conotruncal
  heart lesion, hypocalcemia, and/or cleft palate.

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Initial studies 

• Infants with suggestive signs and symptoms should
  have the following performed
• Cardiac evaluation and echocardiogram (urgently)
• Serum calcium and phosphorus levels
• Complete blood count with differential to
  evaluate for lymphopenia
• Chest radiograph to evaluate for absence of a
  thymic shadow
• T and B cell subsets by fluorescence activated
  cell sorting (FACS)
• Immunoglobulin levels

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DiGeorge syndrome

• Therapy
• cardiac anomaly operation,
• Ig substitution IVIG/SCIG according to
  levels,
• chemoprophylaxis,
• bone marrow transplantation or thymus
  transplantation.

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Prognosis

• Depends on severity of cardiac anomaly and depth
  of T-lymphocyte decrease
• The life expectancy for infants with complete DGS
  who do not undergo transplantation is less than
  one year. In contrast, overall mortality rate for
  patients with partial DGS or 22qDS has been
  estimated to be less than 10 years.

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Primary combined antibody and cellular
immunodeficiencies

• Sever combined immunodeficiency (SCID)
• Combined immunodeficiency (CID)
• Wiskott-Aldrich Syndrome
• Ataxia-Telangiectasia
• Hyper IgE Syndrome
• Purine nucleoside phosphorylase deficiency
• Cartilage hair hypoplasia
• Omenn syndrome

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Severe Combined Immunodeficiency
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Severe Combined Immunodeficiency

• 110 million
• Recurrent infections, by three months can be
  life-threatening.
• Absence of lyphoid tissue, lymphopenia, no thymic
  shadow.
• Anergy, abnormal T-Cell proliferation, /- B-Cell
  dysfunction.
• Absence of adaptive immunity.

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• Recurrent bacterial and fungal infections without
  pus.
• Severe gingivitis, periodontitis, alveolar bone
  loss.
• Candida, PCP, cryptosporidiosis, HSV, RSV,
  rotavirus, adeno, entero, EBV, CMV.
• Decreased or absent CD18/CD11 by flow.
• Delayed separation of umbilical cord.

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SCID

• Various possibilities of classification according
  to cellular populations
• T-B variants
• T-B- variants
• Various types of inheritance X-linked, AR

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SCID T-B

• X-linked SCID
• Common ? chain mutation
• Impairs receptors for IL-2, IL-4, IL-7, IL-9,
  IL-15 and IL-21
• T-BNK- SCID
• Gene therapy (Paris, London, USA)
• AR-SCID
• JAK-3 deficiency
• T-BNK- SCID
• AR-SCID
• IL-7 deficiency T-lymphocyte growth factor
• T-BNK SCID

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SCID can result from defects in the IL-2 receptor
subfamily (A) defective expression of the
common ? chain, or (B) defective receptor
signaling due to a missing tyrosine kinase
T- B phenotype
40-50 of SCID cases
Rare
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T- B- SCID

• Adenosine Deaminase Deficiency (ADA)
• ADA is an enzyme in the purine salvage pathway
• pathway is important for T B-cell development
  differentiation
• T- B- phenotype
• Accounts for about 20 of all SCID cases
• Autosomal recessive
• Treatment
• Bone marrow transplant
• Continuous enzyme supplement
• Gene Therapy

Purine nucleoside phosphorylase deficiency and
recombinase deficiencies (RAG-1 and -2) also
cause SCID of the T-B- phenotype
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Other forms of SCID (cont)

• TB- phenotype
• Omenn Syndrome (partial RAG deficiency)
• Cartilage hair hypoplasia.
• TB phenotype
• Bare Lymphocyte Syndrome (no MHC class II)
• ZAP-70 deficiency (defective T cell signaling)
• Multisystem Disorders
• Wiskott-Aldrich Syndrome (mutation in gene for
  WASP protein)
• Ataxia Telangiectasia (mutation in gene for ATM
  protein)

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OMENN SYNDROME
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Cartilage-Hair hypoplasia
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Bare Lymphocyte Syndrome

