IMMUNODEFICIEN

CIES
AIDS
 INTRODUCTION

■ The immune system is not fully mature at birth and may not fully grown until the child
reaches the age of 6 (school age)
■ Sometimes, even this defense system is functional, a child, in the first decade of life, can
present 5-6 infectious respiratory episodes each year
■ Immunoglobulins transmitted via placenta provides protection for the new-borns and
infants in the first months of life, but, as this passive protection decreases, clinical
symptoms related to the anomalies of the B cells appear.
INTRODUCTION

■ The defence system of the host develops in order to protect the individual against the
invasion of micro-organisms
■ The components of the immune system are:
– The anatomical and physico chemical barriers of skin and mucous membranes.
– The innate or non specific immune system which includes phagocytic cells, natural killer
cells (NK), the complement system and other plasmatic factors.
– The specific or adaptive immune system which includes B and T lymphocytes and their
secretion products
■ Specific elements of the immune system plays a specific role in defence of the host and in
close interaction with each other means of adequate protection of the host.
INTRODUCTION

■ Typically, children with an intact immune system and no other predisposing factors handle
the infections well, with rapid resolution of bacterial infections using appropriate
antibiotics.
INTRODUCTION

■ Several factors contribute to the risk for infections during childhood

– Increased infectious agent exposure, school-aged siblings, peer group
– passive smoking
– atopy, hyper reactive air –way disease
– anatomic factors, structural or ciliary defects
– foreign body
– cystic fibrosis
– gastroesophageal reflux
■ A. Thymus: is an organ located in the upper chest.
Immature lymphocytes leave the bone marrow
and find their way to the thymus where they are
“educated” to become mature T-lymphocytes.
■ B. Liver: is the major organ responsible for
synthesizing proteins of the complement system.
In addition, it contains large numbers of
phagocytic cells which ingest bacteria in the blood
as it passes through the liver.
■ C. Bone Marrow: is the location where all cells of
the immune system begin their development from
primitive stem cells.
■ D. Tonsils: are collections of lymphocytes in the
throat.
■ E. Lymph Nodes: are collections of B lymphocytes
and T-lymphocytes throughout the body. Cells
congregate in lymph nodes to communicate with
each other.
■ F. Spleen: is a collection of T-lymphocytes, B
lymphocytes and monocytes. It serves to filter the
blood and provides a site for organisms and cells of
the immune system to interact.
■ G. Blood: is the circulatory system that carries cells
and proteins of the immune system from one part
of the body to another.
 A. Bone marrow: The site in the body where most
of the cells of the immune system are produced as
immature or stem cells.
B. Stem cells: These cells have the potential to
differentiate and mature into the different cells of
the immune system.
C. Thymus: An organ located in the chest which
instructs immature lymphocytes to become mature
T-lymphocytes.
D. B-Cells: These lymphocytes arise in the bone
marrow and differentiate into plasma cells which in
turn produce immunoglobulins (antibodies).
E. Cytotoxic T-cells: These lymphocytes mature in
the thymus and are responsible for killing infected
cells.

F. Helper T-cells: These specialized lymphocytes “help” other T-cells and B-cells to perform their functions.
G. Plasma Cells: cells develop from B-cells; the cells that make immunoglobulin for the serum and the secretions.
H. Immunoglobulins: These highly specialized protein molecules, also known as antibodies, fit foreign antigens, such as
polio, like a lock and key. Their variety is so extensive that they can be produced to match all possible microorganisms in
our environment.
I. Neutrophils (Polymorphonuclear PMN Cell): that rapidly ingests microorganisms and kills them.
J. Monocytes: phagocytic cell which develops into a macrophage when it migrates to tissues.
K. Red Blood Cells carry oxygen from the lungs to the tissues.
L. Platelets: important in blood clotting.
M. Dendritic Cells: Important cells in presenting antigen to immune system cells.
 DEFINITION

■ Immunodeficiencies (ID) include a group of heterogeneous disorders, different both by the

immunological and clinical expression, as well as the cellular and molecular mechanisms
involved, determined by the immune system defects in development and/or in function.
INCIDENCE, PREVALENCE

■ ranges from 1:300 (sIgA deficiency) to 1:100 000 live births (SCID)
■ 80% of affected persons < 20 years of age
■ 70% males (5:1 males in children; 1:1 in adults)
■ over 120 different entities described; of them, about 20 account for > 90% of cases

■ increasing due to better methodologies and newborn screening programs (2000s: 1 / 10 000
European Society for Immunodeficiencies EDIS Registry)
60 Humoral

50
Cellular
40
Combined
30

20 Phagocytic

10 Complement
0
% others
 CLASIFICATION
■ Disorders of adaptive immunity ( LyT or B or both) or
■ Disorders of innate immunity ( phagocytes, dendritic cells, complement * the first line in defence
against microorganisms)
■ Total or partial
■ Primary – congenital deficit of any immune system components or
■ Secondary – direct result of a known cause

Although clinical manifestations are highly variable most primary immunodeficiencies is characterized
by an increased susceptibility to infection; early diagnosis and treatment is necessary in order to
improve the morbidity.
CAUSES
 Genetic defect (deletion and/or rearrangements of genes, usually associated to X
crs and autosomal recessive transmission)
 Biochemical and/or metabolic deficiency ( ex ADA deficiency)
Primary – congenital
 Vitamins and oligoelements deficiency ( biotin, B12, Zn++)
 Embryogenesis anomalies

 After viral infections (rubella, measles, herpes virus, cytomegalovirus, hepatitis)

 Nutritional deficit
 Long term drugs use
 Alcoholism
 Immunosuppressive therapy, Radiotherapy,
Secundary
 Extremes of pediatric age: premature, small for date
 protein losing enteropathy
 Renal chronic disease, which requires dialysis
 Leukaemia or Lymphoma
 Acquired immunodeficiency syndrome (AIDS)
 Post transfusion
■ 50% - deficits in antibodies synthesis
■ 10% - cellular immunodeficencies
■ 20% - combine immunodeficencies
■ 18% - phagocytes defects
■ 2% - complement defects
10 WARNING SIGNS OF PRIMARY IMMUNODEFICIENCY

Eight or more new ear Recurrent, deep skin or

infections within 1 year. organ abscesses.

