Approach ofPrimary Immune Deficiencies

شیرکانی افشین دکتر

ایمنی نقص های بیماری و آلرژی و آسم تخصص فوقدانشگاه استادیار

آمریکا ایمونولوژی و آلرژی و آسم آکادمی عضو

Comparison of hypersensitivity reactions

reaction

Lymphocyte

Effector cells

Antibody Antigen Time Complement

Diseases

Type I B Eosinophils and basophils

IgE Allergen 15-20 min

- Asthma, atopic dermatitis urticaria

Type II B PMN IgM , IgG Surface Ag

? + Hemolytic disease of newborns

Type III

B PMN IgM, IgG Soluble Ag

6-8 h + SLE

Type IV

T Macrophages

- Intracellular Ag

24-72 h _ Tuberculosis

Immunity Innate & Adaptive

• First line of defense• Nonspecific• Rapid onset• No protective

immunity• No memory• Phagocyte-

mediated

• Activated• Very specific• Slower• Protective immunity

possible• Memory possible• Lymphocyte-

mediated

Definition

• Any defect in the integrity of the immune systems – It may be congenital or late onset– It may be inherited or non hereditary – It may be in innate or adaptive parts of immune

system

Components of Immunity• Skin and mucosal barriers

• Innate immune system (nonspecific)–Phagocytic cells, NK cells, complement

• Adaptive immune system (specific)–T and B lymphocytes, antibodies

Increasing susceptibility to infections

Increasing duration of infections

Increasing severity of infection

Continuous illness

Dependence to antibiotics

Infection with opportunistic agents

Unusual infection

Characteristics of infections

Eight or more new ear infections within 1 year.

Recurrent, deep skin ororgan abscesses.

Two or more serious sinus infections within 1 year.

Persistent thrush in mouth orelsewhere on skin, after age 1.

Two or more months on antibiotics with little effect.

Need for intravenousantibiotics to clear infections.

Two or moredeep-seated infections.

A family history ofPrimary Immunodeficiency.

Two or more pneumonias within 1 year.

Failure of an infant to gainweight or grow normally.

The 10 Warning Signs Of Primary Immunodeficiency

Primary Immunodeficiency

• B cell (Antibody ) system• T cell (cellular ) system• Phagocyte (PMN and mononuclear )• Complement

Classification of Immunodeficiency

1. Humoral (B-cell) – quantitative or qualitative defects in antibody production account for more than 50% of defects.

2. Cellular (T-cell) – usually combined with humoral; account for 20-30%.

3. Phagocytic – defects in migration, or killing; account for ~18%.

4. Complement – account for ~2%

About %40 of cases are diagnosed in the first year

Another %40 by age 5 years

Another %15 by age 16

Only %5 in adulthood

About %10 of registered cases are adults

Late-onset Patients exhibit CVID

• Common Risk Factors for Frequent Infections– Day-care, school– Second-hand smoke– Atopy– Anatomic abnormalities including ciliary

defects– Retained foreign body– Gastroesophageal reflue– Cystic fibrosis

Children referred for evaluation for immuno deficiency

%50 Turn out to be normal

%30 have allergy

%10 have a serious but nonimmunologic

disorder

Only %10 have an immunodeficiency

Allergic disorders in contrast to immunodeficiency

Absence fo fever

Clear nonpurulent discharge

Prior history of colic, food intolerance, ezema or other

allergic symptoms

A Positive family history of allergy

A Characteristic seasonal or exposure pattern

Poor respons to antibiotic

Good respons to antihistamines or bronchodilators

Approach for Suspected Immune Deficiency are as

following:

FAMILY HISTORY

Consanguinity of the parents

History of a sibling dying early in life of infections

Family history of an X-linked or autosomal recessive inheritance of a primary immunodeficiency

GENERAL

• Complete blood count, including hemoglobin, differential white blood cell count(ALC , ANC) and morphology, and platelet count,ESR

• Radiographs to document infection in chest, sinus, mastoids, and long bones, if indicated by clinical history

• Cultures, if appropriate

History Our Guide

• Predominant B-Cell defects– Onset after maternal antibodies diminish, usually

after 5-7 mos, later childhood to adulthood.– Bacteria: strep, staph, H.flu; Campylobacter,

enteroviruses, giardia, cryptosporidia– Recurrent sinopulmonary infections, chronic GI

symptoms, malabsorption, arthritis, viral meningoencephalitis

– Autoimmunity, lymphoreticular malignancy; thymoma, lymphoma

SCREENING TESTS FOR B CELLIMMUNE FUNCTION

• Quantitative serum immunoglobulins• Specific antibodies to vaccine responses• Tetanus, diphtheria (IgG1)• Pneumococcal and meningococcal polysaccharides (IgG2)• Viral respiratory pathogens (IgG1 and IgG3)• Other vaccines: hepatitis B, influenza, MMR, polio (killed vaccine)• Isohemagglutinins (IgM antibodies to A and B blood group• antigens)• B cell quantitation by flow cytometry

Laboratory Evaluation

• Qualitative Evaluation of Antibodies– Isohemagglutins – Antibodies to ABO blood-group

determinants– Antibodies to tetanus and diptheria glycoproteins

and pneumococcal polysaccharides.

