Approach to the child with immune based and/or allergic disease

Introduction Recurrent infections is a common reason for seeking medical advice in pediatrics. This may refer to infections that are: great in number long lasting Very severe Associated with unusual complications Or fail to resolve with standard therapy

Theses children can be grouped into 4 categories: 1. The “normal” child 2. The child with atopic disease 3. The child with another chronic condition 4. The child with immunodeficiency

The “normal” child 50% of children with recurrent infections The average child has (+/-) 4-8 respiratory infections per year The mean duration of viral respiratory symptoms is 8 days (however can extend beyond two weeks) Normal growth and development Respond quickly to treatment, with complete recovery Appear healthy between infections Physical examination and lab tests are normal

Child with atopic disease Account for 30% of children with recurrent infection Increased susceptibility to URTI Usually develop coughing and wheezing following respiratory infections (reactive airway disease/asthma)

Respond well to allergy or asthma medications Growth and development are usually normal Characteristic physical findings Elevated serum IgE

Child with chronic disease 10% of children with recurrent infection Cystic fibrosis, GERD, CHD, chronic aspiration, cerebral palsy Increased susceptibilty to infection: ◦ Inadequate clearance of secretions ◦ Increased pulmonary blood flow ◦ FB – artificial cardiac valve, VP shunt, indwelling catheter

Child with immunodeficiency Account for 10% of children with recurrent infection PID usually affect B cells Secondary immune deficiency usually affects T cells (aging, malnutrition, drugs)

Types of immunity Innate (natural) immunity A – Innate (natural) immunity  responds to infection regardless of previous exposure to the agent Ex: PNL, phagocytic cells, complement system Acquired (adaptive) immunity B – Acquired (adaptive) immunity  develops as a result of exposure to previous immunogens Ex: T lymphocytes, B lymphocytes, NK cells

Clinical features suggestive of a primary 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 onset ◦ Birth 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 PID

◦ 2 to 6 years – children developing infection in this age group may also fit into any of the 4 categories. 2ry immunodeficiencies resulting from malignancy, nephrotic syndrome, or gastrointestinal problems start at this age ◦ 6 – 18 years – it is unusual for recurrent infections to first present beyond the age of six

Infection history (cont’d) 2. Sites of infection:  Upper respiratory tract  Most common site, usually viral  Chronic purulent nasal discharge and cough  chronic siusitis  Chronic or seasonal clear nasal discharge, congestion, itchy eyes, nocturnal cough  allergic disease  Recurrent oral thrush, stomatitis, gingivitis,  t- cell and phagocytic cell disorder  Recurrent pharyngitis, or tonsillitis usually not associated with immunodeficiency

 Lower respiratory tract  Recurrent pneumonia is rare in normal children or children with allergic disease  Suggest chronic cardiopulmonary disease or immunodeficiency  Recurrent 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

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, omenn syndrome

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.

Clinical patterns of immunodeficiency Wiskott – 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 Include: CBC with differential count Electrolytes, glucose, KFT, albumin Urine analysis ESR CRP CXR

CBC ◦ With special attention paid to the total absolute lymphocyte count: lymphopenia <1500cells/uL in patients over 5 years or <2500 cells/uL in younger children ◦ Eisinophilia suggests allergy ◦ Thrombocytosis suggests chronic inflammation

ESR, CRP, appropriate cultures should be done for evaluation of infection CXR 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

Lymphocyte subset analysis 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. The ability of lymphocytes to proliferate to mitogens, stimulatory monoclonal antibodies, or allogenic cells indicates intact lymphocyte activation to nonspecific stimuli. However, diminished or absent proliferation indicates derangement in T cell function

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)

Summary and Recommendations The majority of children who present with recurrent infections, have increased exposure, allergy, or an anatomic problem rather than an immunodeficiency Primary immunodeficiency should be considered in children who have recurrent and/or complicated bacterial infections; persistent oral candidiasis; infection with opportunistic, unusual, or "signature" organisms; failure to thrive; or a family history of immunodeficiency

B cell and combined B and T cell abnormalities account for nearly three- fourths of the primary immunodeficiencies and should be considered initially. Isolated T cell, phagocytic, and complement defects are rare.

Screening tests may include a complete blood count with differential, chemistry studies, urinalysis, sedimentation rate or CRP, appropriate cultures, radiologic imaging of the infection site, immunoglobulin levels, antibody titers to vaccine antigens, and complement activity. Definitive diagnostic testing should be performed if the initial screening evaluation is abnormal, and should be done in consultation with a pediatric immunologist.