• MHC Class II Negative APCs
• -Defective Transcription Factors
• -Normal T- B-cell numbers
• Inverse CD4CD8 Ratio
• Any CD4 cells cannot be activated
• Help is not provided to B cells and CD8 T cells
• Combined immunodeficiency

APC
T cell

• MHC Class I Negative Cells
• -Defective TAP genes
• -Deficient CD8 cells
• -Usually asymptomatic

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SCID

• Signs (common for the whole group)
• Unusual or opportunistic infections
• Intracellular bacteria Mycobacterium spp.
  (incl. BCG), Listeria, Salmonella spp.
• Viruses
• Yeast and fungi Candida spp., Aspergillus
  fumigatus, Cryptococcus neoformans
• Parasites Pneumocystis carinii, Isospora belli,
  Microsporidium spp.
• Malaise / waisting / failure to thrive
• Chronic diarrhea/malabsorption and dermatitis.

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SCID

• Work-up CBCdiff, Ig levels,cellular immunity,
  further according to results stimulations,
  burst test, bone marrow, genetic investigation,
  HLA typing.
• Therapy aggressive antimicrobial and antifungal
  therapy, prevention of Pneumocystis infection,
  bone marrow transplantation, gene therapy.
• Prognosis severe, lethal without transplantation

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The Wiskott-Aldrich Syndrome

• Primary immune deficiency disorder
• Entails part of the bodies immune system is
  missing or does not function properly
• Caused by genetic defects in the immune system
• X-linked recessive trait
• Genetic defect causing deficiency is on the
  X-chromosome
• Only affects males and is passed to child from
  the mother, a healthy carrier of the disorder

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Symptoms

• Thrombocytopenia (low platelet count and
  disturbed platelet function)
• Recurrent infections
• Eczema
• Malignancies in the form of leukemia and lymphoma
  occur in more severe cases

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Normal platelets
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Small Platelets
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History

• First described by German physician Alfred
  Wiskott in 1937
• Robert Anderson Aldrich described the disease as
  an X-linked recessive trait in 1954
• Joined the list of Primary Immune Deficiency
  Diseases in the 1960s

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Mutations

• WAS is associated with the absence of the
  Wiskott-Aldrich Syndrome protein (WASP) which is
  caused by simple mutations in the WASP gene.

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Actin Reorganization

• WASP is involved in the reorganization of the
  actin skeleton. When the WAS protein is altered,
  it does not properly bind and actin
  reorganization is prohibited.

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Affect on T Lymphocytes

• Cytoskeleton reorganization is involved in the
  binding of T lymphocytes to antigen-presenting
  cells through CD3 cross linking.
• Without actin reorganization, CD3 is not properly
  presented at the cells surface and the T cell is
  not activated.
• Causes recurrent viral and fungal infections (as
  noted in symptoms).

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Affect on B Lymphocytes

• Thymus dependent B lymphocytes need T cells for
  activation and differentiation.
• B cells only able to produce IgM through thymus
  independent B lymphocytes.
• Causes recurrent bacterial infections because
  proper antibodies are not produced against
  certain bacteria.

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Treatment

• Intravenous immunoglobulin substitution
• Specialized antibiotics
• Splenectomy
• Hematopoietic stem cell transplantation

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Ataxia-Telangiectasia
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Ataxia-Telangiectasia

• Recurrent sinopulmonary disease.
• Telangiectasias between 3-6 years.
• Ataxia soon after learning to walk, in wheelchair
  by 10-12 years.
• Often low or absent IgA. Varaible depressions of
  other immunoglobulins.
• Anergy and depressed mitogen studies.
• Risk for lymphoreticular malignancy.

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CLINICAL MANIFESTATIONS 

• Neurologic abnormalities
•   Ataxia is the earliest clinical manifestation
  of AT
• Most children appear healthy for the first year
  of life, but are slow to develop fluidity of
  gait. They also have difficulty on standing .
• Unlike most ataxic disorders, individuals with AT
  walk on an unusually narrow base.

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• Gross motor function remains abnormal, but
  relatively stable until school age, and cerebral
  palsy is often misdiagnosed.
• Eye movements are often normal in preschoolers,
  but children later develop is oculomotor apraxia
  the inability to coordinate head and eye
  movements naturally when shifting gaze rapidly.

