IMMUNODEFICIENCY

DISORDERS
DR MBURU
CLINICAL PHARMACIST
INTRODUCTION
 The immune system is capable of distinguishing self from non
self and eliminates potentially harmful non self molecules and
cells from the body
 It also has the capacity to recognize and destroy abnormal cells
derived from host tissues
 Any molecule capable of being recognized by the immune
system is considered an antigen

2
 Two types of immune response: Innate or Acquired
Innate/ Natural/ Non-Specific
 Does not require prior exposure to an antigen(i.e memory) to be
effective
Components:
 Phagocytic cells(neutrophils, monocytes in blood, macrophages
& dendritic cells in tissue)
 Antigen presenting cells(macrophages & dendritic cells)

 Natural Killer cells- kill virus infected cells and some tumor
cells
 Polymorphonuclear leukocytes(eosinophils, basophils,
neutrophils, mast cell) 3
 Complement system
INTRODUCTION CONTD..
Acquired/ Adaptive/Specific
 Remembers past exposures and antigen specific

 Components:

 B & T lymphocytes,Antibodies

 Makes up the humoral and cell mediated immunity

 NOTE: Innate and acquired immunity interact

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5
ORGANS OF THE IMMUNE SYSTEM

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LEUCOPOIESIS

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LEUCOPOIESIS CONTD…

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IMMUNODEFICIENCY DISORDERS

 Immunodeficiency disorders associated with:

 Defect or impairment in immune function.

OR
 Induced through infections and various environmental factors.

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 Immunodeficiency
Diseases

Primary: Usually congenital, Secondary (Acquired):

resulting from genetic defects as a result of other
in some components of the diseases or conditions
immune system.

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SECONDARY IMMUNODEFICIENCIES
Can be due to various causes:
 Endocrine- diabetes mellitus

 Malnutrition, alcoholism

 Infections – HIV, EBV, CMV

 Renal – nephrotic syndrome, renal insufficiency, uremia

 Physiologic- infants due to immaturity of the immune system, aging

 Iatrogenic- anticancer agents, radiation therapy,

anticonvulsants(cause IgA deficiency), general anaesthesia,
corticosteroids, splenectomy
 Prolonged severe illnesses

 Conditions that result in loss of serum proteins(particularly IgG and

albumin)- nephrotic syndrome, severe burns or dermatitis or GI
enteropathy 11
PRIMARY IMMUNODEFICIENCIES
 Are genetically determined
 May occur alone or as part of a syndrome

 Typically manifest in infancy and childhood (about 80%

are < 20years) as abnormally frequent or unusual
infections
 Transmission is often X-linked therefore 70% are male

 Overall incidence is about 1/10,000 people

 Are classified by the main component of the immune

system that is deficient, absent or defective

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 AETIOLOGY
 Aetiology associated with
Genetic defects of missing enzymes.
Specific development impairment (pre-B-cell
failure).
Infections, malnutrition and drugs

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CLASSIFICATION OF PRIMARY IMMUNODEFICIENCY DISORDERS
DEFECT DISTRIBUT CONDITIONS SUMMARY OF
ION PRESENTATION
B-Cell defects 50-60% Selective IgA deficiency, Serum Ig and
Common Variable antibody titres
Immunodeficiency, decrease
Hyper IgM syndrome, predisposing to
Transient infections with
hypogammaglobulinemia of encapsulated G+
infancy, bacteria
X-linked agammaglobulinemia

T-Cell defects 5-10% Di-George syndrome, ZAP-70 Predispose to

deficiency, X-linked infections by
lymphoproliferative syndrome, viruses, fungi and
Chronic mucocutaneous other opportunistic
candidiasis organisms
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Combined B & T 20% Severe Combined
cell defects Immunodeficiency(SCID),
Ataxia telangiectasia,
Cartilage-hair hypoplsia,
Cytokine deficiency, Hyper
IgE syndrome, MHC
complex deficiencies,
Wiskott Aldrich syndrome

