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Primary Immunodeficiency Syndromes

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Primary Immunodeficiency Syndromes. Jackson Williams, MD. March 24, 2005. Case Presentation ... Barrett. ' Approach to the child with recurrent infections.' on ... – PowerPoint PPT presentation

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Title: Primary Immunodeficiency Syndromes


1
Primary Immunodeficiency Syndromes
  • Jackson Williams, MD
  • March 24, 2005

2
Case Presentation
  • D. George is a 2 year old male brought in
    by his parents Wiskott and Aldrich because of
    concerns about recurrent infections. They state
    he has been sick many times over the last two
    years. He has been in the hospital twice with
    some sort of infection. He has also had frequent
    upper respiratory infections and has had Otitis
    Media 7 times in the last two years.

3
  • The parents of D. George are very
    concerned. They wonder is there something wrong
    with him. Is it normal to have this many
    infections? Could there be something wrong with
    his immune system? How are you going to figure
    this out? Does he need testing?

4
  • What other information should we try to illicit
    from D. George and the family?
  • Are there clues we could be missing in the
    history?
  • Are there clues in the physical?

5
Objectives
  • To have a sense of when to suspect an
    immunodeficiency problem in a child
  • To know what history and physical findings one
    needs to illicit to make this determination.
  • Familiarize self with immunodeficiency syndromes
    that you will encounter (at least that you will
    encounter on the boards if not in real life).
  • Know the role of Primary Care Provider in caring
    for these children (i.e. vaccination).

6
Prevalence
  • The first cause of recurrent infections in
    children is childhood itself.
  • Average number of infections is 6-8 URIs per
    year.
  • Common triggers for more frequent URIs.
  • Daycare
  • Smoking
  • Allergies and asthma

7
Prevalence
  • Most children with recurrent infections dont
    have primary immunodeficiency
  • 90 have secondary cause
  • In one survey at an immunology specialist only 3
    of kids referred had a serious immunodeficiency.
  • 6 had mild IgA deficiency
  • 33 asthma
  • 12 had anatomic cause for recurrent OM.

8
Prevalence
  • When immunodeficiency occurs
  • Antibody/B cell issue 54
  • Combined B/T cell 23
  • Other deficiencies rare (complement deficiency is
    only 2)
  • Over 70 immunodeficiency syndromes have been
    described.

9
Distribution of Immunodeficiencies
10
Secondary Causes of Recurrent Infections
  • HIV, HIV, and HIV
  • Anatomic
  • Foreign Body
  • Central line
  • Eustacian Tube Obstruction
  • Sinus tract/fistula
  • Sacral Dimple
  • Cribiform Plate Disruption
  • Lung sequestration
  • Hypotonia causing aspiration
  • Vesicoureteral Reflux
  • Medications
  • Allergy or Asthma
  • Cystic Fibrosis
  • GERD
  • Malnutrition
  • Sickle Cell
  • Asplenia
  • Diabetes
  • Cancer
  • Colonization with resistant organism (i.e. MRSA)

11
Key History
  • Get history of infections
  • Location
  • Organism
  • Frequency
  • Response to therapy
  • Seriousness (i.e. hospitalization)
  • Family History Including Consanguinity
  • Even if they aint from Tennessee
  • Growth Pattern

12
Red Flags
  • Recurrent and complicated bacterial sinopulmonary
    infections
  • Recurrent abscesses
  • 2 or more episodes of bacterial sepsis or
    meningitis
  • Infection with opportunistic or rare organism
  • Persistent Candida
  • Prolonged need for antibiotics
  • Severe infections that begin after 6 months (when
    maternal antibodies are gone).

13
Red Flags
  • Failure to Thrive
  • Vaccine-acquired infection
  • Presence of autoimmune syndrome
  • Family history of immune deficiency
  • Unexplained infant deaths (particularly males)
  • Skin and mucous membrane abnormalities
  • Lymphopenia in an infant

14
Obligatory Immunology Review
  • Have Lymphoid Progenitor for Lymphocytes
  • Becomes T cell in Thymus
  • Important in Cellular Immunity
  • Develop into CD4, CD8 or other cells
  • Secretes cytokines, interleukins, etc.
  • Assists B cells in making immunoglobulins
  • Becomes B cell in Bone Marrow
  • Begins with IgM
  • Matures to form other immunoglobulins
  • IgA, IgE, or IgG (with subclasses IgG1-4)
  • Mature cell is Plasma cell
  • Immunoglobulins used to surround antigens for
    phagocytosis
  • Responsible for Specific immunity (and memory)

15
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16
More Immunology Review?!?
  • Neutrophils and Macrophages
  • Surround and gobble up organisms, often those
    surrounded by immunoglobulins (Phagocytosis and
    Opsonization).
  • Part of natural or innate or nonspecific
    immunity.
  • Complement system
  • Cascade of plasma proteins which aid in
    chemotaxis and opsonization.

