This document provides an overview of the approach to evaluating primary immunodeficiency. It discusses the importance of differentiating primary from secondary immunodeficiency. The most common presentations of primary immunodeficiency are recurrent infections, especially of the ear, sinus, lungs and gastrointestinal tract. A thorough history and physical exam can provide clues to the underlying immunodeficiency. Initial screening tests include a complete blood count, immunoglobulin levels and lymphocyte subset analysis. Further specialized testing helps characterize the specific immune deficiency.

1. Approach to primary
immunodeficiency
Dr Abdullah Alzahrani

2. Approach to primary immunodeficiency
• PRIMARY IMMUNODEFICINCY
• SECONDARY IMMUNODEFICINCY
• IMMUNODEFICINCY AND ATOPY
• HISTORY
• PHYSICAL EXAMINATION
• INVESTIGATION
• MEANGAMENT

3. INTRODUCTION TO PRIMARY
IMMUNODEFICINCY
• PIDs are inherited defects of the innate or adaptive arms of the immune
system that lead to an increase in the incidence, frequency, or severity of
infections.
• The overall incidence of PIDs is 1 in 10,000. The prevalence of diagnosed
PID in the United States in 2005 was 1 in 2000 children . More than 200
disorders have been characterized.
• It is important to differentiate the child with PIDs from "normal child"
who has more than average number of viral infections or from the child
who has an underlying disease that predisposes him to infections, results
in secondary immune system dysfunction.

4. INTRODUCTION TO PRIMARY
IMMUNODEFICINCY
• The most common presentations are recurrent ear, sinus, and pulmonary
infections, diarrhea and failure to thrive.
• The type and pattern of recurring infections depend on which components
of the immune system are affected
• Infection severity also varies, ranging from mild respiratory infections to
massive systemic infections

5. INTRODUCTION TO PRIMARY
IMMUNODEFICINCY
• Recurrent infections :
• two or more severe infections in one year
• three or more respiratory infections in one year
• the need for antibiotics for two months/year.
• Severe/serious infections
• persistent fever
• failure to respond to oral antibiotics or the need for intravenous antibiotics
• infections with an unusual pathogen, unusual complications (eg mastoiditis, pleural
effusion, abscesses)
• persistent laboratory abnormalities (eg, leukocytosis, elevated ESR or CRP
• persistent imaging abnormalities

7. Clinical features suggestive of a primary
immunodeficiency
Adaptive immunity
T cell defectsB cell defects
Recurrent, severe, or unusual viral infections (VZV, CMV, HSV)
Recurrent bacterial sinopulmonary infections or
sepsis, particularly with polysaccharide
encapsulated organisms (S. pneumoniae, H.
influenzae type b)
Chronic diarrheaUnexplained bronchiectasis
Chronic candidiasis
Chronic or recurrent gastroenteritis (often with
Giardia or enterovirus)
Failure to thriveFailure to thrive
Lymphopenia during the neonatal period or in infancyChronic enteroviral meningoencephalitis
Pneumocystis pneumoniaArthritis
Graft-versus-host disease
Severe/neonatal eczematoid or seborrheic rashes

8. Clinical features suggestive of a primary
immunodeficiency
Innate immunity
Complement defectsPhagocytic defects
Angioedema of face, hands, feet, gastrointestinal tractPoor wound healing
Autoimmune disease, lupus-like symptomsDelayed separation of the umbilical cord
Pyogenic bacterial infections (eg, N. meningitidis)Lymphadenitis or soft tissue abscesses
History suggestive of autosomal dominant inheritanceHepatosplenomegaly
Chronic gingivitis, oral mucosal ,ulcerations
Infection with catalase positive bacteria and fungi
Recurrent gastrointestinal or genitourinary tract obstruction

9. Clinical features suggestive of a primary
immunodeficiency
• Family history of immunodeficiency or unexplained early death (eg,
before age 30 years)
• Complications from a live vaccine (eg, rotavirus, varicella, and BCG)
• Persistent lymphopenia (a count of <1500 cells/uL in patients over five
years and <2500 cells/uL in younger children
• Features typical of syndromic PIDs (eg, cartilage-hair hypoplasia,
Chediak-Higashi syndrome, ataxia-telangiectasia)
• absence of LN and tonsils or absence of thymus shadow on chest
radiograph

10. SECONDARY IMMUNODEFICINCY
• Underlying disease states, medications, injury, previous surgical
procedures, and prematurity can lead to immune system
dysfunction.
• more common than PIDs.
• Common examples:

11. IMMUNODEFICINCY WITH ATOPY
• Approximately 30 percent of children with recurrent infections have atopic
disease.
• Chronic allergic rhinitis may be mistaken for recurrent upper respiratory
infections.
• Asthma exacerbation frequently misdiagnosed as pneumonia or bronchitis
rather than reactive airways disease/asthma.
• These episodes respond poorly to antibiotics but well to allergy medications.