Two or more serious sinus Persistent thrush in mouth or

infections within 1 year. elsewhere on skin, after age 1.

Two or more months on Need for intravenous

antibiotics with little effect. antibiotics to clear infections.

Two or more pneumonias Two or more

within 1 year. deep-seated infections.

Failure of an infant to gain A family history of

weight or grow normally. Primary Immunodeficiency.
CHARESTERISTICS OF INFECTION

■Increasing susceptibility to infections

■Increasing severity of infection
■Increasing duration of infections
■ Unusual infection
■ Infection with opportunistic agents
■Continuous illness
■Dependence to antibiotics
CLINICAL FEATURES ASSOCIATED WITH
IMMUNODEFICIENCY

Feature frequency present and highly suspicious:

 Chronic infection
 Recurrent infection (more than expected)
 Unusual microbial agents
 Incomplete clearing of infection
 Incomplete response to treatment
 CLINICAL FEATURES ASSOCIATED
WITH IMMUNODEFICIENCY
 Feature moderately suspicious
Diarrhea (chronic)
Growth failure
Recurrent abscesses
Recurrent osteomyelitis
 Feature associated with specific immunodeficiency disorder
Telangiectasia
Partial albinism
PRIMARY IMMUNODEFICIENCY

■ 1) B-cell defects
■ 2) T-cell defects
■ 3) complement system defects
■ 4) phagocytic system defects .
 X-linked SCID (common gamma-chain
deficiency)
T-cell
X-linked hyper-IgM syndrome
defects Wiskott-Aldrich syndrome
X-linked lymphoproliferative syndrome

B-cell
Bruton's X-linked agammaglobulinemia
defects
Antibody deficiencies include:

• X-linked agammaglobulinemia (XLA)

• Common variable immunodeficiency (CVID)

• Selective IgA deficiency (SIgAd)

• Hyper IgM syndrome (HIgM)

• Transient hypogammaglobulinemia of Infancy (THI)

Cellular deficiencies include:

• Combined immunodeficiency (CID)

• Severe combined immunodeficiency (SCID)

• Ataxia-Telangiectasia syndrome (AT)

• Wiskott-Aldrich syndrome (WAS)

• DiGeorge syndrome
Phagocytic disorders include:

• Chronic granulomatous disease (CGD)

• Leukocyte adhesion defect (LAD)

• Chediak-Higashi syndrome (CHS)

• Swhachman syndrome (Swh.S)

• Hyper IgE syndrome (Job syndrome)

Complement deficiencies
 B-Cell Defect

Age at the Onset after maternal antibodies diminish, usually after 5-7
onset mo of age, later childhood to adulthood

Specific Bacteria: streptococci, staphylococci, Haemophilus,

pathogens Campylobacter Viruses: enterovirus Fungi and parasites:
involved giardia, cryptosporidia

Recurrent sinopulmonary infections, chronic gastrointestinal

Affected
symptoms, malabsorption, arthritis, enteroviral
organs
meningoencephalitis

Special Autoimmunity, lymphoreticular malignancy: lymphoma,

features thymoma; postvaccination paralytic polio
 T-Cell Defect

Age at the onset Early onset, usually 2-6 mo of age

Specific Bacteria: mycobacteria Viruses: CMV, EBV, varicella,

pathogens enterovirus
involved Fungi and parasites: Candida; opportunistic infection

Failure to thrive, protracted diarrhea, extensive

Affected organs
mucocutaneous candidiasis

Graft-versus-host disease caused by maternal AB or

Special features nonirradiated blood transfusion; Postvaccination,
disseminated BCG or paralytic polio;
APROACH TO A CHILD WITH
PRIMARY
IMMUNODEFICIENCY
 AGE AT ONSET

■ 2 – 5 months of age – T cell defect

(severe combined immunodeficiency)
■ 5 – 7 months of age – B cell defect
(X linked agammaglobinimia)
Later childhood & adult hood – common variable immunodeficiency
■ Younger age at onset – severe the deficiency
 MICROORGANISM SUSCEPTIBILITY

■ AGAMMAGLOBULINEMIA - encapsulated bacteria - Streptococcus pneumoniae or

Haemophilus influenzae. Complicating septicemia; viral meningoencephalitis caused by
enteroviruses ( coxsakie virus or echovirus)
■ Giardia lamblia - CVID and IgA deficiency.
■ Small-bowel bacterial overgrowth with Yersinia and Campylobacter – CVID
■ bacterial infections and opportunistic infections. Mycobacterium avium-intracellulare and
Pneumocystis carinii severe T-cell defects
 FAMILY HISTORY

■ A family history of maternal male relatives affected with unusually frequent infections or who
died in early infancy should alert the possibility of an X-linked immunodeficiency .

■ family history is the presence of relatives with autoimmune disorders, which commonly occurs
in families with patients who have CVID and IgA deficiency

■ A negative family history does not rule out this inheritance pattern , a significant rate of new
mutations for X-linked disorders exists.
MEDICAL HISTORY

■ VACCINE - Adverse reaction to live viral vaccines , Paralytic polio has occurred in
patients with B-cell deficiency and in patients with combined T-cell and B-cell
immunodeficiency.
■ BLOOD TRANSFUSION
– Only irradiated blood products should be given to patients with severe T-cell defects
because blood transfusions contain lymphocytes that can cause graft-versus-host
disease.
– Patients with complete IgA deficiency can produce IgE antibodies to IgA, so they
are at risk for an anaphylactic reaction to plasma or blood transfusions
PHISICAL EXAMINATION

■ A normal physical examination does not rule out an underlying immunodeficiency.

