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The PNP ’ s Guide to Primary Immunodeficiencies

The PNP ’ s Guide to Primary Immunodeficiencies. …So How Many Ear Infections Are too Many? M. Elizabeth M. Younger CRNP, PhD Assistant Professor, Pediatrics The Johns Hopkins University School of Medicine Baltimore, Maryland. Presented by: M. Elizabeth M. Younger CRNP, PhD. Disclosures.

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The PNP ’ s Guide to Primary Immunodeficiencies

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  1. The PNP’s Guide toPrimary Immunodeficiencies …So How Many Ear Infections Are too Many? M. Elizabeth M. Younger CRNP, PhD Assistant Professor, Pediatrics The Johns Hopkins University School of Medicine Baltimore, Maryland Presented by: M. Elizabeth M. Younger CRNP, PhD

  2. Disclosures Consultant, CSL Behring Speaker, CSL Behring Advisory Boards: CSL Behring RMS Medical Products Immune Deficiency Foundation Chair, Nurse Advisory Committee

  3. Systemic Responses to Infection • Host Defenses • Skin • Mucus Membranes • Normal Flora • Non-Specific Responses • Complement • Phagocytes • Natural Killer Cells • Specific Responses • Antibody Formation • Cellular Immunity

  4. Cells of the Immune System

  5. Primary Immunodeficiencies • ~150 recognized defects of immunologic function • Another 39 disorders of which immunodeficiency is recognized as a component • May present at any age • Do not always present with severe infections

  6. Primary Immunodeficiencies • Disorders of Humoral Immunity-affecting B cell differentiation and antibody production • Disorders of Cellular Immunity-T cell defects • Combined T cell and B cell defects • Phagocytic Defects • Complement Deficiencies

  7. Does your patient have a primary immunodeficiency?

  8. Things to consider… • What kinds of infections • How frequently • Co-morbidities • Factors that might contribute to infections (e.g. day care!) • Family history

  9. Imperatives for the Primary Care Provider • Accurate record of immunizations • Maintain accurate and ongoing growth charts • Complete family history with genogram • Follow-up after antibiotic treatment (i.e. did what you prescribed work?)

  10. Screening Tests for Primary Immunodeficiencies

  11. …But always start with a CBC

  12. Rule of 2/3’s For a child under the age of 3 years: 2/3 of WBC should be lymphocytes 2/3 of lymphocytes should be T cells 2/3 of T cells should be CD4 cells For someone older than 3 yoa 2/3 of WBC should be neutrophils 2/3 of lymphocytes should be T cells 2/3 of T cells should be CD4 cells

  13. Normal Ranges of Immunoglobulins Immunoglobulins (mg/dL) AgeIgG IgAIgM Newborn 636-1606 1-4 6-25 1-3 months 176-906 1-53 17-105 4-6 months 172-814 4-84 27-108 7-9 months 217-904 11-90 34-126 10-12 months 294-1069 16-84 41-149 1 year 345-1213 14-106 43-173 2 years 424-1051 4-123 18-168 3 years 441-1135 22-159 47-200 4-5 years 463-1236 25-154 43-196 6-8 years 633-1280 33-202 48-207 9-10 years 608-1572 45-236 52-242 Adult 639-1349 70-312 56-352

  14. Clinical Features of Immunodeficiency • Increased susceptibility to infection • Predisposition for autoimmune or inflammatory diseases, e.g. - Inflammatory bowel disease - Autoimmune cytopenias - Type I Diabetes - Juvenile rheumatoid arthritis • Predisposition for lymphoreticular cancers • Syndrome complex

  15. Infections in Immunodeficient Patients • Chronic/recurrent infections without other explanation • Infection with organisms of low virulence • Infection of unusual severity • Any site of infection is possible, but different kinds of infection are characteristic of the specific immunodeficiency suspected

  16. Disorders of Humoral Immunity 1. Transient Hypogammaglobulinemia of Infancy • X-linked Agammaglobulinemia (Bruton’s Agammaglobulinemia, BTK deficiency, X-LAG) • Common Variable Immunodeficiency (CVID) • Selective IgA deficiency

  17. Transient Hypogammaglobulinemia of Infancy • Characterized by • Low serum immunoglobulins • Little antibody response to vaccines • Frequent sinopulmonary infections • Condition may last into pre-school years • Diagnosis can only be made definitively in retrospect

  18. Care and Treatment of the Child with Suspected Transient Hypogam • Serial monitoring of immunoglobulins and antibody titers • Reimmunization may be necessary • PNP needs to be aware that infections may require longer courses of antibiotics for treatment than usually prescribed • Gamma globulin is seldom necessary • Any fever of 101.5F or greater requires that the child have a CBC, blood culture and physical exam • Live viral vaccines should be held until immunocompetency is demonstrated

  19. X-linked Agammaglobulinemia • 1:200,000 live births • No/few B cells, normal T cells • No tonsils, small lymph nodes • Usually not diagnosed until after 4 months when maternal immunity wanes

  20. Common Variable Immunodeficiency (CVID) • Approximately 20% of these patients are diagnosed under the age of 16 • Characterized by low serum immunoglobulins and susceptibility to infections because of impaired antibody responses • Sinopulmonary infections are most common • Predisposition for autoimmune diseases

  21. Treatment of Humoral Immune Disorders • Regular infusions of pooled human gamma globulin (either IV every 3-4 weeks or subq weekly) • Aggressive treatment of infections • Surveillance for co-morbidities

  22. Primary Care of the Child with Humoral Immunity Defects • Low tolerance for fever, signs of infection • No live viral vaccines (Varivax, MMR, Pro-Quad, Flu-Mist, Rota-Teq) • Because of the increased incidence of autoimmune disease in this population, monitor growth curves, carefully assess new complaints or signs and symptoms of problems • Do not need routine immunization since they do not make protective levels of antibodies