12. IMMUNODEFICINCY WITH ATOPY
• It is important to note that PIDs and allergic disease can coexist.
• Immunodeficiencies with associated atopy:
• selective IgA deficiency, CVID, CGD, and DiGeorge syndrome.
• Immunodeficiencies with elevated levels of IgE
• hyperimmunoglobulin E syndrome, Wiskott-Aldrich syndrome, Omenn syndrome, and
IPEX syndrome.

13. HISTORY
• Birth history :
• Growth and development
• often have poor weight gain or even weight loss
• Chronic disease and some PIDs can lead to delay in developmental milestones.
• Progressive neurologic dysfunction is seen in young adults with Chediak-Higashi
syndrome.
• Delayed speech can occur with recurrent and chronic otitis media

14. HISTORY
• Immunization history:
• any adverse effects from a vaccine, particularly live-virus vaccines
( CNS complications from oral polio, or diarrhea
following rotavirus vaccine) as well as vaccine failure (eg, chicken
pox in a varicella-vaccinated child).
• Live attenuated vaccines given in early infancy, including BCG,
rotavirus, and oral polio vaccine, are of special threat to patients
with congenital immunodeficiencies (eg, agammaglobulinemia or
combined immunodeficiency).

15. HISTORY
• Medications
• Use of any immunosuppressive medications, glucocorticoids
• If immunoglobulin has been given, the route, brand, dose, frequency, use of
premedication, and adverse effects should be noted.
• Other illnesses
• The severity of childhood diseases, such as chicken pox and febrile
illnesses, ICU admission , need of ventilation
• past hospitalizations, injuries or accidents, surgeries, or prolonged school
absences may provide clues to the present illness.

16. HISTORY
• Family history:
• similar diseases, recurrent infections, unexplained death, or
autoimmune disease
• Inheritance patterns are variable. X-linked transmission : X linked
agammaglobulinemia and CGD.
• autosomal-recessive pattern : some complement defects and ataxia-
telangiectasia. inconstant familial tendency (CVID, IgA deficiency,
hyperimmunoglobulin E syndrome) .
• Certain immunodeficiencies are more common in particular populations
• infections in family members: tuberculosis, hepatitis B, herpes simplex,
and HIV.

17. HISTORY
• Social history
• Daycare and school attendance increases the risk of exposure to
respiratory pathogens.
• Infection history
• The infection history should include the age of onset, duration,
frequency, sites, organisms, treatment, and response to therapy

18. HISTORY
• Recurrent pneumonia limited to a particular anatomic region is typically
caused by a local anatomic abnormality . By contrast, patients with
lower respiratory tract infections involving different regions of the lung
often have an underlying systemic disorder
• Abscesses of the skin, lymph nodes, or internal organs suggest a
phagocytic or antibody deficiency. Recurrent abscesses at the same site
may indicate an underlying anatomic defect
• Recurrent or chronic gastrointestinal infections occur in patients with IgA
deficiency or CVID .
• Recurrent urinary tract infections are uncommon in immunodeficiency

19. HISTORY
• Recurrent sinopulmonary infections with encapsulated organisms (eg,
pneumococcus, Haemophilus influenzae type b) suggest B cell
abnormalities.
• Pneumocystis jiroveci pneumonia is a hallmark of SCID and other
primary or secondary T cell immunodeficiencies, such as HIV or
immunosuppressive therapy
• Pseudomonas sepsis occur in phagocytic disorders or profound
antibody or T cell immunodeficiency
• Enteroviral meningoencephalitis can be the presenting infection in
children with X-linked agammaglobulinemia (XLA)

