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April 18, 20151 The PNP’s Guide to Primary Immunodeficiencies …So How Many Ear Infections Are too Many? M. Elizabeth M. Younger CRNP, PhD Assistant Professor,

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Presentation on theme: "April 18, 20151 The PNP’s Guide to Primary Immunodeficiencies …So How Many Ear Infections Are too Many? M. Elizabeth M. Younger CRNP, PhD Assistant Professor,"— Presentation transcript:

1 April 18, 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

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

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4 April 18, 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

5 Cells of the Immune System

6 April 18, 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

7 April 18, 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

8 April 18, Does your patient have a primary immunodeficiency?

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10 April 18,

11 Things to consider… What kinds of infections How frequently Co-morbidities Factors that might contribute to infections (e.g. day care!) Family history April 18,

12 April 18, 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?)

13 Screening Tests for Primary Immunodeficiencies Suspected AbnormalityDiagnostic tests AntibodySerum IgG, IgA, IgM Antibody response to vaccines Cell-mediated immunityLymphocyte count T cell enumeration (CD4, CD8) HIV serology/PCR ComplementTotal hemolytic complement (CH 50 ) Alternative Pathway (AH 50 ) Mannan Binding Lectin PhagocytesNeutrophil count Dihydrorhodium (DHR) test Nitroblue tetrazolium (NBT) dye test

14 …But always start with a CBC RangeUnits2/28/03 Age-4 mos 3/17/033/21/03 WBC 5.7K-17.7K /cu mm13, RBC M/cu mm Hgb9-20g/dL Hct29-41% Lymph %43-73%136 Mono %3-9%567 Neutro %17-49% Eo %1-4%211 Baso %0-2%000 # Lymph 2.5K-12.9K /cu mm # Mono /cu mm ANC /cu mm13,6005,8503,830

15 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 CD 4 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 15

16 Normal Ranges of Immunoglobulins Immunoglobulins (mg/dL) Age IgG IgAIgM Newborn months months months months year years years years years years Adult

17 April 18, 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

18 April 18, 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

19 April 18, Disorders of Humoral Immunity 1. Transient Hypogammaglobulinemia of Infancy 2.X-linked Agammaglobulinemia (Bruton’s Agammaglobulinemia, BTK deficiency, X-LAG) 3.Common Variable Immunodeficiency (CVID) 4.Selective IgA deficiency

20 April 18, 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

21 April 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  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

22 April 18, 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

23 April 18, 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

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26 April 18, 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

27 April 18, 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

28 April 18, Disorders of Cellular Immunity 1. Severe Combined Immunodeficiency (SCID)

29 April 18, 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

30 April 18, 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

31 April 18, Combined T cell and B cell disorders 1. DiGeorge Syndrome 2.Wiskott-Aldrich Syndrome 3. Ataxia Telangiectasia

32 April 18, 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

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

34 April 18, DiGeorge Syndrome Catch 22 Mnemonic C ardiac defects (75%) A bnormal facies (70%) T hymic a- or hypoplasia (60-77%) C left palate (69-100%) H ypocalcemia (17-60%) 22- chromosome 22

35 April 18, C-Cardiac Defects Tetralogy of Fallot (17-22%) Interrupted Aortic Arch (14-15%) Ventriculoseptal defect (13-14%) Truncus arteriosus (7-9%)

36 April 18, 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

37 April 18, 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 % have IgA deficiency

38 April 18, C-Cleft Lip/Palate (velopharyngeal abnormality associated issues) Cleft palate (submucous cleft is common) Recurrent otitis media and sinusitis Problems with speech articulation

39 April 18, 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

40 April 18, Variability of Phenotype Driscoll et al. J Med Genet 1993;30:813

41 April 18, 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)

42 April 18, 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

43 April 18, 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

44 April 18, 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

45 April 18, 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

46 April 18, 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

47 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 April 18,

48 April 18, 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

49 April 18, 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

50 April 18, Disorders of Phagocytes 1.Chronic Granulomatous Disease 2.Leukocyte Adhesion Deficiency 3.Chédyak-Higashi Syndrome

51 April 18, Chronic Granulomatous Disease (CGD) Phagocytes have normal function, EXCEPT they cannot make an oxidative burst So…phagocytes successfully defend against some organisms, but not those that require an oxidative burst to kill them; these are usually catalase-postive bacteria and fungi