Phagocytic cell 10-15% Chronic granulomatous Cutaneous

defects disease, leucocyte adhesion staphylococcal &
deficiency, Chediak- Higashi gram negative
syndrome infections are
characteristic
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Complement <2% Isolated Recurrent
deficiencies deficiencies of infections due to
complement impaired
componentse.g opsonization,
C1.C2, C3,C4, autoimmune
Membrane attck disorders eg SLE,
complex etc glomerulonephritis
due to defective
clearance of Ag-Ab
complexes
Primary Di-George Are genetically
immunodeficiency syndrome, Wiskott determined
syndromes Aldrich , Cartilage- immunodeficiencie
Hair, Ataxia s with immune and
telangiectasia non immune
defects

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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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 SYMPTOMS:
 Recurrent respiratory infections.
 Persistent bacterial infections →sinusitis, otitis, pneumonia and
bronchitis.
 Increased susceptibility to opportunistic infections (OIs) and
recurrent fungal yeast infections.
 Skin and mucous membrane infections.

 Resistant thrush, oral ulcers and conjunctivitis.

 Diarrhoea due to unusual organisms e,g fungi and

malabsorption.
 Failure to thrive and delayed or incomplete recovery from
illness.
 Severe viral infections may occur e.g herpes simplex, VZV,
and CNS problems e.g chronic encephalitis, delayed 18
development, seizure disorders
 NOTE: Antibiotics may mask many of the common s&s
DIAGNOSIS
 History – helps to establish the onset, symptoms and risk
factors
 Note: the earlier the age at onset in children, the more severe
the immunodeficiency
 Certain infections suggest certain immunodef disorders e.g
recurrent gingivitis- neutrophil defect; clinical infection due to
live attenuated vaccine- T cell disorder

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DX: PHYSICAL EXAMINATION
 Skin manifestations- macular rashes, vessicles, eczema,
pyoderma, petechiae or spider veins may be evident
 Lymph nodes- may be atrophied or absent in certain IDD e.g in
SCID or may be enlarged and suppurative e.g in chronic
granulomatous disease
 Tympanic membranes may be scarred or perforated

 Nostrils may be crusted indicating purulent nasal discharge

 Chronic cough, lung crackles

 Enlarged liver and spleen e.g in CVID

 Muscle mass and fat deposits of the buttocks are decreased

 In infants, the skin around the anus may break down due to
chronic diarrhoea
 Delayed developmental milestones or ataxia 20
DX: IMMUNE FUNCTION TESTING
 CBC with manual differentials, quantitative Ig measurements, Antibody
titres
 Skin testing for delayed hypersensitivity

 Peripheral blood films – granulocytes may have abnormal morphology e.g

giant granules in Chediak Higashi syndrome
 Testing for specific disorder eg HIV, DM- where a specific secondary IDD
is suspected
 Chest xrays- useful in infants: absent thymic shadow suggests T cell disorder

 Lymphocyte phenotyping using flow cytommetry and monoclonal antibodies

to T, B and NK cells- shows lymphocyte deficiency
 Flow cytommetric respiratory burst assay to detect whether O2 radicals are
produced during phagocytosis- for CGD
 Prenatal diagnosis: sex determination(X linked disorders), chorionic villus
sampling, cultured amniotic cells, fetal blood sampling
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LABORATORY EVALUATION OF
IMMUNODEFICIENCY DISORDERS

 Routine investigations:
 Total and differential leucocyte counts
 Absolute lymphocyte count
 Normal result rules out T- cell defect
 Absolute neutrophil count
 Normal study rules out granulocyte defect
 Platelet count and morphology
 Normal result rules out WAS
 Howell- Jolly bodies
 ESR 22
Suspected B cell defect Serum Electrophoresis

Hypogammaglobulinemia

B cell count Immunoglobulin pattern

Normal
Low Normal Abnormal

Possible CVID Consider complement or

XLA
phagocytic dysfunction
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PROGNOSIS
 Depends on the primary ID disorder
 Ig or complement deficiency- good prognosis with near normal
life expectancy if dx early, Rx appropriately and have no co-
existing chronic disorders
 Phagocytic cell defects, Wiskott Aldrich or Ataxia
telangiectasia- guarded prognosis. Most require intensive and
frequent Rx
 SCID- death occurs during infancy unless immunity is restored
through transplantation

