Immune Deficiency

Immunoglobulin levels vs. age

Types of immunity

Innate (natural) immunity responds to infection regardless of previous

exposure to the agent

Ex: PNL, phagocytic cells, complement system

Acquired (adaptive) immunity develops as a result of exposure to previous

immunogens

Ex: T lymphocytes, B lymphocytes, NK cells

Immunologic defects

(1) T cell

(2) B cell

(3) Macrophage

(4) Complement

• Primary immunodeficiency

Inherited genetic defects in the immune cell development or

function or inherited deficiency in a particular immune molecule

• Secondary immunodeficiency

Loss of previously functional immunity due to infection, toxicity,

radiation, splenectomy and malnutrition

When to suspect immunodeficiency ?

Family history of immunodeficiency

Failure to thrive

Need for IV antibiotics and or hospitalization to clear infection

4 or more ear infections with in one year

2 or more episodes of sepsis or meningitis in a life time

2 or more months of antibiotic treatment with little effect

Recurrent or resistant candidiasis

Serious infections occuring at unusual sites (brain, liver abscess)

Infection with opportunistic organisms

Complications from live vaccines (rota virus, varicella)

Non healing wounds

Granulomas

Lymphoma in infancy

Features suggestive of PID in neonates

Hypocalcemia

Congenital heart defects (conotruncal anomalies)

Absence of thymic shadow in CXR

Delayed umbilical cord detachment (>30 days)

History

Birth history – maternal illness, drug intake, length of gestation, birth weight

neonatal problems, umbilical cord detachment

Feeding history

Growth and development

Immunization history – especially live vaccines (OPV, rota virus vaccines),

vaccine failure

Previous illnesses, school abscences

Family history

Consanguinity (autosomal recessive immunodeficiencies)

Infection history

1. Age of onsetBirth to 6 months – congenital neutropenias, leukocyte adhesion defects, severe combined immunodeficiency (SCID), and complete DiGeorge syndrome.6 months to 2 years – normal child, child with allergy. Persistent diarrhea, chronic cough, or failure to thrive suggests cystic fibrosis, or PID2 to 6 years – children developing infection in this age group may also fit into any of the 4 categories. Secondary immunodeficiencies resulting from malignancy, nephrotic syndrome, or gastrointestinal problems start at this age6 to 18 years – it is unusual for recurrent infections to first present beyond the age of six

2. Sites of infection:Upper respiratory tract

Most common site, usually viralChronic purulent nasal discharge and cough chronic siunsitisChronic or seasonal clear nasal discharge, congestion, itchy

eyes, nocturnal cough allergic diseaseRecurrent oral thrush, stomatitis, gingivitis, t-cell and

phagocytic cell disorderLower respiratory tract

Recurrent pneumonia is rare in normal children or children with allergic diseaseSuggest chronic cardiopulmonary disease or immunodeficiencyRecurrent pneumonia limited to a particular anatomic region local anatomical abnormality

Blood and brain

Bacterial meningitis and sepsis suggest antibody deficiency or complement

defect

Chronic enteroviral encephalomyelitis occurs in patients with profound

antibody deficiency and commonly follows OPV

Other

Recurrent and or chronic GIT infections occur in patients with IgA

deficiency

Recurrent UTI is uncommon in immunodeficiency and suggests structural

abnormality

Abscesses of the skin, intestine, or LN suggest phagocytic or antibody

deficiency

3. Isolated organisms

Recurrent sinopulmunary infections with encapsulated organisms

B cell abnormalities

Pneumocystis carnii is the hallmark of SCID and other T cell defects

Enteroviral meningoencephalitis x-linked agammaglobulinemia

Recurrent staph infections hyperimmunoglubulin E syndrome

Severe candidiasis abnormal t cell immunity

Organisms that suggests an immunodeficiency

Organism disease

Pneumocystis jiroveci HIV,SCID,HyperIgM,XLA

Serratia marcescens Chronic granulomatous disease

Aspergillus, nocardia Chronic granulomatous disease

Psedomonas sepsis XLA,ARA

Mycobacteria/salmonella IFN-gamma,IL12 pathway

Physical Examination

General appearance, dysmorphic features

Failure to thrive (growth charts)

Discharging ears, perforated tympanic membrane suggest

immunodeficiency

Pallor without anemia, allergic shiners, conjunctivitis, transverse nasal

crease, clear nasal discharge, suggest allergy

Mouth ulcers, gingivitis, oral thrush, poor dentition, suggest

immunodeficiency

Atopic dermatitis (eczema) suggest allergic disease.

• Immunodeficiencis associated with eczema: wiskott-aldrich, hyper IgE,

SCID,

• Diminished or absent tonsils and cervical lymph nodes in the presence

of recurrent respiratory infections suggest antibody deficiency

• Absence of lymphoid tissue suggest SCID or x – linked

agammaglobulinemia

• Adenopathy and HSM can be seen in IgA deficiency, common variable

immunodeficiency, and HIV infection.

