Primary Immunodeficiency Syndromes

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Primary Immunodeficiency Syndromes

• Jackson Williams, MD
• March 24, 2005

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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.

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• 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?

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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).

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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

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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.

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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.

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Distribution of Immunodeficiencies
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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)

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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

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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).

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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

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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)

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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.

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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.

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Humoral / B-cell Defects
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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

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Humoral Defects

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

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Humoral Defects

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

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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

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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

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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

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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)

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Cell-Mediated/T cell Immunity
                                                
                                             .  
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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.

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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).

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Defects of Cell Mediated Immunity

• Signature Organisms
• Chronic Candidiasis
• Severe Viral infections
• Zoster
• CMV
• HSV
• RSV
• Influenza
• Extensive Molluscum or warts
• Pneumocystis carinii pneumonia

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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

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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

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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

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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

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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.

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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.

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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

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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

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Phagocytic Disorders
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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

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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

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Phagocytic Disorders

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

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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

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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

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Complement Disorders
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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

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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

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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

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Vaccination

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

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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

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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

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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

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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.

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• 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?

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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.