20. HISTORY
• Aspergillus, Staphylococcus aureus, coagulase-negative
staphylococci, Serratia marcescens, and Chromobacterium are common
organisms found in abscesses or soft-tissue infections in patients with
CGD
• Recurrent staphylococcal skin infections, abscesses, lung cysts, or
pneumonia are characteristic of hyperimmunoglobulin E syndrome.
• Invasive infection with Neisseria species (N. meningitidis, N.
gonorrhoeae) occurs in patients with deficiencies of the late components
of complement (C5 to C9)
• Infection with vaccine strains following live vaccines, including oral
rotavirus, oral polio, measles, varicella, or BCG, suggest PID. Vaccine
failure (eg, recurrent chicken pox or shingles in the vaccinated child)
also suggests immunodeficiency

21. PHYSICAL EXAMINATION
• Vital signs.
• dysmorphic appearance may signify a genetic syndrome.
• Growth and development is documented by growth charts
• acute or chronic otitis media should be determined since upper
respiratory infections are the most common recurrent infection.
Draining ears and perforated tympanic membranes suggest
immunodeficiency.
• Pallor without anemia, dark circles under the eyes, conjunctivitis,
a transverse nasal crease, congested turbinates, and clear nasal
discharge suggest allergy.

22. PHYSICAL EXAMINATION
• Purulent nasal discharge, postnasal drip, and diminished gag reflex
are consistent with chronic sinusitis.
• Mouth ulcers, gingivitis, mucosal candidiasis, and poor dentition
suggest immunodeficiency.
• Diminished or absent tonsils and cervical nodes in the presence of
recurrent respiratory infections suggest an antibody deficiency.
• Nasal polyps suggest cystic fibrosis.
• A productive or wheezy cough suggests bronchitis, pneumonia, or
asthma.

23. PHYSICAL EXAMINATION
• Digital clubbing suggests longstanding lung or heart disease,
inflammatory bowel disease, or chronic infection.
• Cutaneous granulomas, impetigo, or nonhealing sores suggest antibody
or phagocytic immunodeficiency.
• Facial rashes, vitiligo, alopecia, and vasculitic lesions suggest
autoimmunity
• The absence of lymph tissue suggests XLA or SCID.
• adenopathy and hepatosplenomegaly can be seen in B cell disorders (eg,
CVID, IgA deficiency) and HIV infection. Suppurative adenitis is common
in CGD.

24. PHYSICAL EXAMINATION
• Ataxia, telangiectasia, and developmental delay in ataxia-telangiectasia
• Petechiae, easy bleeding, eczema, and chronic draining ears in Wiskott-
Aldrich syndrome
• Coarse features, chronic infected eczema, and deep-seated abscesses in
hyperimmunoglobulin E syndrome
• Short stature with chondrodystrophy and fine hair in cartilage-hair
hypoplasia
• Congenital heart disease, developmental delay, and dysmorphic facies
with low-set ears, hypertelorism, downturning eyes, and micrognathia in
DiGeorge syndrome

25. PHYSICAL EXAMINATION
• Early onset of seborrheic dermatitis and alopecia in some forms of
SCID
• Oral ulcers, gingivitis, and impetigo in CGD, or leukocyte-adhesion
defects
• Oculocutaneous albinism in Chediak-Higashi disease
• Abnormal dentition, decreased sweating, and sparse hair
associated with frequent infection suggest ectodermal dysplasia
• Dermatomyositis-like rash in XLA
• Lupus-like rash in early complement component defects

26. INVESTIGATION(General screening tests)
• The screening evaluation should include both quantitative and
qualitative tests
• Abnormalities of the following initial tests may suggest allergy,
immunodeficiency, or a chronic illness and serve as a guide for
subsequent investigations
• Complete blood count with differential
• Electrolytes, glucose, blood urea nitrogen (BUN), creatinine, and albumin
• Urinalysis
• Erythrocyte-sedimentation rate (ESR) or C-reactive protein (CRP)
• Appropriate cultures
• Radiologic imaging of the site(s) of suspected infection
• Immunoglobulin levels

27. INVESTIGATION(General screening tests)
• Lymphopenia is defined as a count of <1500 cells/uL in patients over
five years and <2500 cells/uL in younger children.
• elevated ESR or CRP suggests systemic or regional infection or an
autoimmune process.
• A chest radiograph is indicated if the child has a chronic cough or
other features suggesting lung problems.
• Sinus and lateral neck films or sinus (CT) scan with a lateral
pharyngeal view for adenoidal size is indicated for the patient with
suspected sinusitis or obstructive breathing . Complete absence of
adenoidal tissue suggests immunodeficiency

29. INVESTIGATION(General screening tests)
• Immunoglobulin levels
• IgG, IgM, IgA, and IgE, are included in the initial tests.
• Antibody deficiency is suggested by an IgG less than 200 mg/dL and a total Ig (IgG
plus IgM plus IgA) less than 400 mg/dL, or the complete absence of IgM or IgA (after
infancy).
• elevated IgE (>100 int. units/mL) suggests allergy, eczema, or chronic skin
infections, or may occur in Omenn syndrome, phagocytic disorders, or
hyperimmunoglobulin E syndrome (levels are generally >2000 int. units/mL for this
syndrome).
• Low or absent IgE levels suggest absence of IgE-mediated allergic disease.