Characteristic features of primary immunodeficiencyCharacteristic Predominant T-

cell defectPredominant B-cell defect

Granulocyte defect

Complement defect

Age Early onset,2-6mo

After maternal antibodies diminish,>5m

Early onset Any age

Sp pathogen involved

Bact:mycobactViruses:CMV,EBV,adenoFungi:candida

Bacteria: strep.staphylo,hemophilusVirus:entero

Bact:staph,pseudo,klebsiella

Neisseria,E-coli

Affected organ FTT,protracted diarrhea,

Recurrent sinupulmonary infections,GI infections,malabsorption

Skin abscess,suppurative adenitis

Meningitis, Recurrent sinupulmonary infections

Special features GVH diseases,post vaccination,disseminated BCG

Autoimmunity,lymphoma,post vaccination paralytic polio

Prolonged attachment of umblical cord,poor wound healing

Rheumatoid disotder:SLE,Vasculitis,glomerulonephritis

Clinical patterns of immunodeficiencyWiskott – aldrich syndrome : petechiae, easy bleeding, eczema, chronic draining ears

Ataxia – telangiectasia: ataxia, telangiectasia, developmental delay

Warts hypogammaglobulinemia infections myelokathexis (WHIM) syndrome : extensive warts or molluscum contagiosum

Hyper IgE syndrome: coarse features, chronic infected eczema, deep seated abscesses

DiGeorge syndrome: short stature, CHD, developmental delay, low set ears, downturning eyes, micrognathia

Chediak Higashi disease: oculocutaneous albinism

Laboratory Evaluation

Initial tests (screening evaluation) – should be done for all children with

recurrent infections

Abnormalities of these initial tests may suggest allergy, immunodeficiency or

a chronic illness, and will need further investigations

If screening tests are normal, the patient’s family can be reassured that a

serious disorder has been excluded.

General screening tests

Complete Blood CountWith special attention paid to the total absolute lymphocyte count:

lymphopenia <1500cells/uL in patients over 5 years or <2500 cells/uL inyounger children

Eisinophilia suggests allergyThrombocytosis suggests chronic inflammation

Electrolytes, glucose, KFT, albuminUrine analysisESR, CRP, appropriate cultures should be done for evaluation of infectionChest X-ray

should be done if the child has chronic cough or other features suggesting lung problems it should also be done in newborns presenting with recurrent infections for assessment of thymic size

Other initial investigations:

Immunoglobulin levels:

Antibody defeciency is suggested by:

◦ IgG <200 mg/dL

◦ Total Ig (M + G + A) <400 mg/dL

◦ Complete absence of IgM or IgA

An elevated IgE (>100mg/dL) suggests allergy, eczema, or chronic skin

infections or may be found in hyper IgE syndrome, phagocytic disorders

Intermediate tests for immunodeficiency

These tests are indicated when the screening tests are abnormal or the

clinical picture is highly suggestive for an immunodeficiency.

Antibody titres The function of the antibody system is best assessed by

checking antibody titres to previously administered vaccines (tetanus,

diphtheria, and hemophilus influenza type b.

Complement activity should be assessed in patients with recurrent sepsis

of neisserial infection. A normal level of CH50 excludes nearly all

hereditary complement deficiencies. Levels of individual complement

componenets are measured of the CH50 is significantly reduced or zero.

Diagnostic tests

Should be done when previous tests are abnormal or if there is a convincing

history of immunodeficiency.

Lymphocyte subset analysis: done by flow cytometry including CD3 (total T

cells), CD4 (T helper), CD8 (cytotoxic), CD19 or CD20 (B cells) and CD16/56

(natural killer cells) is done when B or T cell defect is suspected.

• CD4 is the most valuable reflection of the cellular immune system

• CD19 (B cell) count <100 cells/uL suggests hereditary agammaglobulinemia

• A low CD16/56 count suggests a NK cell deficiency

Vaccine challenge

Vaccine responsiveness is used to further assess the antibody system.

A killed vaccine that has not been administered previously is given and titres

are measured before and 6 weeks after vaccination.

Other tests

HIV Testing should be done in any patient suspected of a T cell deficiency

Lymphoproliferative Assays these are in vitro assays used to further assess

the cellular immune system

Management of the child with recurrent infection

1. Infections should be promptly recognized and treated with emperic

antibiotic therapy until appropriate culture results are available

2. Prophylactic antibiotics may be administered

3. Live – virus vaccines and live BCG vaccines must not be administered to

the child

4. Only irradiated, leukocyte - poor, virus free should be used if blood

transfusion is necessary

5. IVIG should not be administered until there has been a thorough

evaluation of the childs immune system. (expensive, side effects)

Initial immunologic testing of the child with recurrent infections

Complete blood count, differential, ESR• Lymphocyte, neutrophils, platelets,• Howell jolly bodies, ESRScreening tests for B-cell cefects• IgA, if abnormal IgG, IgM measurement• Isohemagglutinins• Antibody titres to tetanus, diphtheria, H.influenzaeScreening test for Tcell defect• Absolute lymphocyte count• Candida albicans intradermal testScreening test for phagocytic cell defect• Absolute neutrophil count• Respiratory burst assayScreening test for complement deficiency• CH50