■ Patients with antibody-deficiency syndromes can demonstrate normal growth and
development despite frequent and severe RTIs. Antibody-deficiency syndromes can be
characterized by asymptomatic periods
■ Some children with underlying immunodeficiency appear chronically ill and underweight.
If initial onset of the disease occurs early in life, growth and development may be delayed,
leading to failure to thrive.
SKIN

Skin Findings Associated Immune Defect

■Eczema and petechiae Wiskott-Aldrich syndrome

■Telangiectasia Ataxia-telangiectasia sdr
■Dermatomyositis-like rash B-cell dysfunction
■Generalized molluscum contagiosum T-cell deficiency
■Extensive warts T-cell deficiency
■Candidiasis T-cell deficiency
DYSMORPHIC FEATURES

■ In patients with DiGeorge anomaly, abnormalities in the embryologic development of the third
and fourth pharyngeal pouches produce dysmorphic features, including hypoplastic mandible,
small mouth, hypertelorism and antimongoloid slant, and low-set and posteriorly rotated ears.
■ DiGeorge anomaly also is associated with hypoparathyroidism; an aplastic or hypoplastic
thymus; and conotruncal abnormalities of the heart, such as tetralogy of Fallot, ventricular
septal defect/atrial septal defect (VSD/ASD), and pulmonic artery atresia or stenosis.
 ENT EXAMINATION

■ Extensive mucous membrane candidiasis suggests a T-cell defect. Examination of the pharynx
and nasal cavities for signs of sinusitis, like, postnasal drainage, or purulent nasal discharge.
Tympanic membranes can appear scarred and disfigured as a sign of previous recurrent and
chronic infection of the middle ear.
 LYMPHIOD SYSTEM

■ Absence of tonsils and lymph nodes suggests a severe immunodeficiency, as seen in patients
with XLA or SCID.
■ Cervical adenopathy and enlarged liver or spleen can be seen in patients with a B-cell
deficiency, such as CVID or IgA deficiency,
■ Lymphoreticular malignancies occur more commonly in certain primary immunodeficiencies,
including Wiskott-Aldrich syndrome, ataxia-telangiectasia, and CVID
SYSTEMIC EXAMINATION

■ RESPIRATORY SYSTEM – Rales on auscultation of the chest may suggest bronchiectasis

occurring as a complication of recurrent lung infections. Digital clubbing points to significant
lung disease.
■ CARDIOVASCULAR SYSTEM – Pulmonary hypertension can occur in patients with chronic lung
disease
NEUROLOGICAL EXAMINATION

■ Progressive ataxia in a young child could be the first sign of ataxia-telangiectasia even
before immunodeficiency becomes clinically apparent.
■ Signs of posterior and lateral column involvement of the spinal cord with loss of vibratory
sense in the lower extremities, positive Babinski's response, or poor finger coordination can
be signs of pernicious anemia complicating the course of CVID or IgA deficiency.
LAB DIAGNOSIS
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

■ EVALUATION OF B-LYMPHOCYTE FUNCTION:

The initial screening test for B-lymphocyte function is the measurement of serum
immunoglobulines.
■ Quantitative measurements of serum IgG, IgA and IgM will identify patients with
panhypogammaglobulinemia as well as patients who have a deficiency of an individual class of
immunoglobulin, such as selective IgA deficiency.
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

■ There are four subclasses of IgG

■ In some instances, the total serum IgG may be normal or near normal but the patient may still
have an IgG subclass deficiency.
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

■ Assessment of antibody function is a necessary part of the evaluation of humoral

immunity.
■ Antibody titers after immunization with protein antigens (e.g. tetanus or diphtheria
toxoids) and polysaccharide (e.g. pneumococcal capsular polysaccharides) are most
convenient.
■ If immunoglobulin levels and/or antibody titers are decreased, the evaluation should
proceed with more advanced tests of B-lymphocyte numbers and function.
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

■ EVALUATION OF T-LYMPHOCYTE FUNCTION:

Testing for defects in T-lymphocyte function is relatively difficult because of the lack of
inexpensive and reliable screening tests.
■ Delayed type hypersensitivity (DTH) skin tests using a panel of ubiquitous antigens can be
used as a screening test in older children and adults.
■ The presence of a positive DTH skin test generally indicates intact T-cell function and cell
mediated immunity.
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

■ More specialized tests of T-cell function include an assessment of lymphocyte

proliferation in response to nonspecific mitogens (e.g. phytohemagglutinin), specific
antigens (e.g. candida) and/or mononuclear cells from an unrelated,
histoincompatible individual (mixed leukocyte reaction).
■ It is also possible, in specialized laboratories, to measure the production of a number
of different cytokines that are involved in T- and B- lymphocyte regulation (e.g.
Interleukin 2, interferon-gamma).
 LABORATORY DIAGNOSIS OF
IMMUNODEFICIENCY

EVALUATION OF PHAGOCYTIC FUNCTION

■ reductions in phagocytic cell number in the peripheral blood and, therefore, can be
detected by using a white blood cell count and differential.
■ measuring the reduction of nitroblue tetrazolium (NBT test).
 EVALUATION OF THE COMPLEMENT
SYSTEM

■ CH50 assay , this assay requires the functional integrity of C1 through C9.
■ The identification of the individual component which is deficient rests on specialized
functional and immunochemical tests which are specific for each component.
 LAB TESTS IN IMMUNODEFICIENCY

■ Anemia of chronic disease can develop in patients with chronic infections, whereas
pure erythrocyte aplasia can be seen in patients with thymoma and CVID.
 LAB TESTS IN IMMUNODEFICIENCY

