The PNPs Guide to Primary Immunodeficiencies So How

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The PNP’s Guide to Primary Immunodeficiencies …So How Many Ear Infections Are too Many?

The PNP’s Guide to Primary Immunodeficiencies …So How Many Ear Infections Are too Many? M. Elizabeth M. Younger CRNP, Ph. D Assistant Professor, Pediatrics The Johns Hopkins University School of Medicine Baltimore, Maryland Presented by: M. Elizabeth M. Younger CRNP, Ph. D 27 November 2020 1

Disclosures • Consultant, CSL Behring • Speaker, CSL Behring • Advisory Boards: – CSL

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

Systemic Responses to Infection • Host Defenses – Skin – Mucus Membranes – Normal

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 27 November 2020 4

Cells of the Immune System

Cells of the Immune System

Primary Immunodeficiencies • ~150 recognized defects of immunologic function • Another 39 disorders of

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 27 November 2020 6

Primary Immunodeficiencies • Disorders of Humoral Immunity-affecting B cell differentiation and antibody production •

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 27 November 2020 7

Does your patient have a primary immunodeficiency? 27 November 2020 8

Does your patient have a primary immunodeficiency? 27 November 2020 8

27 November 2020 10

27 November 2020 10

Things to consider… • • What kinds of infections How frequently Co-morbidities Factors that

Things to consider… • • What kinds of infections How frequently Co-morbidities Factors that might contribute to infections (e. g. day care!) • Family history 27 November 2020 11

Imperatives for the Primary Care Provider • Accurate record of immunizations • Maintain accurate

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? ) 27 November 2020 12

Screening Tests for Primary Immunodeficiencies Suspected Abnormality Diagnostic tests Antibody Serum Ig. G, Ig.

Screening Tests for Primary Immunodeficiencies Suspected Abnormality Diagnostic tests Antibody Serum Ig. G, Ig. A, Ig. M Antibody response to vaccines Cell-mediated immunity Lymphocyte count T cell enumeration (CD 4, CD 8) HIV serology/PCR Complement Total hemolytic complement (CH 50) Alternative Pathway (AH 50) Mannan Binding Lectin Phagocytes Neutrophil count Dihydrorhodium (DHR) test Nitroblue tetrazolium (NBT) dye test

…But always start with a CBC Range Units 2/28/03 Age-4 mos 3/17/03 3/21/03 WBC

…But always start with a CBC Range Units 2/28/03 Age-4 mos 3/17/03 3/21/03 WBC 5. 7 K-17. 7 K /cu mm 13, 600 6500 4470 RBC 3. 1 -4. 5 M/cu mm 3. 26 3. 54 3. 87 Hgb 9 -20 g/d. L 7. 6 8. 0 7. 9 Hct 29 -41 % 25. 3 26. 1 25. 7 Lymph % 43 -73 % 1 3 6 Mono % 3 -9 % 5 6 7 Neutro % 17 -49 % 92 90 86 Eo % 1 -4 % 2 1 1 Baso % 0 -2 % 0 0 0 # Lymph 2. 5 K-12. 9 K /cu mm 136 195 280 # Mono 200 -1600 /cu mm 680 390 290 ANC 1000 -8500 /cu mm 13, 600 5, 850 3, 830

Rule of 2/3’s For a child under the age of 3 years: 2/3 of

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 CD 4 cells 15

Normal Ranges of Immunoglobulins (mg/d. L) Age Newborn 1 -3 months 4 -6 months

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

Clinical Features of Immunodeficiency • Increased susceptibility to infection • Predisposition for autoimmune or

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 27 November 2020 17

Infections in Immunodeficient Patients • Chronic/recurrent infections without other explanation • Infection with organisms

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 27 November 2020 18

Disorders of Humoral Immunity 1. Transient Hypogammaglobulinemia of Infancy 2. X-linked Agammaglobulinemia (Bruton’s Agammaglobulinemia,

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 Ig. A deficiency 27 November 2020 19

Transient Hypogammaglobulinemia of Infancy • Characterized by – Low serum immunoglobulins – Little antibody

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 27 November 2020 20

Care and Treatment of the Child with Suspected Transient Hypogam • Serial monitoring of

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 27 November 2020 21

X-linked Agammaglobulinemia • • 1: 200, 000 live births No/few B cells, normal T

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 27 November 2020 22

Common Variable Immunodeficiency (CVID) • Approximately 20% of these patients are diagnosed under the

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 27 November 2020 23

Treatment of Humoral Immune Disorders • Regular infusions of pooled human gamma globulin (either

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 November 2020 26

Primary Care of the Child with Humoral Immunity Defects • Low tolerance for fever,

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 27 November 2020 27

Disorders of Cellular Immunity 1. Severe Combined Immunodeficiency (SCID) 27 November 2020 28

