Immunodeficiency Disorders

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Clinical evaluation:

Þ    Signs of immunodeficeincy disorders primarily include recurrent infections, chronic infections, usually (opportunistic) infecting agents

 Þ    When immunodeficiency is suspected on the basis of persistent and recurrent infections, the workup should include an evaluation of the patients native and acquired immune capabilities

Clinical features

Highly suggestive features

            Infections recurrent or chronic characterised by:

                        Opportunistic infections

                        Normal flora

                        Common environmental organisms

            Slow recovery or poor response to treatment

Features frequently seen are

            Chronic diarrhoea

            Eczema

            Failure to thrive

            Hepatosplenomegaly

            Autoantibodies or autoimmune disease

Initial Evaluation of a patient suspected of Immunodeficiency

Management of the Immunodeficient Patient

Treatment of immunodeficiency has two goals:

A.     Minimize the occurrence and impact of infection by:

1.     Avoidance of contact with people with contagious disease

2.     Close monitoring of patients for infection

3.     Prompt and vigorous use of antibiotics when appropriate

4.     Active or passive immunization if possible

B.      Replace the defective component of the immune system by passive transfer or transplantation:

1.     Administration of pooled gamma globulin to patients with certain immunodeficiencies e.g. Burton’s hypogammaglobulinemia

2.     Infusion of cytokines e.g. IL2, GM - CSF IFN - gamma in particular diseases

3.     Transfusions - Neutrophils in phagocytic defects. Irradiated erythrocytes in treatment of ADA deficiency

4.     Transplantation of fetal thymus or bone marrow stem cells in attempts to restore immune competence

SPECIFIC IMMUNODEFICIENCY DISORDERS

I.     Quantitative Defects

Neutropenia or Granulocytopenia

    1. Causes of decreased neutrophil production

a.      Administration of bone marrow depressant drugs

b.     Leukemia

c.      Inherited conditions with defective development of stem cells

d.     Spontaneously arising autoantibody that inhibits granulopoiesis

     2. Causes of increased neutrophil destruction

a.      Autoimmune phenomenon following administration of certain drugs (e.g.                quinine,  oxacillin ) that may induce antibodies capable of opsonising normal neutrophils

b.     Hypersplenism characterised by exaggeration of the destructive functions of the spleen with resultant deficiency of peripheral blood elements

Asplenia

Asplenia whether congenital, surgical or due to organ destruction by malignancy or sickle cell disease, can result in increased incidence of infections, particularly septicemia caused by Streptococci pneumoniae

II.  Qualitative Defects

     The phagocytes fail to engulf and kill the micro-organisms. The defect may involve any of the phagocytic activities: chemotaxis, ingestion, killing or digestion.

Chronic granulomatous disease (CGD)

Þ    Recurrent infections by both Gram positive and Gram negative organisms e.g. Escherichia, Serratia, Klebsiella, Staphylococci

Þ    X-linked recessive disorder

Þ    Appears in the first 2 years of life

        Clinical and Immunological features:

·        Ganuloma formation occurs in many organs reflecting the body’s attempt to mount a T cell response to compensate for the inability of the neutrophils to kill the organisms

·        Enzymatic inability to produce toxic oxygen metabolites, resulting from a defect in the neutrophilic cytochrome b which is a part of an enzyme complex catalysing the conversion of oxygen to superoxide

·        Superoxide dismutase converting superoxide to hydrogen peroxide is normal

·        Myeloperoxidase generating hypochlorite from hydrogen peroxide and chloride ions is also normal

·        The neutrophils of patients with CGD are unable to kill bacteria such as Staphylococci and Pseudomonas aeruginosa that produce the enzyme catalase because:

a.      Catalase breaks down the small amount of hydrogen peroxide produced in cells and protects the microbe

b.     Catalase negative bacteria are less of a problem because they cannot detoxify the phagosome and also they generate hydrogen peroxide themselves, thus contributing to their own death

           Diagnosis:

           Depends upon the invitro demonstration of defective killing

           Treatment:

·        Use of antibiotics

·        Interferon - gamma may stimulate the production of superoxide anions and may restore microbicidal activity of the neutrophils

Glucose - 6 - phosphate dehydrogenase (G6PD) deficiency

An X - linked immunodeficiency state with a clinical picture similar to CGD along with hemolytic anemia. The disorder is due to the deficient generation of NADPH, which is a necessary reducing equivalent for the oxidase.

