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Approach to primary immunodeficiency
- 1. Approach to primary immunodeficiency DrAbdullah Alzahrani
- 2. Approach to primaryimmunodeficiency • 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 suggestiveof 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 suggestiveof 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 suggestiveof 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 • Underlyingdisease 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 • Useof 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 pneumonialimited 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 sinopulmonaryinfections 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, Staphylococcusaureus, 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 • Vitalsigns. • 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 • Purulentnasal 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 • Digitalclubbing 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 • Earlyonset 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 mustbe 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 exposureinfectious 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.
Editor's Notes
- #4 • Most often this can be done from the history, physical examination, and screening investigations
- #7 Almost three-fourths of the PIDs are caused by an antibody (B cell) deficiency or a combined antibody plus cellular (T cell) abnormality . Isolated T cell defects, as well as phagocytic cell, complement, and other innate immune defects, are less common. B cell (antibody) or combined B and T cell diseases should be considered initially, unless clinical features suggest otherwise
- #8 GVSD: (maculopapular and/or desquamating skin, abnormal liver function tests, and/or chronic diarrhea)
- #9 Delay separation >3weeks
- #10 Family history of immunodeficiency was the most predictive factor of any PID in a retrospective survey of 563 children who presented to two pediatric immunodeficiency centers for evaluation of possible PID Need for intravenous antibiotics and/or hospitalization to clear infections, Six or more new infections within one year, Two or more serious sinus infections or pneumonias within one year, Four or more new ear infections within one year, Two or more episodes of sepsis or meningitis in a lifetime, Two or more months of antibiotics with little effect the use of intravenous antibiotics for sepsis and failure to thrive were strong identifiers of neutrophil PID and T cell PID, respectively.
- #11 Infections (e.g., HIV, EBV) Nutritional deficiencies (e.g., protein, calorie, vitamin, or mineral malnutrition) Protein-losing states (e.g., nephrotic syndrome, protein-losing enteropathy diabetes mellitus malignancy Immunosuppressive agents (e.g., antineoplastic drugs, corticosteroids, radiation)
- #12 Atopy increased susceptibility to infection may be due to enhanced adherence of pathogens to inflamed respiratory epithelium, increased mucosal permeability, or an altered immune response to certain viral and bacterial pathogens Growth and development are usually normal. A normal total IgE tends to exclude IgE-mediated allergy. An elevated IgE (eg, >100 int. units/mL) is suggestive of allergy, but an elevated IgE alone is not diagnostic for atopic disease.
- #13 IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)
- #14 exposure to toxins, prescription medications, illicit drugs, tobacco, and alcohol. These factors can increase the risk of secondary immunodeficiency in the newborn Gestation age, birth weight, and neonatal problems, such as jaundice, respiratory distress, or need for intensive care. Transfusions , food intolerance and duration of breastfeeding ataxia-telangiectasia and DiGeorge syndrome, can lead to delay in developmental milestones.
- #15 Patients with T cell deficiencies or who are on immunosuppressive drugs including glucocorticoids may develop progressive infections following live-virus vaccines.
- #16 Current and past medications, including duration, effectiveness, and adverse reactions.
- #18 home, parents' work environment, and daycare or school should be explored for exposures, such as ill classmates, allergens, tobacco smoke, contaminated water supply, farm animals, solvents, and toxins, as well as location near industrial plants . Prior residences and travel history may be important in exposure to infectious agents or allergens Congenital antibody deficiencies and many combined immunodeficiencies (eg, zeta-chain associated protein 70 [ZAP-70] deficiency, CD25 deficiency) usually present at 7 to 12 months, as maternal immunoglobulin G (IgG) disappears.
- #19 reactive airways disease/asthma is often misdiagnosed as pneumonia or bronchitis in young children. (eg, foreign body, bronchial compression by mediastinal adenopathy or vascular anomaly, bronchial sequestration or cyst). (eg, cystic fibrosis, immotile cilia syndrome, recurrent aspiration. such as a congenital branchial cleft cyst, pilonidal cyst, hidradenitis suppurativa, or a retained foreign body. and usually reflect a structural abnormality, such as obstruction, reflux, or bladder dysmotility.