30. INVESTIGATION
• Antibody titers
• Complement activity
• Lymphocyte-subset analysis
• IgG subclass determinations
• HIV testing
• Delayed-cutaneous hypersensitivity
• Lymphoproliferative assays
• Phagocytic-oxidative responses
• Leukocyte-adhesion defect testing

31. INVESTIGATION
• Antibody titers
• Response to protein antigens can be assessed by measurement of titers to tetanus,
diphtheria, pneumococcal conjugate, and H. influenzae type b vaccines.
• Response to polysaccharide antigens can be determined by measurement of titers to
polysaccharide pneumococcal vaccine (unconjugated) in adults and children over 24
months of age
• Complement activity
• screening test is a total hemolytic complement determination (CH50). A normal CH50
level excludes nearly all hereditary complement deficiencies.
• IgG subclass determinations
• In patients with a slightly low total IgG level and poor antibody response to
vaccinations
• HIV testing
• (HIV) testing, antibody titers or PCR, should be done in any patient suspected of a T
cell deficiency

32. INVESTIGATION
• Lymphocyte-subset analysis:
• By flow cytometry,
• including CD3 (total T cells), CD4 (T helper), CD8 (T cytotoxic),
CD19 or CD20 (B cells), and CD16/56 (natural killer cells)
• The CD4 count is the most valuable reflection of the cellular
immune system. An absolute CD4 count of <500 cells/uL in a person
over five years of age or <1000 cells/uL in younger children
suggests a cellular immunodeficiency.
• An absolute B cell (CD19) count of <100 cells/uL suggests
hereditary agammaglobulinemia.
• A low CD16/56 count (<2 percent) suggests a natural killer cell
deficiency.

33. INVESTIGATION
• Delayed-cutaneous hypersensitivity:
• inflammatory reactions initiated by mononuclear leukocytes.
• mediated by T cells and monocytes/macrophages rather than by
antibodies. They are also termed type IV hypersensitivity reactions
• Children under age two years often have negative tests despite
intact cellular immunity.
• The usual skin tests employ Candida antigen, tetanus or tetanus-
diphtheria antigen, and/or tuberculin.

34. INVESTIGATION
• Lymphoproliferative assays
• Diminished or absent proliferation to mitogens signals a serious derangement of T
cell function, such as severe combined immunodeficiency (SCID).
• Phagocytic-oxidative responses
• correlated with the ability of leukocytes to kill bacteria. This is best assessed using a
fluorescent dye (dihydrorhodamine) and flow cytometry.
• A negative response is seen in CGD. This procedure is faster and more informative
than nitroblue tetrazolium dye reduction assays used previously
• Leukocyte-adhesion defect testing
• examination of cell surface marker expression by flow cytometry. CD11 and CD18 are
absent in LAD I and CD15a is absent in LAD II. Patients with LAD III have normal
integrin expression.

35. MEANGAMENT
• Infections must be recognized and aggressively treated.
• Empiric antibiotic therapy should be instituted pending culture results.
• Prophylactic antibiotics may be administered depending upon the type
of disorder suspected.
• Live-virus vaccines (eg, oral polio, oral rotavirus, varicella, MMR
smallpox, intranasal influenza) and live (BCG) vaccine must not be
administered
• Family members may receive varicella, MMR, and shingles vaccines, but
not oral polio or smallpox vaccines.
• Inactive influenza vaccine may be preferred for household contacts of
some immunocompromised individuals.

36. MEANGAMENT
• Post exposure infectious prophylaxis may be necessary following
exposure to varicella.
• Only irradiated, leukocyte-poor, virus-free products should be
used if blood transfusion is necessary.
• IVIG or SCIG should not be given until there has been a thorough
evaluation of the patient's immune system.
• IVIG and SCIG are expensive, will dismiss an antibody investigation
for several months, and have potential adverse effects. Their use
should be carefully considered only after the evaluation is
complete.