  23. Disorders of Cellular Immunity 1. Severe Combined Immunodeficiency (SCID)

  24. Severe Combined Immunodeficiency (SCID) • Severe impairment of humoral and cell- mediated immune function • Susceptibility to infection by virtually any microbe • Unless treated, usually fatal within the first year of life • 12 known genetic causes 45% X-linked 15% Adenosine Deaminase Deficiency

  25. Treatment of SCID • Bone Marrow transplant • Gamma globulin replacement therapy • Antibiotic prophylaxis for PCP and fungal infections • Gene therapy • PEG-ADA (Adagen) IM 2 or 3 times per week (if etiology is ADA deficiency) • Nutritional support

  26. Combined T cell and B cell disorders 1. DiGeorge Syndrome • Wiskott-Aldrich Syndrome 3. Ataxia Telangiectasia

  27. DiGeorge Syndrome • 22q11.2 deletion syndrome • Velocardiofacial (VCF) syndrome • Conotruncal anomaly face syndrome • Autosomal dominant Opitz-G/BBB Incidence: 1 in 3,000 live births

  28. Fluorescence in situ Hybridization Korf B, N Engl J Med 1995;332:1219

  29. DiGeorge SyndromeCatch 22 Mnemonic C ardiac defects (75%) A bnormal facies (70%) Thymic a- or hypoplasia (60-77%) Cleft palate (69-100%) H ypocalcemia (17-60%) 22- chromosome 22

  30. C-Cardiac Defects • Tetralogy of Fallot (17-22%) • Interrupted Aortic Arch (14-15%) • Ventriculoseptal defect (13-14%) • Truncus arteriosus (7-9%)

  31. A-Abnormal Facies • Ocular hypertelorism • Lateral displacement of inner canthus • Short palpebral fissure • Low nasal bridge • Nasal dysmorphism • Small mouth • Low set ears • Cleft lip

  32. T-Thymic aplasia or hypoplasia • Thymic aplasia requires thymic or bone marrow transplant • Those with thymic hypoplasia must be protected from live viral vaccines, transfusions of unirradiated blood, and opportunistic infections until T cell numbers normalize • 10% have delayed production of IgG • 2 - 4 % have IgA deficiency

  33. C-Cleft Lip/Palate (velopharyngeal abnormality associated issues) • Cleft palate (submucous cleft is common) • Recurrent otitis media and sinusitis • Problems with speech articulation

  34. H-Hypocalcemia • Neonatal hypocalcemia occurs in 50-70% of patients • Problem generally resolves with increased dietary calcium intake and growth of parathyroid glands • Hypocalcemia can develop in older patients who are stressed by acute medical illnesses, trauma or cardiopulmonary bypass

  35. Variability of Phenotype Driscoll et al. J Med Genet 1993;30:813

  36. In a study of 195 patients: Associated Manifestations • Speech delay and other neurodevelopmental problems (75%) • Kidney and urinary tract defects (36%) • Skeletal defects (18%) • Feeding problems • Psychiatric problems (onset of schizophrenia during adolescence)

  37. Autoimmune Disease in DiGeorge Patients • Immune thrombocytopenia • 200x  over rate in general population • Juvenile rheumatoid arthritis • 20x  over rate in general population • Skin disease (psoriasis, vitiligo) • Autoimmune hemolytic anemia • Inflammatory bowel disease

  38. Neurodevelopmental Problems • Delayed acquisition of language milestones • At 2 y/o, 90% nonverbal or used only single words • At 3 y/o, 80% nonverbal or used only words and simple phrases • At 4 y/o, 30% nonverbal or not speaking in sentences • Articulation disorders • Cognitive abnormalities

  39. Primary Care of the DiGeorge Patient • Once 22q11 deletion syndrome is identified, be prepared for a multi-dimensional approach • Complex medical needs • School problems • Refer for genetic counseling • Routine immunization if immunocompetent • Antibiotic prophylaxis if T-cell numbers are low

  40. Wiskott-Aldrich Syndrome • X-linked • Clinical Presentation Small platelets (Low MPV) and/or thrombocytopenia Impaired antibody responses Recurrent bacterial, viral and fungal infections Eczema • Associated Problems Increased incidence of autoimmune disease Increased incidence of malignancies, especially leukemias and lymphomas

  41. Primary Care of the Child with Wiskott-Aldrich Syndrome • Vigilance for signs of bleeding • Low tolerance for fever, signs of infection • Treat eczema aggressively to prevent suprainfection

  42. Treatment of the Wiskott-Aldrich Patient • Gamma globulin replacement therapy if antibody production is impaired • Treatment of acute thrombocytopenia • Platelet transfusion for acute bleed • IV Gamma globulin • Anti CD20 monoclonal antibody therapy (e.g. rituximab) • Treatment of chronic thrombocytopenia • Steroids • Splenectomy

  43. Ataxia Telangiectasia • Autosomal recessive disease • Ataxia (wobbly, scissor type gait) • Telangiectasias of eyes and skin • Cellular and humoral immunodeficiencies • Predisposition to lymphoreticular cancers • Effects cerebellar function • Progressive neurologic deterioration

  44. Care of the Child with AT • Gamma globulin replacement therapy if indicated • Need a team of care providers (i.e. primary care, neurology, immunology, nutritionist, pulmonologist, developmentalist) • Supportive care Use X-rays ONLY when absolutely necessary as exposure to x-rays causes cell death or chromosomal breakage

  45. Disorders of Phagocytes • Chronic Granulomatous Disease • Leukocyte Adhesion Deficiency • Chédyak-Higashi Syndrome

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