17
Immunodeficiency Overview
  • Humoral Defect (B cells and Antibodies)
  • Defect of Cell-mediated Immunity (T cells)
  • Combined Humoral and Cellular Immunodeficiencies
    (B and T cells)
  • Phagocytic Dysfunction (PMNs)
  • Complement Deficiency
  • Note There is significant overlap among
    syndromes.
  • Also Note Great variability in expression
    of disorders for all categories from mild to
    severe/fatal.

18
Humoral / B-cell Defects
19
Humoral Defects
  • Most common cause of Primary Immunodeficiency
  • Variable Degree of Symptomatology
  • Some Asymptomatic
  • Some Improve over time
  • Examples
  • Common Variable Immunodeficiency
  • X-linked Agammaglobulinemia (Brutons
    Agammaglobluinemia)
  • Selective IgA Deficiency
  • IgG Subclass Deficiency

20
Humoral Defects
  • Signs
  • Recurrent sepsis and bacterial sinopulmonary
    infections.
  • Bronchiectasis
  • Chronic Gastroenteritis
  • Failure to thrive
  • Autoimmune Disease
  • Arthritis
  • Dermatomyositis (Esp. Brutons syndrome)
  • Lupus

21
Humoral Defects
  • Signature Organisms
  • Encapsulated organisms
  • S. Pneumoniae
  • H. influenza B
  • Gastroenteritis
  • Giardia
  • Enterovirus
  • Pseudomonal sepsis with Brutons Syndrome

22
Common Variable Immunodeficiency
  • Present in 125,000.
  • Bimodal b/t 1-5 y/o and 18-25 y/o
  • Unknown defect that causes final common pathway
    of hypogammaglobulinemia
  • Manifestations
  • Pneumococcus, Hemophilus, and Mycoplasma
    infections
  • Bronchiectasis and Chronic Lung Disease
  • Autoimmune disease (RA, Pernicious Anemia,
    hemolytic anemia)
  • GI and Liver Disease
  • Increased risk of Non-Hodgkins Lymphoma
  • Noncaseating Granulomas

23
Common Variable Immunodeficiency
  • Diagnosis/Labs
  • Low serum total IgG (lt 2 SD)
  • Poor response to immunization
  • No other cause of hypogammaglobulinemia can be
    identified
  • Often have low CD4/CD8 ratio
  • Treatment
  • IVIG
  • Prognosis somewhat decreased survival

24
IgA Deficiency
  • Most common immunodeficiency syndrome
  • 1142 in Arabic countries to 118,000 in Japan
  • Problem with an interleukin deficiency
  • IL which is needed to mature lymphocyte to
    mature IgA plasma cell.
  • Actually able to express IgA on cells.
  • Manifestations
  • Many asymptomatic 85-90
  • Children with mild deficiency often outgrow their
    deficiency (one study showed 50)
  • Others do have true disease manifestation

25
IgA Deficiency
  • Manifestations
  • Recurrent Sinopulmonary infections
  • Autoimmune Disorders
  • GI Disease Celiac disease, Giardia
  • Anaphylaxis to transfusions
  • Diagnosis Age gt 4 and IgA lt 7
  • Treatment
  • Short term antibiotic prophylaxis
  • IVIG in severe cases (with caution)

26
Cell-Mediated/T cell Immunity
                                                
                                             .  
27
Defects of Cell-Mediated Immunity
  • Cell mediated defects includes combined
    immunodeficiency syndromes
  • B cells rely on signals from T cells to work
    properly.
  • Some syndromes with normal B cell number and
    function in vitro, but B cells dont work in vivo
    due to lack of signals from T cells.
  • Some syndromes have underlying abnormalities of
    both B and T cells
  • Some with T cell dysfunction where Humoral
    immunity may be preserved.

28
Defects of Cell-Mediated Immunity
  • Recurrent severe infections
  • Often with unusual organisms
  • Often will have a history of sepsis
  • Failure to Thrive particularly prominent
  • Chronic Diarrhea
  • Lymphopenia during infancy
  • Graft verses Host Disease (after blood
    transfusion).