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53 April 18, Frequent Pathogens Staph aureus ~ 30-56% of clinical isolates Other Gram positives e.g. Nocardia Gram negative ~ 30% e.g. E. coli, Serratia marcescens, Klebsiella, Enterobacter species, Burkholderia, Salmonellae, Pseudomonas Fungi: ~ 20% Aspergillus ~ 78% Candida species

54 Diagnosis: Nitroblue Tetrazolium Test negative positive

55 April 18, Clinical Presentation of CGD X linked or, more rarely, autosomal recessive) Recurrent bacterial infections of any organ system or tissue Pneumonias: (50% are fungal, frequently caused by Aspergillis) Other frequent infections include lymphadenitis, retropharyngeal and liver abscesses, osteomyelitis

56 April 18, Primary Care of CGD Bacterial prophylaxis with trimethoprim/sulfamethoxazole Dose: 5-10 mg/kg/day divided BID Fungal prophylaxis with Itraconazole Dose: 2-5 mg/kg/dose BID Interferon  Dose: 50 μg/m 2 sq 3x/week or 1.5 mcg/kg if < 0.5 m 2 Routine primary care and immunization are critical Infections need to be treated for a long time and may require parenteral antibiotics

57 Complement Deficiencies Activation of the Complement System: –Classical Pathway –Alternative Pathway –Lectin Pathway April 18,

58 Problems for Complement Deficient Patients Higher susceptibility to bacterial infections, especially with encapsulated organisms N. meningitidis particularly problematic for those with deficiencies of C5,6,7,8, or 9 Higher propensity for autoimmune diseases, especially SLE or glomeronephritis April 18,

59 Primary Care across the Spectrum of Primary Immunodeficiencies April 18,

60 April 18, Role of the PNP in Pediatric Primary Immunodeficiency Routine primary care is critical, particularly in the assessment of growth and development Toddlers and pre-schoolers should be seen at least twice a year for well-child visits (on an alternate schedule with the immunologists so that they are seen every three months) School-age children and adolescents should be seen yearly (on an alternate schedule with the immunologists so that they are seen every six months) Insure immunization when appropriate

61 Vaccines Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) Unnecessary as child does not make antibody and receives gamma globulin therapy Live vaccines are ABSOLUTLEY contraindicated Family members need influenza vaccine Need all immunizations including an annual flu vaccination Need all immunizations including an annual flu vaccination April 18,

62 Treatment of Infections Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) May need a longer course of antibiotics than usual Any child with a fever > needs an urgent (i.e. same day) physical exam, a CBC and Blood culture and, if he appears ill, he will also need a dose of Ceftriaxone May need a longer course of antibiotics than usual Need to follow WBC count and CRP, as well as the physical exam April 18,

63 Use of Steroids Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) CVID/XLA: Usually okay, if indicated Avoid in SCID patients Usually okay, if indicated Try to avoid steroid use, especially inhaled steroids April 18,

64 Diagnostics Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) PCR’s, Not serologies CRP, Not ESR Routine diagnostics (CBC with differential, ESR or CRP, cultures) are appropriate Try to get cultures and sensitivities before treating infection Remember that the infection may be fungal rather than bacterial April 18,

65 Co-morbidities Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) Autoimmune disease, including IBD, JRA, and cytopenias SLE Glomerulonephritis GI disease secondary to granuloma formation in the gut Urinary tract obstruction, secondary to granuloma formation April 18,

66 Antibiotic Prophylaxis Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) Usually not needed for Agammaglobulinemia or CVID patients For children with SCID- need PCP prophylaxis: Bactrim 4-5 mg/kg/day divided BID on 3 consecutive days/week Penicillin mg BID Bacterial prophylaxis: usually Bactrim 4-5 mg/kg/day divided BID May need fungal prophylaxis: usually Itraconazole 2-5 mg/kg/day as a single dose April 18,

67 Routine Medications Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) Gamma globulin IV: mg/kg/month SQ: mg/kg/week Interferon gamma 50 mcg/m 2 sq TIW or 1.5 mcg/kg if BSA < 0.5 m 2 April 18,

68 Environmental Issues Antibody Deficient Child (e.g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e.g. CGD) Need to avoid: -outside play near mulch -swimming in fresh water -being around new construction or remodeling projects April 18,


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