■ Persistent lymphopenia can be a sign of cellular immunodeficiency. Lymphopenia is

defined as less than 3000 cells/mm3 in infants, whereas in older children or adults, a
total lymphocyte count of less than 1500 cells/mm3 is abnormal.
 LAB TESTS IN IMMUNODEFICIENCY

■ Thrombocytopenia and small platelet size are characteristic of patients with Wiskott-
Aldrich syndrome.
■ Autoantibodies causing autoimmune hemolytic anemia, thrombocytopenia, or
neutropenia can occur in some of the B-cell immunodeficiencies
LAB TESTS IN IMMUNODEFICIENCY

■ Serum immunoglobulins (IgG, IgM, IgA) is the first step in evaluating humoral or B-cell
immunity
■ Low IgA level - IgA deficiency or other immunoglobulin deficiency diseases.
■ High IgM level - hyper-IgM syndrome
 ROLE OF PEDIATRICIAN

■ Prompt recognition of infection and aggressive treatment are essential to avoid life-
threatening complications and improve prognosis and quality of life. Initiation of early
empiric coverage for suspected pathogens till appropriate cultures obtained.
■ Prophylactic antibiotics are recommended for children with significant T-cell defects
because of the risk for Pneumocystis carinii pneumonia - Cotrimaxazole.
■ Children with B-cell defects who continue to experience recurrent infections despite
adequate intravenous immunoglobulin therapy , should be considered for
antimicrobial therapy to avoid complications, such as bronchiectasis.
 IMMUNISATION

■ Live-attenuated vaccines, such as oral polio, varicella, and BCG should not be given to
children with suspected or diagnosed antibody or T-cell defects, because vaccine-
induced infection is a risk in these patients. Inactivated polio vaccine should be given to
household members to prevent transmission of the virus that can occur by shedding of
the attenuated virus in the stool.
■ Measles-mumps-rubella, varicella, and BCG vaccines can be given to family members
BLOOD TRANSFUSION

■ Only irradiated, leukocyte-poor, and virus-free (i.e., cytomegalovirus) products should

be used in patients with T-cell defects to avoid graft-versus-host disease and
cytomegalovirus infection.
PRIMARY B CELL
IMMUNODEFICIENCIES

1. X-linked Agammaglobulinemia (Bruton's syndrome); btk deficiency

2. Common Variable Immunodeficiency (acquired hypogammaglobulinemia)
3. Selective IgA deficiency (most common immunodeficiency disorder)
4. Other (minor):
(a) Transient hypogammaglobulinemia of infancy
(b) Selective deficiency of IgG subclasses
(c) Immunodeficiency with hyper IgM
B - CELL DEFECTS
AGAMMAGLOBULINE
MIA

■Agammaglobulinemia is the severe of the antibody-deficiency syndromes

■Significant decreases in all major classes of immunoglobulins.
■An absence of circulating B cells .
■Small tonsils and no palpable lymph nodes.
■T cells are present normally, with preservation of delayed hypersensitivity and other
cell-mediated immune functions.
■Neutropenia
 ETIOLOGY

■ X-linked recessive –most commune form

■ XLA is caused by mutations in the Btk gene, located on chromosome Xq 21.3-22
■ autosomal recessive - caused by abnormalities in the mu-chain gene that codes for the
heavy chain of IgM or the B-cell linker protein
 CLINICAL FEATURES

■ Extracellular pyogenic bacterial infections, particularly otitis, sinusitis, and pneumonia,

may begin as early as age 4 to 6 months, when the maternal IgG level decreases.
Approximately 20% of patients present with overwhelming sepsis.
■ Fatal meningoencephalitis with enteroviruses can occur due to lack of Ig A
 DIAGNOSIS

■ The diagnosis is supported by the presence of affected maternal male cousins,

uncles, or nephews.
■ The serum IgG level is usually less than 200 mg/dL.
■ IgM and IgA levels typically are less than 20 mg/DL
 DIAGNOSIS

■ Test for natural antibodies to A & B RBC antigens will be abnormal.

■ Tests for antibodies to routine vaccines will be abnormal.
■ Flow cytometry showing less than 2% CD19+ B cells in circulation.
■ Normal number of Pre B - cells in bone marrow
■ Treatment – prevent complication
– Iv immunoglobulin
– Wide spectrum antibiotics
■ Complications: chronic pulmonary disease, bronchiectasis, autoimmune disease,
malignancies
 COMMON VARIABLE
IMMUNODEFICIENCY
■ CVID is a late-onset, highly variable hypogammaglobulinemic primary immune deficiency
that can occur after age 18 months, with two peaks at approximately ages 1 to 5 years
and 16 to 20 years.
■ It affects approximately 1 in 10,000 to 100,000 general population
■ It is characterized by:
– Variable deficiency of immunoglobulins.
– Normal number of B – cells.
– Normal sized or enlarged tonsils, lymph nodes & splenomegaly.
– Autoimmune diseases.
– Malignancies.
 ETIOLOGY

■ The exact cause is unknown.