- #20 Certain immunodeficiencies commonly present with infections caused by "signature" organisms. Children who present with such infections should undergo laboratory evaluation for immunodeficiency. As examples : Recurrent pneumococcal disease suggests a PID, such as agammaglobulinemia or complement defect. Secondary immunodeficiency, due to sickle cell disease, asplenia, HIV/AIDS, or nephrotic syndrome, also results in recurrent pneumococcal disease Pseudomonas infection also occurs in patients with cystic fibrosis, burns or soft tissue injury, or neutropenia Enteroviral meningoencephalitis is rare in children receiving regular doses of intravenous immunoglobulin (IVIG)
- #21 Prolonged and severe candidiasis involving the buccal mucosa, tongue, and palate may be the earliest sign of abnormal T cell immunity Deep or systemic infections with nontuberculous mycobacteria suggest an interferon-gamma receptor or interleukin-receptor deficiency.
- #22 Weight loss or failure to thrive is suggested by muscle wasting or atrophy of the buttock fat deposits
- #25 certain findings are characteristic of specific immunodeficiency syndromes as example:
- #27 Look for any systemic disease Evaluation for infection
- #28 The presence of anemia, thrombocytopenia, or an abnormal differential count warrants further investigation. Eosinophilia suggests allergy. Thrombocytosis suggests chronic inflammation.
- #29 The top chest radiograph shows a normal thymic shadow. The bottom radiograph shows absence of the thymic shadow in an infant with severe combined immunodeficiency (SCID). Normal adenoid (left); absent adenoid in agammaglobulinemia (right)
- #30 Levels must be compared with age-matched controls, particularly in the first two years of life.
- #31 These tests are indicated when the screening tests are abnormal or the clinical picture is highly suggestive for an immunodeficiency Specific Tests for Suspected Immunodeficiencies Tests of B-Lymphocyte Function Quantitative immunoglobulins: IgG (consider subclasses), IgA, IgM B-lymphocyte quantitation by flow cytometry Antibody response to protein vaccines (tetanus, diphtheria, polio, measles, mumps, rubella antibody titers) Antibody response to polysaccharide vaccine (pneumococcal polysaccharide vaccine) Isohemagglutinins (only if child >1 yr; assesses IgM response to carbohydrate antigen) Tests of T-Lymphocyte Function Total lymphocyte count T-cell and subset quantitation by flow cytometry (CD3/total T-cell, CD4/T-helper, CD8/T-suppressor/cytotoxic counts) CXR for thymic shadow Delayed-type hypersensitivity skin test (intradermal skin test with 0.1 mL heat-killed Candida 1:100 dilution) In vitro T-cell proliferative responses to mitogens, antigens, or allogenic cells (day 3 and day 6 proliferations) Thymic biopsy Tests of Phagocytic Cell Function Neutrophil count and morphology NOBI by flow cytometry Adhesion antigen (CD11/CD18) by flow cytometry Chemotaxis assays Tests of Complement System Function Total hemolytic complement (CH50), C3, C4 Other Tests HIV testing ADA and PNP levels
- #32 Vaccine challenge — Vaccine responsiveness is used to further assess the antibody system. A killed vaccine that has not been administered previously is given, and titers are measured before and four to six weeks after vaccination. Levels of individual complement components are measured if the CH50 is significantly reduced A complete absence of IgG1, IgG2, or IgG3 suggests immune dysregulation and may indicate the early onset of common variable immunodeficiency (CVID).
- #33 indicated when a B or T cell defect is suspected. Comparison with age-matched controls is necessary (infants and young children normally have lymphocytosis compared with adults) Low levels of any lymphocyte subset should be repeated and, if confirmed, followed by functional analysis of the respective immune system component.
- #34 The term delayed is used to differentiate a secondary cellular response, which appears 48-72 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. A documented history of Candida infection; a recent diphtheria, tetanus, or BCG vaccine; or a previously positive tuberculin reaction is necessary to interpret a response to these antigens
- #35 used to further assess the cellular immune system. The ability of lymphocytes to proliferate to mitogens (phytohemagglutinin, concanavalin, pokeweed), stimulatory monoclonal antibodies (anti-CD3), or allogeneic cells (in a mixed leukocyte reaction) indicates intact lymphocyte activation to nonspecific stimuli.
- #36 Children undergoing evaluation for recurrent infection need special care during the evaluation process . This includes: measle-mumps-rubella MMR