Disorders of Cellular Immunity 1. Severe Combined Immunodeficiency (SCID) 27 November 2020 28

Severe Combined Immunodeficiency (SCID) • Severe impairment of humoral and cellmediated immune function •

Severe Combined Immunodeficiency (SCID) • Severe impairment of humoral and cellmediated 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 27 November 2020 29

Treatment of SCID • Bone Marrow transplant • Gamma globulin replacement therapy • Antibiotic

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 27 November 2020 30

Combined T cell and B cell disorders 1. Di. George Syndrome 2. Wiskott-Aldrich Syndrome

Combined T cell and B cell disorders 1. Di. George Syndrome 2. Wiskott-Aldrich Syndrome 3. Ataxia Telangiectasia 27 November 2020 31

Di. George Syndrome • • 22 q 11. 2 deletion syndrome Velocardiofacial (VCF) syndrome

Di. George Syndrome • • 22 q 11. 2 deletion syndrome Velocardiofacial (VCF) syndrome Conotruncal anomaly face syndrome Autosomal dominant Opitz-G/BBB Incidence 1 in 3, 000 live births : 27 November 2020 32

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

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

Di. George Syndrome Catch 22 Mnemonic C ardiac defects (75%) A bnormal facies (70%)

Di. George 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 27 November 2020 34

C-Cardiac Defects • • Tetralogy of Fallot (17 -22%) Interrupted Aortic Arch (14 -15%)

C-Cardiac Defects • • Tetralogy of Fallot (17 -22%) Interrupted Aortic Arch (14 -15%) Ventriculoseptal defect (13 -14%) Truncus arteriosus (7 -9%) 27 November 2020 35

A-Abnormal Facies • • Ocular hypertelorism Lateral displacement of inner canthus Short palpebral fissure

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 27 November 2020 36

T-Thymic aplasia or hypoplasia • Thymic aplasia requires thymic or bone marrow transplant •

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 Ig. G • 2 - 4 % have Ig. A deficiency 27 November 2020 37

C-Cleft Lip/Palate (velopharyngeal abnormality associated issues) • Cleft palate (submucous cleft is common) •

C-Cleft Lip/Palate (velopharyngeal abnormality associated issues) • Cleft palate (submucous cleft is common) • Recurrent otitis media and sinusitis • Problems with speech articulation 27 November 2020 38

H-Hypocalcemia • Neonatal hypocalcemia occurs in 50 -70% of patients • Problem generally resolves

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 27 November 2020 39

Variability of Phenotype Driscoll et al. J Med Genet 1993; 30: 813 27 November

Variability of Phenotype Driscoll et al. J Med Genet 1993; 30: 813 27 November 2020 40

In a study of 195 patients: Associated Manifestations • Speech delay and other neurodevelopmental

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) 27 November 2020 41

Autoimmune Disease in Di. George Patients • Immune thrombocytopenia – 200 x over rate

Autoimmune Disease in Di. George Patients • Immune thrombocytopenia – 200 x over rate in general population • Juvenile rheumatoid arthritis – 20 x over rate in general population • Skin disease (psoriasis, vitiligo) • Autoimmune hemolytic anemia • Inflammatory bowel disease 27 November 2020 42

Neurodevelopmental Problems • Delayed acquisition of language milestones – At 2 y/o, 90% nonverbal

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 27 November 2020 43

Primary Care of the Di. George Patient • Once 22 q 11 deletion syndrome

Primary Care of the Di. George Patient • Once 22 q 11 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 27 November 2020 44

Wiskott-Aldrich Syndrome • X-linked • • Clinical Presentation Small platelets (Low MPV) and/or thrombocytopenia

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 27 November 2020 45

Primary Care of the Child with Wiskott-Aldrich Syndrome • Vigilance for signs of bleeding

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 27 November 2020 46

Treatment of the Wiskott-Aldrich Patient • Gamma globulin replacement therapy if antibody production is

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 CD 20 monoclonal antibody therapy (e. g. rituximab) • Treatment of chronic thrombocytopenia – Steroids – Splenectomy 27 November 2020 47

Ataxia Telangiectasia • • Autosomal recessive disease Ataxia (wobbly, scissor type gait) Telangiectasias of

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 27 November 2020 48

Care of the Child with AT • Gamma globulin replacement therapy if indicated •

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 27 November 2020 49

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

Disorders of Phagocytes 1. Chronic Granulomatous Disease 2. Leukocyte Adhesion Deficiency 3. Chédyak-Higashi Syndrome 27 November 2020 50

Chronic Granulomatous Disease (CGD) • Phagocytes have normal function, EXCEPT they cannot make an