■ Most cases of CVID occur sporadically; however, familial inheritance - (Chromosome 6)
may be found in as many as 25% of cases. In 10% of patients, CVID or a related
immunodeficiency disease (e.g., IgA deficiency) is found in more than one family
member
■ CVID is commonly associated with HLA – B8 & HLA – DR3.
PATHOGENESIS

■ T- cell signaling to B- cells is defective in CVID

■ B – cells do not function properly and fail to receive proper signals from T – cells .
■ T- cell defects have not been well defined.
■ Frequent bacterial infections of the ears, sinuses, bronchi, and lungs
■ Painful swollen joints in the knee, ankle, elbow, or wrist
■ Problems involving the digestive tract
■ An enlarged spleen and swollen glands or lymph nodes
 CLINICAL FEATURES

An increased susceptibility to Respiratory tract infections and gastrointestinal infection is

the commune clinical presentation of CVID. RTI may be caused by H. influenzae and S.
pneumoniae, whereas G. lamblia and Campylobacter jejuni are responsible for most
gastrointestinal infection
 CLINICAL FEATURES

■ Autoimmune disorders, such as idiopathic thrombocytopenia (ITP), autoimmune

hemolytic anemia, pernicious anemia, rheumatoid arthritis, systemic lupus
erythematosus, autoimmune thyroiditis, vitiligo, and primary biliary cirrhosis also may
develop in patients with CVID. Sarcoid-like granulomata of the lungs, liver, spleen, and
conjunctivae also may affect patients with CVID.
■ Malignancies are increased in patients with CVID. A 100-fold increased risk for
malignant lymphoma and a 50-fold increased risk for gastric cancer with CVID.
 LAB TESTS

■ Serum concentrations of IgM ,IgG , IgA are reduced .

■ A normal number of B cells .
■ A variable degree of T-cell dysfunction .
■ Isohemagglutinins are absent.
■ Responses to protein and polysaccharide vaccines are poor
SELECTIVE IgA DEFICIENCY
■ It is the most prevalent primary immunodeficiency disease, occurring in approximately
1/500 to 1/1000 general population.
■ Serum IgA levels less than 7 mg/dl with normal levels of other immunoglobulin classes
■ Normal serum antibody responses.
■ Normal cell mediated immunity
ETIOLOGY

■ The exact cause is unknown

■ Since the associated factors like malignancy, family history, autoimmunity are
common to both CVID & IgA deficiency , same genetic cause may be present.
PATHOGENESIS

■ Terminal differention of B – cells fails to result in IgA deficiency.

TYPES

■ ISOLATED IgA DEFICIENCY

■ ASSOCIATED WITH
IgE DEFICIENCY
IgG2 OR IgG4 DEFICIENCY
■ Many people with IgA-deficiency are healthy, with no more than the usual number of
infections. Those who do have symptoms typically have recurring ear, sinus, or lung
infections that may not respond to regular treatment with antibiotics. People with IgA-
deficiency are likely to have other problems, including allergies, asthma, and
autoimmune diseases.
CLINICAL FEATURES

■ Susceptibility to recurrent RTI, GIT infections.

■ RTI may be caused by H. influenzae and S. pneumoniae, whereas G. lamblia
and Campylobacter jejuni are responsible for most gastrointestinal infection.
■ Associated autoimmune disorders may be present.
 DIAGNOSIS

■ serum IgA level of less than 7 mg/Dl

■ normal serum IgG and IgM levels and a normal IgG antibody response to vaccination.
■ Normal number of B – cells.
■ Diagnosed reliably only after age 4 years.
■ Differentiate between
(1) patients in whom no IgA is detected
(2) patients who have low but detectable IgA concentrations
HYPERIgM SYNDROME
■ Hyper-IgM is a rare immunodeficiency disease in which the immune system fails to
produce IgA and IgG antibodies
■ The faulty T cells do not give B cells a signal they need to switch from making IgM to
making IgA and IgG. Most cases of hyper-IgM syndrome are linked to the X
chromosome.
■ Most male patients with the hyper-IgM syndrome have a mutation in the CD40L gene on
the X chromosome. The interaction between CD40 on the B cell and the CD40L on the
activated T cell is essential for the switch from IgM to IgG production, which explains why a
deficiency in CD40L leads to hyper-IgM production with deficient IgG. These patients have
normal or elevated numbers of B cells, normal numbers of T cells and normal T-cell
proliferation
■ In addition to the recurrent RTIs, patients with CD40L deficiency also have an increased
susceptibility to infections with some intracellular pathogens, such as P. carinii pneumonia,
CNS histoplasmosis, and toxoplasmosis. The increased susceptibility to intracellular
pathogens is caused by the role of the CD40L in host defenses against some intracellular
pathogens
■ The hyper-IgM syndrome also should be suspected in the presence of cryptosporidium-
related diarrhea, sclerosing cholangitis, or parvovirus-induced aplastic anemia.
■ Infants usually develop recurring upper and lower respiratory infections within the first
year of life. Other signs of the disease include enlarged tonsils, liver, and spleen, chronic
diarrhea, and an increased risk of unusual or opportunistic infections.
LAB TESTS

Normal numbers of T and B cells.

High levels of IgM
Very low IgG and IgA.
Neutropenia.
HYPOGAMMAGLOBULINEMIA OF
INFANCY
■ Transient hypogammaglobulinemia of infancy is an ill-defined entity in which a child's postnatal
decrease in serum IgG level is accentuated
■ A delay in the onset of endogenous immunoglobulin synthesis occurs, possibly because of
deficiency in T helper cells
■ Most patients have normal IgM and IgA concentrations and a normal circulating B-cell
level. The initial serum IgG levels are typically higher than those of patients with
agammaglobulinemia.
■ IgG concentrations usually normalize by the time these patients reach age 2 or 3 years.
 XLA Hyper IgM CVID HGI

AGE >6m >6m anytime 1-2yrs

IgG low Low Low Low

IgM low High Low Normal

IgA low Low Low Normal

B cell low normal Present Present

CD40
defect B tk unknown unknown
legand
 TREATMENT OF B CELL
DEFECTS

■ General management of patients with immunodeficiency requires an extraordinary

amount of care to maintain optimal health and nutrition, manage infections, prevent
emotional problems related to their illness, and cope with costs.
■ Antibiotics are lifesaving for treating infections; selection and dosage are identical to
those used normally