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• Telangiectasias 
•  Telangiectasias of blood vessels are seen
  primarily on the bulbar conjunctivae and on
  exposed areas of the skin, typically the pinnae,
  nose, face, and neck.
• In most cases, they first appear when the child
  reaches three to five years of age.

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• Immune deficiency 
•  Immune deficiency, affecting both cellular and
  humoral immunity, occurs in approximately 70
  percent of patients. The defect is quite variable
  but often manifests as recurrent sinopulmonary
  infections.
• Progressive pulmonary disease caused by chronic
  or recurrent infections is a major cause of
  morbidity and mortality in patients with AT.

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• Malignancy 
•  Beyond age 10 years, the incidence of cancer in
  AT is 1 percent per year
• overall, approximately 10 to 20 percent of
  patients will develop malignancy .
• Of these neoplasms, 85 percent are lymphomas and
  acute leukemias, but a predisposition to other
  cancers may exist.

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Laboratory abnormalities 

• The most consistent laboratory abnormality is an
  elevation of serum alpha-fetoprotein level in
  children over the age of eight months . The level
  does not necessarily rise over time, and does not
  correlate with severity of disease.

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• Immunoglobulin deficiency, especially absence or
  marked reduction of IgA, IgG2, and other IgG
  subclasses.
• Inability to produce antibodies to polysaccharide
  antigens such as those forming the capsule of
  pathogenic bacteria such as the pneumococcus.
• Lymphopenia with the most prominent reduction in
  T cells.

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DIAGNOSIS 

• The diagnosis is established by the presence of
  characteristic clinical findings (particularly
  progressive cerebellar ataxia) and identification
  of disabling mutations on both alleles for the
  gene AT mutated (ATM).

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PROGNOSIS  

• AT is a difficult disease to treat and has an
  especially poor prognosis because of its
  multisystem involvement.
• Many patients succumb to progressive pulmonary
  disease caused by repeated infection or to
  cancer, and the median age at death is
  approximately 25 years.

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MANAGEMENT

• Acute infection should be treated with
  appropriate antibiotics and simple maneuvers such
  as postural drainage.
• Antibiotic prophylaxis should be considered in
  patients with recurrent sinopulmonary bacterial
  infections.

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MANAGEMENT

• Those with hypogammaglobulinemia or impaired
  specific antibody production, should be given
  gamma globulin infusions.
• Children who have the capacity to produce
  antibodies should be immunized with pneumococcal
  and influenza vaccines.

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Hyper-IgE Syndrome

• Chronic pruritic dermatitis.
• Recurrent staph infections of skin, lungs,
  joints, and dental infections.
• Course facial features.
• Markedly elevated IgE and eosinophilia.

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Hyper IgE

• Abscesses (staph), esp skin (boils) but also lung
• Lung abscesses progressing to giant
  cysts/pneumatocoeles.
• No diagnostic test markedly elevated levels of
  IgE are even seen in atopic dermatitis

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Hyper IgE
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Treatment for Primary Immune Deficiencies

• Bone marrow transplantation
• Immunoglobulin replacement
• Enzyme replacement
• Gene therapy

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Management Issues

• Prompt recognition of infection and aggressive
  treatment
• Obtain cultures, and initiate early empiric
  therapy for suspected pathogens
• Prophylactic antibiotics for patients with
  significant T-cell defects. (trimethoprim-sulfamet
  hoxazole)
• Live vaccines should not be given to children
  with T-cell defects
• Only irradiated, leukocyte reduced, virus-free
  blood products should be given.
• Monitor growth and weight gain.

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Primary ImmunodeficienciesVaccination
Pneumo T. tox. DiPe Polio HiB BCG
WAS Yes Yes Yes Killed Yes no
HIM Not need Not need Not need Killed Not need no
CVID Not need Not need Not need Killed Not need no
CGD Yes yes Yes Yes Yes no
XLA Not need Not need Not need killed Not need no
IgA Yes Yes Yes Yes Yes Yes
DiGeorge Yes Yes Yes Yes Yes Yes
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QUESTIONS?