Myeloperoxidase Deficiency

Presents with recurrent microbial infections. There is increased susceptibility to Candida albicans and S. aureus infections.

a.      Superoxide and hydrogen peroxide are formed in normal amounts, but because the myeloperoxidase enzyme is lacking, neutrophil killing is impaired

b.     Treatment involves the use of appropriate antimicrobial agents

Chediak - Higashi Syndrome

        Clinical and Immunological features:

·        Partial albinism and recurrent severe pyogenic infections which are primarily streptococcal and staphylococcal

·        Prognosis is pook with a majority of patients dying in childhood

·        The patients neutrophils contain abnormal giant lysosomes, which can apparently fuse with the phagosome but are impaired in their ability to release their contents, thus resulting in delayed killing of ingested microorganisms

        Diagnosis:

·        Neutrophil chemotaxis and killing are abnormal, NK activity is decreased and lysosomal enzymes are depressed

·        Oxygen consumption, hydrogen peroxide formation and HMP activity are normal

Jobs Syndrome

        Clinical features:

·        Recurrent cold, staphylococcal abscesses, chronic eczema and otitis media

·        Neutrophils have a defective chemotaxis

·        Serum levels of IgE are extremely high in association with increased specificity with staphylococcal antigens

        Treatment:

·        Consists of appropriate antimicrobial agents

“Lazy Leucocyte Syndrome”

        Clinical features:

·        Susceptibility to severe microbial infections

·        Patients have neutropenia, defective chemotaxis and abnormal inflammatory response

        Treatment:

·        Use of suitable anti microbials

Tuftsin Deficiency

It is a familial absence of tuftsin, a phagocytosis promoting serum tetrapeptide that is cleaved from an immunoglobulin - like molecule, leukokinin, in the spleen. Asplenic people lack tuftsin.

Such patients have repeated infections with C. albicans, S. aureus and S. pneumoniae.

Leukocyte Adhesion Deficiency

A rare immunodeficiency disorder with recurrent bacterial and mycotic infections and impaired wound healing.

Burton’s X- Linked Hypogammaglobulinemia

        Clinical features:

·        Susceptibility to severe microbial infections that do not induce Ig synthesis

·        Infections like sinusitis, pneumonia, meningitis caused by organisms like Streptococci, Haemophilus, Staphylococci and Pseudomonas begin when the infant is 5 - 9 months of age

        Immunologic Findings:

·        Low serum levels of all classes of Immunoglobulins

·        Lack of circulating B cells

·        Lack of germinal centers and plasma cells in lymph nodes. Absent or hypoplastic tonsils and peyers patches

·        Intact T cell function

        Treatment:

I/M or I/V injections of pooled human Ig which are usually administered monthly. Treatment of specific infections.

Transient Hypogammaglobulinemia Of Infancy

Ig synthesis particularly Ig G synthesis is delayed. Condition resolves on its own by 15 - 30 months of age. Treatment involves administration of antibiotics or gamma - globulin or both.

Common Variable Hypogammaglobulinemia

        Clinical features:

·        Resembles Burton’s hypogammaglobulinemia except that the symptoms first appear when the patient is 20 - 30 years of age

·        High incidence of associated autoimmune diseases

        Immunologic Findings:

·        Number of B cells normal but their ability to synthesize or secrete immunoglobulin is defective

·        A defect in T helper cell triggering of B cells is suspected

        Treatment:

I/M or I/V injections of pooled human Ig which are usually administered monthly. Treatment of specific infections.

Selective Immunoglobulin Deficiency

In relation to a decrease in Ig A levels

        Clinical features:

·        Recurrent sinopulmonary infections, gastrointestinal disease, autoimmune disease, malignancy and allergy

        Immunologic Findings:

·        Serum levels of  Ig A are decreased but those of Ig M ard Ig G are normal or decreased

·        Ig A bearing B cells are present in normal numbers but they are defective in their ability to synthesize or release Ig A, possible because of the presence of hyperactive Ts cells or excessive number of Ts cells

        Treatment:

These patients should NOT be treated with pooled human gamma-globulin because an anaphylactic sensitivity may be induced in the recepient by infusion of the missing immunoglobulin. Aggressive antibiotic therapy to control the infectious agent must be used.

DiGeorge Syndrome

(congenital thymic hypoplasia)

        Etiology:

·        Caused by the faulty development of the third and fourth pharayngeal pouches during embryogenesis

·        Absence or hypoplasia of both the thymus and parathyroid glands occurs

·        The basis of the developmental defect is not known. An association with maternal alcoholism is evident in some cases.

        Clinical features:

·        Cellular immunodeficiency with profoundly impaired T-cell function.

·        Recurrent infection with fungal, viral, protozoan and certain bacterial agents

·        Hypoparathyroidism leads to hypocalcemic tetany

·        Facial appearance is abnormal with a fish shaped mouth and low set ears

·        Cardiac anomalies are usually present

        Immunologic Findings:

·        Lymphopenia is usually found. T-cells are reduced in number

·        Delayed hypersensitivity reactions and the ability to reject grafts is impaired

·        Most have normal immunoglobulin levels

        Treatment:

·        Transplantation of a thymus from an aborted fetus can result in permanent reversal of the syndrome. The fetus should not be older than 14 weeks gestation to avoid graft versus host reaction

·        Hypocalcemia can be controlled by the administration of Vitamein D and calcium

·        In most patients the condition improves with age, even without thymic transplants. Patients are relatively normal by the age of 5 or 6 years. Extra thymic sites probably serve as areas for T cell maturation or typical thymic and parathyroid tissues develop ectopically

Chronic Mucocutaneous Candidiasis

(Infection of the skin and mucous membranes with C. albicans)