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 27 November 2020 51

Frequent Pathogens • Staph aureus ~ 30 -56% of clinical isolates • Other Gram

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 27 November 2020 53

Diagnosis: Nitroblue Tetrazolium Test negative positive

Diagnosis: Nitroblue Tetrazolium Test negative positive

Clinical Presentation of CGD • X linked or, more rarely, autosomal recessive) • Recurrent

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 27 November 2020 55

Primary Care of CGD • Bacterial prophylaxis with trimethoprim/sulfamethoxazole Dose: 5 -10 mg/kg/day divided

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 3 x/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 27 November 2020 56

Complement Deficiencies Activation of the Complement System: – Classical Pathway – Alternative Pathway –

Complement Deficiencies Activation of the Complement System: – Classical Pathway – Alternative Pathway – Lectin Pathway 27 November 2020 57

Problems for Complement Deficient Patients • Higher susceptibility to bacterial infections, especially with encapsulated

Problems for Complement Deficient Patients • Higher susceptibility to bacterial infections, especially with encapsulated organisms • N. meningitidis particularly problematic for those with deficiencies of C 5, 6, 7, 8, or 9 • Higher propensity for autoimmune diseases, especially SLE or glomeronephritis 27 November 2020 58

Primary Care across the Spectrum of Primary Immunodeficiencies 27 November 2020 59

Primary Care across the Spectrum of Primary Immunodeficiencies 27 November 2020 59

Role of the PNP in Pediatric Primary Immunodeficiency • Routine primary care is critical,

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 27 November 2020 60

Vaccines Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia • Unnecessary

Vaccines Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia • Unnecessary as child does not make antibody and receives gamma globulin therapy • Need all immunizations including an annual flu vaccination Phagocytic Defect (e. g. CGD) • Need all immunizations including an annual flu vaccination • Live vaccines are ABSOLUTLEY contraindicated • Family members need influenza vaccine 27 November 2020 61

Treatment of Infections Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia

Treatment of Infections Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia • May need a longer • Any child with a fever course of antibiotics than > 100. 5 needs an urgent usual (i. e. same day) physical exam, a CBC and Blood culture and, if he appears ill, he will also need a dose of Ceftriaxone 27 November 2020 Phagocytic Defect (e. g. CGD) • May need a longer course of antibiotics than usual • Need to follow WBC count and CRP, as well as the physical exam 62

Use of Steroids Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia

Use of Steroids Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic Defect (e. g. CGD) • CVID/XLA: Usually okay, • Usually okay, if indicated • Try to avoid steroid use, if indicated especially inhaled • Avoid in SCID patients steroids 27 November 2020 63

Diagnostics Antibody Deficient Child (e. g. CVID, SCID) • PCR’s, Not serologies • CRP,

Diagnostics Antibody Deficient Child (e. g. CVID, SCID) • PCR’s, Not serologies • CRP, Not ESR Complement Deficiency or Asplenia • Routine diagnostics (CBC with differential, ESR or CRP, cultures) are appropriate Phagocytic Defect (e. g. CGD) • Try to get cultures and sensitivities before treating infection • Remember that the infection may be fungal rather than bacterial 27 November 2020 64

Co-morbidities Antibody Deficient Child (e. g. CVID, SCID) • Autoimmune disease, including IBD, JRA,

Co-morbidities Antibody Deficient Child (e. g. CVID, SCID) • Autoimmune disease, including IBD, JRA, and cytopenias 27 November 2020 Complement Deficiency or Asplenia • SLE • Glomerulonephritis Phagocytic Defect (e. g. CGD) • GI disease secondary to granuloma formation in the gut • Urinary tract obstruction, secondary to granuloma formation 65

Antibiotic Prophylaxis Antibody Deficient Child (e. g. CVID, SCID) • Usually not needed for

Antibiotic Prophylaxis Antibody Deficient Child (e. g. CVID, SCID) • Usually not needed for Agammaglobulinemia or CVID patients • For children with SCIDneed PCP prophylaxis: Bactrim 4 -5 mg/kg/day divided BID on 3 consecutive days/week 27 November 2020 Complement Deficiency or Asplenia • Penicillin 125 -250 mg BID Phagocytic Defect (e. g. CGD) • 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 66

Routine Medications Antibody Deficient Child (e. g. CVID, SCID) • Gamma globulin IV: 400

Routine Medications Antibody Deficient Child (e. g. CVID, SCID) • Gamma globulin IV: 400 -500 mg/kg/month SQ: 100 -125 mg/kg/week 27 November 2020 Complement Deficiency or Asplenia Phagocytic Defect (e. g. CGD) • Interferon gamma 50 mcg/m 2 sq TIW or 1. 5 mcg/kg if BSA < 0. 5 m 2 67

Environmental Issues Antibody Deficient Child (e. g. CVID, SCID) Complement Deficiency or Asplenia Phagocytic

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 27 November 2020 68