■ fever or other manifestations of infection are assumed to be secondary to bacterial

infection, and antibiotic treatment is begun immediately. Throat, blood, or other cultures
are obtained before most therapy; these are especially useful subsequently when the
infection does not respond to the initial antibiotic and when the infectious organism is
unusual.
■ Continuous prophylactic antibiotics often are beneficial, particularly in recurrent infection
in agammaglobulinemia despite IG therapy.
■ Immune globulin (IG) is effective replacement therapy in most forms of antibody
deficiency. It is a 16.5% solution of IgG with trace quantities of IgM and IgA for IM or
subcutaneous injection, or a 3 to 12% solution for IV infusion (IVIG).
■ The loading dose is 200 mg/kg given in 2 or 3 doses over 2 to 5 days followed at monthly
intervals by 100 mg/kg .
■ High doses of IVIG (400 to 800 mg/kg/mo) can be given and are beneficial to some
antibody-deficient patients not responding well to conventional doses, particularly those
with chronic lung disease. The aim with high-dose IVIG is to keep IgG trough levels in the
normal range (ie, > 500 mg/dL)

■ Plasma has been used as an alternative to IG, but because of the risk of disease
transmission, it is rarely indicated
T CELL DEFECTS
■ Primary T-cell immunodeficiencies are rare inherited disorders that affect T-cell
development and function.
■ These disorders usually present in infancy or early childhood; however, the age of symptom
onset may vary depending on the underlying gene defect.
■ Although T-cell immune responses may be selectively affected, abnormal B-cell function
often is associated, in part because of concomitant intrinsic B-cell defects but also because
production of most antibodies is dependent on T-cell help
SELECTIVE IGG SUBCLASS
DEFICIENCY
 Total serum IgG levels are normal
 One or more subclasses are below normal.
 IgG3 deficiency is the most common subclass in adults.
 IgG2 deficiency associated with IgA deficiency in children.

 Pathogenesis: abnormal B cell differentiation.

 Some individual have recurrent bacterial infection.
SELECTIVE T-CELL
DEFECTS
DiGeorge Syndrome

■ DGS classically includes

– conotruncal cardiac malformations
– persistent hypocalcemia and
– cellular immunodeficiency
■ secondary to a defect in the development of third and fourth pharyngeal pouches that affects
the parathyroid glands and thymus
■ The specific cardiac anomalies most frequently associated with DGS are interrupted aortic
arch, tetralogy of Fallot, and truncus arteriosus
■ dysmorphic features
■ The immune defects in DGS include
– decreased (<1500 cells/mm3 ) CD3+ T lymphocytes, a CD4+ T-cell count of less
than 1000 cells/mm3 , and impaired cellular immunity
– 50% or less of normal T-cell numbers.
– 20% have in vitro T-cell proliferative responses of less than 50% of normal.

■ Treatment - Bone marrow transplantation.

 Combined B and T cell immunodeficiencies

(1) Severe Combined Immunodeficiency (SCID; a group of genetically determined diseases)

(a) X-Linked combined immunodeficiency (accounts for 50-60% of all SCID; defect in
cytokine receptors)

(b) Adenosine deaminase deficiency (an autosomal recessive SCID; accounts for ~20% of all
SCID)

(c) Other mechanisms of SCIDs: Purine nucleoside phosphorylase deficiency, TCR

immunodeficiency, MHC class I or II deficiency (Bare Lymphocyte Syndrome), Defective
IL-2 production
 SEVERE COMBINED
IMMUNODEFICIENCY
SYNDROMES
■ Severe combined immunodeficiency syndrome (SCID) is a heritable disorder in
children characterized by profoundly defective or absent T-cell and B-cell function
■ Fatal within the first year of life unless curative hematopoietic stem cell
transplantation or, in the case of adenosine deaminase (ADA) deficiency, enzyme
replacement is accomplished
 ETIOLOGY
■ X- LINKED RECESSIVE.
– It accounts for 45% of the cases.
– Occurs due to mutation at Xq 13 which codes for gamma chain of the cytokine
receptors,( IL-2, IL-4, IL-7, IL-9, IL15, IL-21) which mediates intracellular
signalling.
■ AUTOSOMAL RECESSIVE FORM
– There are 6 subtypes.
– Most frequent - Adenosine deaminase deficiency –
■ Accounts for 15% of cases due to mutation at 20q 13.
■ Accumulation of adenosine, 2’ deoxy adenosine, 2’ 0 methyladenosine leads
to T cell apoptosis.
 CLINICAL FEATURES

■ Despite underlying genetic heterogeneity, patients with SCID present similarly within
the first 6 months of life with recurrent diarrhea, pneumonia, otitis media, sepsis,
cutaneous infections.
■ In general, the following infections may develop in affected infants:
– Bacteria
Gram-negative sepsis
Disseminated BCG after immunization
– Fungi and protozoa
Candidiasis
Aspergillus
Pneumocystis carinii pneumonia
– Viruses
Cytomegalovirus
Parainfluenza viruses
Adenovirus
Respiratory syncytial virus
Disseminated varicella
Vaccine-acquired paralytic poliomyelitis
Molluscum contagiosum
■ Failure to thrive secondary to diarrhea and malabsorption also may be present. The
appearance of an early-onset erythematous maculopapular rash unresponsive to
medical management may suggest chronic graft-versus-host disease (GVHD) from
engrafted maternal T cells.
■ Most SCID patients have thymic hypoplasia and absent or small, poorly developed
lymph nodes and tonsils; hepatosplenomegaly may be detected in affected infants
with maternal GVHD
A diagnosis of SCID is suggested when an affected infant has
■ lymphopenia (<1500 cells/mm3; normal range, 4000-13,500 cells/mm3),
■ less than 20% CD3+ T lymphocytes,
■ and severe hypogammaglobulinemia (IgG, <150 mg/dL).
TREATMENT

■ Bone marrow transplantation

OMENN SYNDROME

■ OS is a rare AR disorder described in 1965 by Omenn as SCID characterized by

profound susceptibility to infection with T cell infiltration into skin, intestine,
liver and spleen leading to
Erythroderma
Lymphadenopathy
Hepatosplenomegaly
Failure to thrive secondary to diarrhea
Fever
 PATHOGENESIS