29
Defects of Cell Mediated Immunity
  • Signature Organisms
  • Chronic Candidiasis
  • Severe Viral infections
  • Zoster
  • CMV
  • HSV
  • RSV
  • Influenza
  • Extensive Molluscum or warts
  • Pneumocystis carinii pneumonia

30
Defects of Cell Mediated Immunity
  • Includes
  • Severe Combined Immunodeficiencies
  • Enzyme Defects
  • Adenosine Deaminase
  • Purine Nucleoside Phosphorylase
  • MHC I and II Defects (Bare Lymphocyte Syndrome)
  • DiGeorge Syndrome
  • Wiskott-Aldrich Syndrome
  • Ataxia-Telangiectasia
  • Cartilage-Hair Hypoplasia

31
DiGeorge Syndrome
  • Deletion of chromosome 22q11.2
  • Defective development of 3rd and 4th pharyngeal
    pouches
  • Absence of Thymus
  • Therefore low or absent T cells
  • No B cell abnormalities except in more severe
    forms.
  • Associated Anomalies
  • Conotruncal Cardiac Defects
  • VSD
  • Tetralogy of Fallot
  • Interrupted Aortic Arch
  • Parathyroid Hypoplasia
  • Low Calcium
  • Tetany

32
DiGeorge Syndrome
  • Other Anomalies
  • Cleft Palate
  • Velocardiofacial Syndrome
  • Esophageal abnormalities
  • Ocular anomalies
  • Renal anomalies
  • Increased incidence of Autoimmune disease
  • Diagnosis FISH
  • Will often have decreased CD3 T cells
  • Treatment
  • IVIG and antibiotic prophylaxis
  • Should be on TMP/SFA for PCP prophylaxis
  • Thymic transplant or Bone marrow transplant

33
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34
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35
Severe Combined Immunodeficiency (SCID)
  • Rare
  • Genetics many different types/defects
  • 50-60 X-linked
  • Autosomal recessive
  • Sporadic
  • Symptoms
  • Failure to Thrive
  • Severe infections
  • Common viruses may cause severe disease and death
  • Alopecia and Seborrheic Dermatitis

36
SCID
  • Diagnosis
  • Less than 20 lymphocytes are T cells
  • Absolute lymphocytes lt 3,000
  • Response to mitogens lt 10
  • Have cutaneous anergy
  • Treatment
  • Antibiotic prophylaxis
  • Stem cell transplant
  • Some gene therapy being done
  • No live virus vaccinations
  • Prognosis often fatal in first year of life.

37
XL-SCID
  • Affects males
  • Defect
  • Gene encoding for cytokine receptor
  • Receptor normally responds to
  • Interleukin 2,4, 7,9, 15, and 21
  • Results
  • Peripheral T cells absent
  • Thymus small and devoid of lymphocytes
  • Normal number of B cells, but they dont produce
    immunoglobulin due to defect.

38
Wiskott-Aldrich Syndrome
  • X-linked Recessive
  • Gene defect of WASP protein causes cytoskeletal
    dysfunction
  • B and T cell dysfunction
  • Associated Symptoms
  • Thrombocytopenia severe w/ petechiae
  • Eczema
  • Hepatosplenomegaly
  • Autoimmune Hemolytic Anemia
  • High incidence of lymphoma CNS
  • Treatment Stem cell or Bone Marrow transplant
  • Prognosis - Average life expectancy 11 years

39
Ataxia-Telangiectasia
  • Autosomal Recessive
  • Have both B and T cell dysfunction
  • more characteristics of B cell dysfunction
  • Associated Symptoms
  • Ataxia from early age progressive
  • Telangiectasia develop after 2 y/o
  • High risk for various malignancies
  • Endocrine abnormalities many w/ Diabetes
  • Liver Dysfunction
  • Treatment suppportive
  • Prognosis death often in early childhood

40
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41
Phagocytic Disorders
42
Phagocytic Disorders
  • Rare set of disorders
  • Symptoms
  • Poor wound healing
  • Delayed separation of umbilical cord and
    omphalitis (esp in Leukocyte Adhesion Defects)
  • Soft Tissue Abscesses
  • Chronic Gingivitis, oral ulcers, and peridontal
    disease

43
Phagocytic Disorders
  • Signature Organisms often Catalase Positive
  • Staph aureus and epidermidis
  • Pseudomonas (esp Burkholderia cepacia)
  • Aspergillosis (esp w/ Chronic Granulomatous)
  • No problems in handling viruses

44
Phagocytic Disorders
  • Examples
  • Chronic Granulomatous Disease
  • Severe G6PD
  • Chediak-Higashi Syndrome
  • Partial Occulocutaneous Albinism
  • Neurologic abnormalities
  • Jobs Syndrome
  • Leukocyte Adhesion Defect
  • Congenital Neutropenia

45
Chronic Granulomatous Disease
  • Rare 20 cases/year in the US
  • Genetics
  • 70 X-linked recessive
  • Defect in NADPH oxidase
  • Cant form reactive oxygen species to destroy
    micro-organisms
  • Symptoms
  • Pneumonia, Abscesses, Adenitis, Osteomyelitis
  • Uniquely susceptible to Aspergilosis