        Immunologic Findings:

·        TLC appears to be normal. Presence of T cells is confirmed through their response to PHA and E - rosette test

·        T cells show an impaired ability to produce macrophage migration inhibition factor (MIF) in response to Candida antigen, although their response to other antigens may be normal

·        The delayed hypersensitivity response to the Candida antigen is also negative

·        The antibody response to the candida antigen is normal

        Treatment:

·        Antifungal drugs and thymic transplant have given variable results

·        Patients must be observed carefully for the onset of endocrine dysfunctions, particularly Addison’s disease which is a major cause of death

Bare Lymphocyte Syndrome

A recently described autosomal recessive immunodeficiency characterised by a deficiency in the expression of class II MHC gene products on the T cell Surface

Severe Combined Immunodeficiency Disease ( SCID)

It is an X linked recessive or autosomal recessive disease that involves a combined defect in both humoral and cell mediated immunity. Patients usually die within the first or the second year of life from overwhelming microbial infections.

        Immunologic Findings:

·        Classically SCID is associated with lymphopenia and hypoplasia of the thymus. Affected people do not have T cells and are unable to mount a humoral immune response

·        The autosomal recessive form of SCID often involves an enzyme defect:

a.      About 50% of the patients with autosomal recessive form have an ADA deficiency

ADA is widely distributed in the mammalian tissues but is particularly abundant in RBC and lymphocytes. Its deficiency leads to the accumulation of metabolites that are toxic to lymphocytes because thay block DNA synthesis

b.     Another form of SCID is caused by a deficiency of the purine nucleotide phosphorylase (PNP) , an enzyme involved in purine catabolism. This defect also leads to the accumulation of catabolites toxic to DNA synthesis

        Treatment:

·        Specific antibodies and gamma globulin are helpful but successful immunologic reconstitution requires transplantation of histocompatible bone marrow

·        Transplantation of fetal liver and thymus has also shown some promise

·        Therapy for ADA deficiency form of SCID:

                        Irradiated erythrocytes have been used as an enzyme source

                        ADA deficiency has been successfully treated using gene therapy

Nezelof’s Syndrome

It is a group of several disorders that have similar immunologic features. All patients with this syndrome are susceptible to recurrent microbial infections but their clinical presentations may vary.

        Immunologic Findings:

·        T cell immunity is markedly reduced

·        B cell deficiency varies

        Treatment:

·        Fetal thymic transplant has shown some been somewhat successful

·        Aggressive treatment of infections with specific antibiotics and gamma globulin is useful

Wiskott Aldrich Syndrome

Has 3 main features :

Þ    Thrombocytopenia which is present at birth

Þ    Eczema, usually present by the age of 1 year

Þ    Recurrent pyogenic infections beginning after 6 months of age

        Immunological features:

·        Serum Ig M levels are low, Ig G levels are normal.

·        Levels of Ig A and Ig E are elevated

·        The number of B cells are normal

·        T cell immunity is usually intact in the early phases of the disease but wanes as the disease progresses

        Treatment:

        Vigorous use of antibiotics and bone marrow transplantation

Ataxia - telangiectasis

An autosomal recessive disease that involves the nervous, endocrine and the vascular system.

        Clinical Features:

·        Un co-ordinated muscle movements and dilatation of the small blood vessels that is readily observed in the sclera of the eye

·        First appears in children below 2 years of age and is associated wit repeated sinopulmonary infections

        Immunologic Findings:

·        Selective Ig A deficiency is apparent

·        T cell deficiency is variable. First appears in children below 2 years of age and is associated with repeated sinopulmonary infections

        Treatment:

Antibiotics for sinopulmonary infections. Fetal thymic transplant and bone marrow transplant is of uncertain value.

Other immunodeficiency Conditions may be secondary to measles, AIDS.

C1 esterase inhibitor (C1 INH) deficiency:

Associated with hereditary angioedema, a condition characterised by transient but recurrent localized edema

The defect leads to uncontrolled C1s activity and the resultant production of a kinin that increases capillary permeability

The skin, GI tract and respiratory tract may be affected. Laryngeal edema may be fatal

C1q deficiency:

It is reported to be associated with hypogammaglobulinemia, SCID and repeated infections. The level of C1q in affected people appears to be 50% of the normal level

C2 and C4 deficiency:

Cause a disorder similar to SLE, possibly as a result of a failure of complement dependant mechanisms to eliminate immune complexes

C3 deficiency:

Can result in severe, life threatening infections, particularly with Neisseria meningitidis and S. Pneumonia. Absence of C3 means that the chemotatic fragment of C5a is not generated. C3b is not deposited on membranes and impaired opsonization results

C5 deficiency:

Increased susceptibility to bacterial infections associated with impaired chemotaxis

C6, C7 and C8 deficiency:

Results in increased susceptibility to meningococcal and gonococcal infections because complement mediated lysis is a major control mechanism in immunity against Neisseria

In patients with these protein deficiencies, the severity of the Neisserial infections is greater and the incidence of arthritis, sepsis and disseminated intra vascular coagulopathy is increased

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