■ mutations in RAG1 or RAG2 that result in partial recombinase activity and the
development of rare activated, but anergic, oligoclonal T cells were identified in
patients with OS.
Laboratory findings
Hypoalbuminemia

Eosinophilia (>1000 cells/mm3 )

Variable lymphocyte counts

Decreased CD3+ T-cell count

low or Absent B cells

Normal NK-cell count

Markedly defective T-cell and B-cell function

Hypogammaglobulinemia

Severely decreased IgG, IgM, and IgA levels

 Wiskott-Aldrich Syndrome

■ Wiskott-Aldrich syndrome (WAS) is an X-linked inherited immunodeficiency

characterized by eczema, congenital thrombocytopenia with small platelets, and
recurrent infections
 ETIOLOGY

■ Due to mutation at Xp11 coding for WASP which is required for microvesicles formation
in blood cells.
 CLINICAL FEATURES

■ Present in the newborn period or early infancy with petechiae, bloody diarrhea,
intracranial hemorrhage, and excessive bleeding from an umbilical stump or after
circumcision
■ Eczema develops in more than 80% of patients and often is seen before 6 months of age
■ Recurrent sinopulmonary infections with encapsulated organisms develop within the first
2 years of life
■ Opportunistic infections, such as Pneumocystis carinii pneumonia and recurrent
herpesvirus infections
■ The prevalence of leukemia, lymphomas of the abdomen and CNS, and Epstein-Barr
virus (EBV) - associated tumors is markedly increased
■ Autoimmune disease, including hemolytic anemia, arthritis, vasculitis, inflammatory
bowel disease, and glomerulonephritis, is seen in approximately 40% of patients with
WAS.
 LAB DIAGNOSIS

■ Lymphopenia (<1000 cells/mm3 ) with declining numbers of CD3+ and CD8+ T cells
■ B-cell and NK-cell numbers remain normal.
■ Normal serum IgG but decreased IgM, in association with defective production of
pneumococcal antibodies and absent isohemagglutinins,
TREATMENT

■ Bone marrow transplantation.

 ATAXIA TELANGIECTASIA

■ Ataxia-telangiectasia (AT) is a complex AR disorder characterized by cerebellar

ataxia, oculocutaneous telangiectasia, radiosensitivity, predisposition to malignancy
and combined immunodeficiency
ETIOLOGY

■ Due to mutation at 11q22.

■ There is incraesed sensitivity to ionising radiation and defective DNA repair.
CLINICAL FEATURES

■ The presenting symptom in AT is ataxic gait seen in more than 85% of patients 4 years
of age
■ The ataxia progressively involves the trunk, extremities, and palatal muscles, resulting
in dysarthric speech, drooling, ocular apraxia, and inability to ambulate
independently by 10 years of age
■ Telangiectasia of the sclerae and skin subsequently develops between the ages of 4 and 8 years
■ recurrent upper and lower respiratory tract infections and chronic lung disease.
■ increased predisposition to T-cell and B-cell malignancies, particularly leukemia and Hodgkin and
non-Hodgkin lymphomas
■ growth retardation, hypogonadism and pubertal delay, and insulin-resistant nonketotic diabetes
mellitus
■ progressive lymphopenia involving both T and B cells, including selective loss of CD4+ T cells, with
inversion of the normal CD4-CD8 ratio.
■ IgA and IgE deficiency in most AT patients and decreased isohemagglutinins and serum IgG2 levels
 TREATMENT

■ Cellular radiosensitivity does not make transplantation a viable option for the
treatment of AT. Moreover, standard chemotherapy protocols cannot be used in the
management of AT-associated malignancies.
■ Some AT patients have survived for several years with lymphoid tumors, but the long-
term outcome is dismal. Most patients with AT do not survive beyond the third decade
of life
 Primary complement deficiencies

Deficiency of Complement Components

 (a) Classic pathway: C1, C4, C2, C3
 (b) Alternative pathway: Factor D, Properdin
 (c) MAC: C5, C6, C7, C8, C9
 (e) Regulator proteins: Factors H, I, C1 inhibitor - Hereditary Angioedema
(C1INH deficiency)
PHAGOCYTE
DEFICIENCIES:

 Chronic granulomatous disease (CGD)

 Leukocyte adhesion deficiency (LAD I)
 Chediak- Higashi syndrome
 IL-12 / IFN pathway deficiencies
 Chronic or cyclic neutropenia
 HUMAN
IMMUNODEFICIENCY
VIRUS (HIV)

ACQUIRED
IMMUNODEFICIENCY
SYNDROME (AIDS)
INTRODUCTION
■ HIV Etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). RNA
retrovirus
■ first recognized 1981 - Los Angeles - pneumocystic pneumonia in 5 young
homosexuals - 2 died
■ Discovered independently by Luc Montagnier of France and Robert Gallo of the
US in 1983-84.
■ Former names of the virus include:
– Human T cell lymphotrophic virus (HTLV-III)
– Lymphadenopathy associated virus (LAV)
– AIDS associated retrovirus (ARV)
■ severe immunosupression - opportunistic infections, secondary tumors, neurologic
symptoms
■ 1998 - 33,4 million of infected (22,5 in sub-Saharian Africa)
■ number of both infected and ill patients increases - USA, Africa (2/3 of all cases in the
world), Southeast Asia (Thailand, India, Indonesia)
Epidemiology - 6 risk groups

■ 1. homosexual males (60%)

■ 2. intravenous drug abusers (24%)
■ 3. hemophiliacs (1%)
■ 4. other blood recipients (2%)
■ 5. heterosexual partners of other high-risk groups members
■ 6. children of parents from groups 1.-3. - transplacentar

■ HIV cannot be transmitted by casual personal contact !!!