• If low titers, give booster, then repeat titers 4 weeks later.

History Our Guide

• Predominant T-Cell Defects– Early onset, usually 2-6 mos– Bacteria, mycobacteria, viruses: CMV, EBV,

varicella; fungi, parasites, PCP, -intracellulare– FTT, diarrhea, extensive mucocutaneous

candidiasis– GVHD caused by nonirradiated blood– Hypocalcemic tetany in infancy(DiGorje)

SCREENING TESTS FOR T CELLIMMUNITY

• Newborn screening for TREC analysis (not available in iran)

• Absolute lymphocyte count• Chest radiograph for thymus shadow in

newborns• Delayed skin hypersensitivity to recall antigens• Quantification of T cell subsets

History Our Guide for B and T cell defficiency

• ATAXIA TELLANGIECTASIA

• SCID

• WISKOTT- ALDERICHE SYNDROME

History Our Guide

• Granulocyte Defects– Early onset, delayed separation of cord (>8 weeks),

poor wound healing(LAD)– Bacteria: staph, Pseudomonas, Serratia, Klebsiella;

Fungi: Candida, Nocardia, Aspergillus(CGD)– Dermatitis, impetigo, cellulitis, abscesses,

lymphadenitis, periodontitis, osteomyelits

History Our Guide

• Complement Defects– Late (C5-C9) – Neisserial infections: meningitidis,

septic arthritis from gonorrhoeae.– Early (C1, C4, and C2) – autoimmune disease– C3 deficiency – overwhelming sepsis, especially

with gram negative organisms

SCREENING TESTS FOR INNATEDEFENSE FACTORS

• Absolute granulocyte count, cell morphology• Serum total hemolytic complement for classic pathway

(CH50), alternative pathway hemolytic activity (AH50)• Nitroblue tetrazolium (NBT) test or flow cytometry

using dihydrorhodamine (DHR) « Staphylococcus aureus, Serratia marcescens, and Aspergillus”

• Flow cytometry for leukocyte adhesion molecules (CD11/CD18

• and CD15a)• IgE (JOB )

B Cell Immunodeficiencies

• Bruton Bruton’ s (X-linked) Agammaglobulinemia• Autosomal Recessive Hyper-IgM Syndrome • X-linked Lymphoproliferative Syndrome• Transient Hypogammaglobulinemia of Infancy• Common Variable Immunodeficiency (CVID)• Selective IgA Deficiency • IgG Subclass Deficiency

General Management of Patients withImmunodeficiency

• Avoid transfusions with blood products unless they are irradiated and cytomegalovirus-negative.

• Avoid live virus vaccines, especially in patients with severe T-cell deficiencies or agammaglobulinemia, and in household members.

• Use prophylaxis to Pneumocystis jiroveci (carinii) in T-cell immunodeficiency, and in X-linked hyper-IgM, consider antifungal prophylaxis in T-cell immunodeficiency.

• Follow pulmonary function in patients with recurrent pneumonia.

• Use chest physiotherapy and postural drainage in patients with recurrent pneumonia.

• Consider using prophylactic antibiotics because minor infections can quickly disseminate.

• Examine diarrheal stools for Giardia lamblia and Clostridium difficile.

• Avoid unnecessary exposure to individuals with infection.

• Boil water for T-cell defects and hyper-IgM syndrome (Cryptosporidium risk).

• Use immunoglobulin for severe antibody deficiency states (400–600mg/kg q3–4 wk IV).

• BMT for T cell and Innate defect

When IgG level are normal or near normal but Antibody deficiency is susceptible

IgG subclasses should be measured (IgG=70%, IgG 2 =20%, IgG3=7%, IgG4=3%)

Antibody function should be measured

In patient with selective IgA deficiency IgG subclasses should be measured

Many IgA deficiency patients have IgG2 subclass deficiency

In older children and adults , a total Ig level above 800 mg/ dl with normal screening antibody test excludes antibody deficiency

Total Ig (IgG+IgM +IgA )< 400 or IgG level <200 mg /dl usually indicates antibody immunodeficiency