46
Chronic Granulomatous Disease
  • Associated Symptoms
  • Severe Acne
  • Excessive Granulomata often in GI tract (IBD
    like diseases)
  • Lupus
  • Chorioretinitis
  • Diagnosis Nitroblue Tetrazolium Test (NBT)
  • Treatment
  • Antibacterial and antifungal prophylaxis
  • Interferon Gamma
  • Stem cell or Bone Marrow Transplant

47
Complement Disorders
48
Complement Deficiency
  • Rarest of Immunodeficiencies
  • Most autosomal recessive
  • Symptoms depend on where in pathway defect occurs
  • May be early or late in classical pathway
  • May involve alternative complement pathway
  • May involve regulatory proteins
  • i.e. properidin

49
Complement Deficiency
  • Symptoms
  • Autoimmune Disease very prominent (up to 90 in
    some defects) esp. early defects
  • SLE main disease seen
  • Polymyositis
  • Vasculitis
  • Glomerulonephritis from immune complexes
  • Hereditary Angioedema

50
Complement Deficiency
  • Signature Organisms Encapsulated
  • Pyogenic Bacteria
  • Neisseria Meningitidis (esp late defects)
  • Streptococcus pneumoniae
  • Hemophilus influenza B
  • Treatment supportive
  • If susceptible to N. Meningitidis PCN
    prophylaxis.
  • Meningococcal vaccine recommended

51
Vaccination
  • Most of these children should receive routine
    vaccination.
  • Caution with live virus vaccines
  • MMR
  • Varicella
  • Oral Polio (IPV is OK)
  • Intranasal Influenza Vaccine

52
Vaccination
  • Live virus can be given in
  • Mild Humoral Defects
  • IgA Deficiency (if isolated defect)
  • IgG Subclass Deficiency
  • Some Cell Mediated Defects (on a case by case
    basis)
  • Mild DiGeorge
  • Mild Ataxia-Telangiectasia
  • Phagocytic Dysfunction
  • Leukocyte Adhesion Defects
  • Chronic Granulomatous Disease
  • Complement Deficiency

53
Vaccination
  • Live Virus Vaccine contraindicated in
  • More severe forms of Humoral Immunodeficiency
  • Most forms of Cell Mediated Immunodeficiency
  • Severe Combined Immunodeficiency
  • Severe DiGeorge and Ataxia-Telangiectasia
  • Delay vaccination if on IVIG
  • May need to check response to vaccination in
    Humoral Defects
  • IgG subclass deficiency
  • Common Variable Immunodeficiency
  • Meningococcal vaccine for Complement Deficiency

54
Diagnostic Work Up
  • Antibody Defects
  • Quantitative - Immunoglobulin levels
  • Functional - Antibody Titers to immunizations
  • T cell
  • Quantitative CBC, Abs lymphocyte count
  • Functional Skin tests for antigens (Mumps,
    candida, etc.)
  • Phagocyte
  • Quantitative CBC, Abs neutrophil count
  • Functional NBT test
  • Complement
  • Quantitative C3, C4
  • Functional CH50

55
Case Presentation
  • D. George is a 2 year old male brought in
    by his parents Wiskott and Aldrich because of
    concerns about recurrent infections. They state
    he has been sick many times over the last two
    years. He has been in the hospital twice with
    some sort of infection. He has also had frequent
    upper respiratory infections and has had Otitis
    Media 7 times in the last two years.

56
  • What other history should we get?
  • Does the child need work up for immunodeficiency?
  • Depends on history
  • What immunodeficiency should we worry about?
  • What work up should be done?

57
References
  • Puck, JM. Primary Immunodeficiency Diseases.
    JAMA 1997 2781835.
  • Rosen, FS, et al. The Primary
    Immunodeficiencies. New England Journal of
    Medicine. 1995 333 431.
  • Wheeler, J. Evaluating the Child with Recurrent
    Infections. American Family Physician. 1996
    54 2276.
  • Finochi A, et al. Evaluation of the relevance
    of humoral immunodeficiencies in a pediatric
    population affected by recurrent infections.
    Pediatric Allergy and Immunology. 2002 13 443.
  • Herrod, HG. Follow up of pediatric patients with
    recurrent infection and mild serologic immune
    abnormalities. Ann Allergy Asthma immunol.
    1997 79 460.
  • American Academy of Pediatrics. Immunization in
    Special Clinical Circumstances. In Pickering
    LK ed. Red Book. 26th edition. Elk Grove
    Village, Illinois 2003.
  • Finberg, L. Saunders Manual of Pediatric
    Practice. W.B. Saunders Company Philadelphia,
    Pennsylvania 1998.
  • Barrett. Approach to the child with recurrent
    infections. on www.uptodate.com. Accessed
    3/15/2005. As well as various other publications
    on that website.
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