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TREATMENT
 Goals:
 Prevent infection

 Manage acute infection

 Replace missing immune components (where possible)

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PREVENTION
 Prophylactic antibiotics e.g in SCID, Wiskott Aldrich,
CGD
 Avoid live-virus vaccines

 Isolation in a sterile environment like David ‘Bubble

Boy’

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TREATMENT
 IV immune globulin therapy (IVIG)
 Haematopoietic stem cell transplantation
 Early drainage of abscess
 Topical and systemic antifungal therapy
 Timely use of antibiotics during acute infections
 Use of antiviral agents even for self limiting viral infections

 Where blood transfusions are required ensure they are from

CMV negative donors, are filtered to remove WBCs and are
irradiated to prevent Graft-vs-host disease
 Prompt and early instillation of anti retroviral therapy will help
in control of the disease
 Prophylaxis to prevent development of opportunistic
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infections.
IV IMMUNE GLOBULIN THERAPY (IVIG)
 Effective in most forms of antibody deficiency
 Dose: 400mg/kg at monthly intervals

 800mg/kg /month- for those who do not respond well to the

conventional dose, especially those with chronic lung disorder
 IVIG can also be given by slow SC infusions at weekly
intervals

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 HAEMATOPOIETIC STEM CELL TRANSPLANTATION

 Involves use of bone marrow, cord blood or adult peripheral

blood stem cells
 Pre-transplation chemotherapy may be necessary in patients
with some T cell function to ensure graft acceptance.
Unneccessary in patients without T cells

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 Gene therapy has been attempted as an alternative to the bone marrow
transplant
 Transduction of the missing gene to hematopoietic stem cells
using viral vectors is being tested in ADA SCID and X-linked SCID

 In 1990, four-year-old Ashanthi DeSilva (born with ADA- SCID)became

the first patient to undergo successful gene therapy. Researchers collected
samples of Ashanthi's blood, isolated some of her white blood cells, and
used a virus to insert a healthy adenosine deaminase (ADA) gene into the
defective cells.

 These cells were then injected back into her body, and began to express a
normal enzyme. This, augmented by weekly injections of ADA, corrected
her deficiency.
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 This Rx has however not been successful in many other patients. Reported
cases of some patients developing leukaemia
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 DEFECTS IN HUMORAL MEDIATED IMMUNITY
 Caused by the improper production of one or all of the
immunoglobins (antibodies)
 Results in an increased of infections from Staphylococcus,
Streptococcus, Haemophilus, and Pseudomonas.
 Humoral Immunodeficiencies include:

 Bruton’s X-Linked Agammaglobinulinemia

 Common Variable Immunodeficiency (CVID)
 Selective Immunoglobin A Deficiency
 Hyper IgM syndrome
 Transient hypogammaglobulinemia of infancy

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 COMMON VARIABLE
IMMUNODEFICIENCY (CVID)
 Alsoknown as adult onset hypogammaglobulinemia because
onset occurs later
 Associated with mature B cells failure to differentiate
into mature plasma cells (antibody forming cells)
 Characterised by normal B cells and low serum Ig
levels
 Mgt:

 IVIG 400mg/kg/month

 Antibiotics as needed to treat infections 33

 X-LINKED AGAMMAGLOBULINAEMIA (XLA)
(BRUTON’S DISEASE)
 Deficiencyof B cell tyrosine kinase causing failure in
the development of pre-B cell maturation to B cells.
 Majority of XLA patients show:
 Profound hypogammaglobulinaemia involving all immunoglobulin
classes with <1% B cells in normal peripheral blood.

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Clinical presentations of Brutons disease:

 Increased susceptibility to encapsulated recurrent pyogenic bacteria

(S. pneumonia, and pseudomonas species).
 Skin infections (group A streptococci and S. aureus).
 Persistent viral or parasitic infections.