■ No transmission from patient to doctor (and vice versa) by casual contact !!!
■ Prevention of injury - needle sticks, etc.; operation or autopsy - special precautions
■ HIV-1 and HIV-2 - closely related
■ long incubation period
■ tropism for lymphocytes and nervous system
■ immunosupression - CD4+ T-cells (helpers)
■ slowly progressive fatal outcome
 Progression of AIDS

1. Infection

2. viremia (increase of the virus load in blood)

3. immune response to HIV: generation of Tc cells and antibody to

HIV (seroconversion)

4. temporary reduction of virus-infected CD4 T cells (due to HIV-

induced apoptosis and T cell attack)

5. partial recovery of CD4 T cell number

6. gradual decrease of CD4 T cell number over 2-15 years (clinical

latency is a period of active infection and CD4 T cell renewal)

7. AIDS (CD4 T cell count < 200)

 Primary HIV Syndrome
■ Mononucleosis-like, cold or flu-like symptoms may occur 6 to 12 weeks after infection.
– lymphadenopathy
– fever
– rash
– headache
– Fatigue
– diarrhea
– sore throat
– neurologic manifestations.
– no symptoms may be present
Primary HIV Syndrome

■ Symptoms are relatively nonspecific.

■ HIV antibody test often negative but becomes positive within 3 to 6 months,
this process is known as seroconversion.
■ Large amount of HIV in the peripheral blood.
■ Primary HIV can be diagnosed using viral load titer assay or other tests.
■ Primary HIV syndrome resolves itself and HIV infected person remains
asymptomatic for a prolonged period of time, often years.
Clinical Latency Period

■ HIV continues to reproduce, CD4 count gradually declines from its normal value
of 500-1200.
■ Once CD4 count drops below 500, HIV infected person at risk for opportunistic
infections.
■ The following diseases are predictive of the progression to AIDS:
– persistent herpes-zoster infection (shingles)
– oral candidiasis (thrush)
– oral hairy leukoplakia
– Kaposi’s sarcoma (KS)
AIDS
■ CD4 count drops below 200 person is considered to have advanced HIV disease
■ If preventative medications not started the HIV infected person is now at risk
for:
– Pneumocystis carinii pneumonia (PCP)
– cryptococcal meningitis
– toxoplasmosis
■ If CD4 count drops below 50:
– Mycobacterium avium
– Cytomegalovirus infections
– lymphoma
– dementia
– Most deaths occur with CD4 counts below 50.
Opportunistic infections and malignancies kill HIV patients

Figure 9-22
Other Opportunistic Infections
■ Respiratory system
– Pneumocystis Carinii Pneumonia (PCP)
– Tuberculosis (TB)
– Kaposi's Sarcoma (KS)
■ Gastro-intestinal system
– Cryptosporidiosis
– Candida
– Cytomegolavirus (CMV)
– Isosporiasis
– Kaposi's Sarcoma
■ Central/peripheral Nervous system
– Cytomegolavirus
– Toxoplasmosis
– Cryptococcosis
– Non Hodgkin's lymphoma
– Varicella Zoster
– Herpes simplex
■ Skin
– Herpes simple
– Kaposi's sarcoma
– Varicella Zoster
Infants with HIV

■ Failure to thrive
■ Persistent oral candidiasis
■ Hepatosplenomegaly
■ Lymphadenopathy
■ Recurrent diarrhea
■ Recurrent bacterial infections
■ Abnormal neurologic findings.
Laboratory Diagnosis of HIV Infection

■ Methods utilized to detect:

– Antibody
– Antigen
– Viral nucleic acid
– Virus in culture
ELISA Testing

■ ELISA tests useful for:

– Screening blood products.
– Diagnosing and monitoring patients.
– Determining prevalence of infection.
– Research investigations.
Western Blot

■ Antibodies to p24 and p55 appear earliest but decrease or become

undetectable.
■ Antibodies to gp31, gp41, gp 120, and gp160 appear later but are present
throughout all stages of the disease.
■ ‘Gold Standard’ for confirmation
 Polymerase Chain Reaction (PCR)

■ Looks for HIV DNA in the WBCs of a person.

■ PCR amplifies tiny quantities of the HIV DNA present, each cycle of PCR results in
doubling of the DNA sequences present.
■ The DNA is detected by using radioactive or biotinylated probes.
■ Once DNA is amplified it is placed on nitrocellulose paper and allowed to react with a
radiolabeled probe, a single stranded DNA fragment unique to HIV, which will
hybridize with the patient’s HIV DNA if present.
■ Radioactivity is determined.
Testing of Neonates

■ Difficult due to presence of maternal IgG antibodies.

■ Use tests to detect IgM or IgA antibodies, IgM lacks sensitivity, IgA more promising.
■ Measurement of p24 antigen.
■ PCR testing may be helpful but still not detecting antigen soon enough: 38 days to 6
months to be positive.
The Move Toward Lower Pill Burdens
Regimen Dosing Daily pill burden

1996
Zerit/Epivir/Crixivan 10 pills, Q8H

1998
Retrovir/Epivir/Sustiva 5 pills, BID

2002
Combivir (AZT/3TC)/EFV 3 pills, BID

2003
Viread/ Emtriva/Sustiva 3 pills, QD
2004
Truvada/Sustiva 2 pills, QD
■ SPECIFIC TREATMENT OPTIONS
■ Currently available treatment techniques include bone marrow transplantation,
immunoglobulin replacement, and enzyme-replacement. Gene therapy for some
diseases has been initiated in clinical trials.
■ Genetic counseling is important not only for a child's parents but also for siblings .
■ Prenatal diagnosis can be established by performing analyses on fetal blood samples,
amniotic fluid cells, or chorionic villus biopsy specimens.