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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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 SELECTIVE IGA DEFICIENCY (IGA D)
 Patients with IgA deficiency have:
 IgA levels < 10mg/dL with normal levels of other Igs and
 50% have chronic otitis, sinusitis or pneumonia
 IgA committed B lymphocytes fail to mature into IgA-secreting plasma cells caused
by intrinsic B cell defect
 Most common primary immunodeficiency
 Many patients develop recurrent infections and autoimmune disorders
 Dx: measurement of serum Ig
 Prognosis: Some patients develop CVID while others remit spontaneously
 Rx: Avoidance of blood products that contain IgA- anti-IgA antibodies may develop after
exposure to IgA in plasma or to IVIG;anaphylactic reactions may occur IVIG or blood
products that contain IgA
 Antibiotics are given as needed
 NOTE: Where RBC transfusion is needed, only washed RBCs or frozen blood can be use
 Patients advised to wear identification bracelet to prevent inadvertent plasma or IVIG
administration
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Drugs such as phenytoin, sulfasalazine,
colloidal gold and D penicillamine may lead to
IgA deficiency in genetically susceptible
patients
Patients of IgA deficiency are susceptible to:
Allergic conjunctivitis, urticaria and asthma.
Autoimmune disorders – celiac or inflammatory
bowel diseases, SLE
Various gastrointestinal diseases (diarrhoea).
 recurrent sinopulmonary infections.
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 T CELL IMMUNODEFICIENCY
DISEASES
T cell congenital disorders display:
Little or no cell mediated immunity and may
involve B cell deficiencies.

 Patients particularly susceptible to:

Repeated fungal (Candida) infection.
Protozoan and viral infections.

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PRIMARY T CELL IMMUNODEFIENCY
INCLUDES:
 Di-George syndrome
 ZAP-70 deficiency
 X-linked lymphoproliferative syndrome
 Chronic mucocutaneous candidiasis
 Defective expression of class II MHC molecules
 Defective expression of CD3-T cell receptor (TCR) complex

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DI GEORGE SYNDROME (THYMIC APLASIA)
Congenital disorder characterized by:

 Lack of embryonic development or underdevelopment of the

3rd and 4th pharyngeal pouches.

 Thymic hypoplasia, hypothyroidism and congenital heart

disease.
 Patients susceptible to uncontrolled opportunistic
infections.
Impaired in cellular mechanisms.
Profound lymphopenia (T cell <1200L). 42
COMBINED B & T CELL DEFECTS
 Include:
 Severe Combined Immunodeficiency(SCID)

 Ataxia telangiectasia

 Cartilage-hair hypoplasia

 Cytokine deficiency, Hyper IgE syndrome

 MHC complex deficiencies

 Wiskott Aldrich syndrome

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 SEVERE COMBINED
IMMUNODEFICIENCY DISEASE (SCID)
Disorder characterized by:
 Deficiency in both B and T lymphocyte functions with
markedly low IgG, IgA and IgE levels.

 SCID associated with:

 Children failure to thrive.
 chronic respiratory infections.
 Gastrointestinal and/or cutaneous infections particularly recurrent
viral, bacterial, fungal and protozoan infections in 6 months' infants.
NOTE: There is a milder form known as combined immunodeficiency
syndrome having a low, but not absent T-cell function.

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SCID manifests early with:
Persistent and recurrent diarrhoea,
otitis, thrush and respiratory infections
in the first few months of life.
T cell defects associated with:
 Candidiasis, CMV infection, measles and varicella leading to life
threatening pneumonia, meningitis and sepsis.
 SCID managed through Ig infusion, stem cell
transplantation and gene replacement.

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46
 ATAXIA TELANGIECTASIA
(AT)
Autosomal recessive progressive neurodegenerative
childhood disorder associated with:
 Lack of coordination (cerebella ataxia) and dilation of facial blood vessels
(telangiectasis) and slurred speech.

 Patients
have defective mechanisms of DNA repair and are predisposed to
leukaemias and lymphomas.

 Extremely sensitive to radiation exposure and susceptible to chronic

respiratory infections.

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 Ataxia Telangiectasia:
 Results from a mutation on chromosome 11

 Condition consists of worsening ataxia (lack of coordination)

and telangiectasia (dilated capillaries and arterioles) on the
skin and conjunctiva.

 Children have reduced levels of IgA, IgE, and IgG, and

decreased ratio of CD4+ helper T cells to CD8+ cells.

 Children are prone to recurrent upper and lower respiratory

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infections and an increased risk of malignancy.
 Death from lymphoma is common
TELANGIECTASI
S

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 WISKOTT-ALDRICH SYNDROME (WAS)
An X-linked recessive disorder associated with
thyrombocytopenia and eczema.
 Patients have
 Elevated IgA and IgE
 Low IgM
 Low or normal IgG levels
 Thrombocytopenia (there is increased destruction of platelets by the
spleen)
 Small and defective platelets

Variable T cell dysfunctionsT cell dysfunction manifested by:

 Severe herpex virus and Pneumocystis carinii infections
 Increased lymphomas and autoimmune diseases.
 Recurrent pyogenic bacterial infections.
 Usually affecting ears, sinuses and lungs. 50
 Wiskott-Aldrich Syndrome:
 T-cell dysfunction is initially mild then progressively
worsens making child susceptible to Hodgkin’s disease and
lymphoma
 Cancers, especially EBV lymphomas and and acute lymphoblastic
leukaemiadevelop in about 10% of patients
 Rx:
 Splenectomy
 Continuous antibiotics
 IVIG
 HLA identical bone marrow transplantation
 Without transplantation most patients die by age 15 however some 51
may survive till adulthood
 DISORDERS OF COMPLEMENT SYSTEM
 Complement system is an important part of the non-specific
immune response.

 Complement promotes chemotaxis, opsonization, and

phagocytosis of invasive pathogens, bacteriolysis, and
anaphylactic reactions.

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 Primary complement disorders are caused by genetic problems

 Deficiency of C1 to C4 are not at increased risk for infection

because alternate pathways can be activated.
 These patients are more prone to autoimmune diseases such

as Lupus Erythematosus and increased susceptibility to

pyogenic infections

 Deficiency of late complement components (C5, C6, C7, C8)

results in systemic Neisseria infections such as meningococcal
sepsis, meningitis and disseminated gonococcal infections.
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 Abnormalities of the control proteins of the alternative pathway
(factor H, factor I, properdin) may result in recurrent infections.

 Deficiency of complement inhibitors (C1 esterase inhibitor,

carboxypeptidase N) leads to Hereditary Angioneurotic Edema

 Secondary Disorders of Complement

 Occur in persons with normal complement systems who have
rapid activation or turnover of complement components

 Can also occur with conditions where there is a decreased

production complement components such as in liver cirrhosis54
or malnutrition.
55
 DISORDERS OF PHAGOCYTOSIS
 Phagocytic system:
 Composed primarily of:
 Neutrophils, Eosinophils and Monocytes.

 Phagocytic cells function to migrate to site of infection, adhere to

the tissue, engulf invading material, and then digest it.

 A defect in the phagocytic system results in a decreased number

of phagocytic cells.

 Persons are prone to bacterial infections, often by Candida and 56

filamentous fungi.
CHRONIC GRANULOMATOUS DISEASE
 An X- linked recessive trait in 50% of the cases . In the rest is autosomal
recessive
Wbcs are not able to produce acivated O2 compounds e.g H2O2, sueroxide, and
other activated oxygen compounds
Phagocytic cell microbicidal activity is defective thus bacteria and fungi are not
destroyed despite normal phagocytosis
Manifestations:
Recurrent infections
Multiple granulomatous lesions of the lungs, liver, lymph nodes, GI and GU tract
Abscesses, lymphadenitis
Hypergammaglobulinemia
Elevated ESR
Anaemia 57
CHRONIC GRANULOMATOUS DISEASE
 Dx:
 Assessing O2 radical production in WBCs by a flow
cytommetric respiratory burst assay
 Rx:

 Continuous antibiotics- trimethoprim-sulfamethoxazole 960

mg BD alone or with Cephalexin 500mg TDS
 Antifungal drugs as primary prophylaxis or when fungal
infections occur
 Itraconazole PO BD 100mg(<13yrs) or 200mg BD(>13yrs or >
50kg)
 Voriconazole PO BD 100mg(<40kg) or 200mg BD(> 50kg)
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CHRONIC GRANULOMATOUS
DISEASE CONTD…
Rx
 Interferon γ- increases non-oxidative antimicrobial
activity thus reducin =g severity and frequency of
infections
 Dose: 50µg/m2 SC 3 times/week
 Granulocyte transfusions are lifesaving when
infections are severe
 HLA- identical sibling bone marrow
transplantation has been successful after
pretransplantation chemotherapy
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 Gene therapy
CHEDIAK-HIGASHI SYNDROME
 A rare condition
 Autosomal recessive

 Characterised by impaired lysis of phagocytised bacteria

resulting in recurrent bacterial respiratory and other
infections & occulocutaneous albinism
 Giant lysosomal granules develop in neutrophils and
other cells e.g melanocytes, neural schwann cells.
 Abnormal lysosomes cannot fuse with phagosomes so
ingested bacteria cannot be lysed normally
 Transplantation of unfractionated HLA – identical bone
marrow after pretransplantation chemotherapy 60
Disorder Inheritance Clinical Features
1) Chronic X-linked (66%); Infections with catalase producing
granulomatous autosomal bacteria and fungi affecting skin, lungs,
disease recessive (33%) liver; granuloma formation

2)Myeloperoxidase Autosomal Fungal infections (candidiasis) in deep

deficiency Recessive tissues, especially in presence of diabetes

3)Leukocyte Auto­somal Delayed separation of the umbilical cord;

adhesion recessive skin infections; otitis media; pneumonia;
deficiency gingivitis; periodontitis

4)Abnormal Variable Recurrent skin infections with

chemotaxis staphylococci. enteric bacteria,
-Hyper IgE Neuropathy, Occulo-cultaneous albinism
-chediak-Higashi in chediak higashi 61
GIANT GRANULES
IN NEUTROPHILS

CHEDIAK-HIGASHI
SYNDROME

62
 CHRONIC
GRANULOMATOUS
DISEASE
MECHANISM OF
RESPIRATORY BURST
-

Myeloperoxida
se

MYELOPEROXIDAS
63
E
DEFICIENCY
 EVALUATION OF
IMMUNODEFICIENCY
Often present

1. Persistent sinusitis or
Usually Occasionally present
mastoiditis
present
2. Failure to thrive
1. Recurrent 1. Lymphadenopathy
3. Intermittent fever
respiratory tract 2. Hepatosplenomegal
4. Skin lesions
infections y
5. Diarrhea
2. Severe bacterial 3. Severe viral
6. Hearing loss due to
infections illnesses
chronic middle ear
3. Recurrence of same 4. Chronic
infections
type of bacteria encephalitis
7. Chronic conjunctivitis
4. Paucity of lymph 5. Deep infections
8. Bronchiectasis
nodes and tonsils 6. Delayed umbilical
9. Evidence of 64
detachment
autoimmunity
7. Adverse reactions
10. Hematologic
to vaccines
CHARACTERISTIC FEATURES OF
PRIMARY IMMUNODEFICIENCY
DISORDERS

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Characteristic T- cell defect B- cell defect Granulocyte defect Complement defect

Age of onset of Early; 2-6 months After 5-7 months Early onset at birth Any age
infection

Specific pathogens Mycobacteria, Pyogenic bacteria Bacteria; Bacteria

Viruses, Fungus like mainly Streptococci, Staphylococcus
Candida and Staphylococci Pseudomonas
parasites Hemophilus Klebsiella
enteroviruses

Systemic effects Failure to thrive, Recurrent Skin abscesses, Recurrent

Extensive sinopulmonary impetigo, cellulitis sinopulmonary
mucocutaneous infections infections
Candidiasis Malabsorption Meningitis
Enteroviral
encephalitis

Special features GVHD, Post Autoimmunity Prolonged Autoimmune

vaccination Lymphoma attachment of diseases
disseminated BCG Thymoma umbilical cord
or Varicella Post vaccination Poor wound healing
66
Hypocalcemic paralytic polio
tetany in infancy
REFERENCES
 Merck Manual 18th Edition
 Harrison’s Principles of Internal Medicine 17th Edition

67