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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

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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Systemic Responses to InfectionSystemic Responses to Infection

• Host Defenses– Skin– Mucus Membranes– Normal Flora

• Non-Specific Responses– Complement– Phagocytes– Natural Killer Cells

• Specific Responses• Antibody Formation• Cellular Immunity

Cells of the Immune SystemCells of the Immune System

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Primary ImmunodeficienciesPrimary 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

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Primary ImmunodeficienciesPrimary 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

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Does your patient have a primary

immunodeficiency?

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Things to consider…

• What kinds of infections

• How frequently

• Co-morbidities

• Factors that might contribute to infections (e.g. day care!)

• Family history

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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?)

Screening Tests for Primary Screening Tests for Primary ImmunodeficienciesImmunodeficiencies

Suspected Abnormality Diagnostic tests

Antibody Serum IgG, IgA, IgM

Antibody response to vaccines

Cell-mediated immunity Lymphocyte count

T cell enumeration (CD4, CD8)

HIV serology/PCR

Complement Total hemolytic complement (CH50)

Alternative Pathway (AH50)

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 5.7K-17.7K /cu mm 13,600 6500 4470

RBC 3.1-4.5 M/cu mm 3.26 3.54 3.87

Hgb 9-20 g/dL 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 2.5K-12.9K /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 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

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Normal Ranges of Immunoglobulins Immunoglobulins (mg/dL)

Age IgG IgA IgM

Newborn 636-1606 1-4 6-251-3 months 176-906 1-53 17-105 4-6 months 172-814 4-84 27-1087-9 months 217-904 11-90 34-12610-12 months 294-1069 16-84 41-1491 year 345-1213 14-106 43-1732 years 424-1051 4-123 18-1683 years 441-1135 22-159 47-2004-5 years 463-1236 25-154 43-1966-8 years 633-1280 33-202 48-2079-10 years 608-1572 45-236 52-242Adult 639-1349 70-312 56-352

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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

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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

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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

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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

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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 101.5F or greater requires that the childhave a CBC, blood culture and physical exam

• Live viral vaccines should be held until immunocompetency is demonstrated

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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

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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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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

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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

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Disorders of Cellular Immunity

1. Severe Combined Immunodeficiency (SCID)

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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 causes45% X-linked15% Adenosine Deaminase Deficiency

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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

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Combined T cell and B cell disorders

1. DiGeorge Syndrome2. Wiskott-Aldrich Syndrome3. Ataxia Telangiectasia

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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

Fluorescence in situ HybridizationFluorescence in situ Hybridization

Korf B, N Engl J Med 1995;332:1219

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DiGeorge SyndromeCatch 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

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C-Cardiac Defects

• Tetralogy of Fallot (17-22%)

• Interrupted Aortic Arch (14-15%)

• Ventriculoseptal defect (13-14%)

• Truncus arteriosus (7-9%)

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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

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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

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C-Cleft Lip/Palate (velopharyngeal abnormality associated issues)

• Cleft palate (submucous cleft is common)

• Recurrent otitis media and sinusitis

• Problems with speech articulation

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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

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Variability of PhenotypeVariability of Phenotype

Driscoll et al. J Med Genet 1993;30:813

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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)

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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

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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

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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

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Wiskott-Aldrich Syndrome

• X-linked• Clinical Presentation

Small platelets (Low MPV) and/or thrombocytopenia

Impaired antibody responses Recurrent bacterial, viral and fungal infectionsEczema

• Associated ProblemsIncreased incidence of autoimmune disease

Increased incidence of malignancies, especially leukemias and lymphomas

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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

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

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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

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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

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Disorders of Phagocytes

1. Chronic Granulomatous Disease2. Leukocyte Adhesion Deficiency3. Chédyak-Higashi Syndrome

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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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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

Diagnosis: Nitroblue Tetrazolium Test

negative positive

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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

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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/m2 sq 3x/week or 1.5 mcg/kg if < 0.5 m2

• Routine primary care and immunization are critical

• Infections need to be treated for a long time and may require parenteral antibiotics

Complement Deficiencies

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

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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

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Primary Care across the Spectrum of Primary Immunodeficiencies

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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

VaccinesVaccines

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor 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

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Treatment of InfectionsTreatment of Infections

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor Asplenia

Phagocytic Defect(e.g. CGD)

• May need a longer course of antibiotics than usual

• Any child with a fever > 100.5 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

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Use of SteroidsUse of Steroids

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor 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

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DiagnosticsDiagnostics

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor 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

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Co-morbiditiesCo-morbidities

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor 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

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Antibiotic ProphylaxisAntibiotic Prophylaxis

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor 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 125-250 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

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Routine MedicationsRoutine Medications

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor Asplenia

Phagocytic Defect(e.g. CGD)

• Gamma globulin IV: 400-500 mg/kg/month SQ: 100-125 mg/kg/week

• Interferon gamma50 mcg/m2 sq TIW or1.5 mcg/kg if BSA < 0.5 m2

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Environmental IssuesEnvironmental Issues

Antibody Deficient Child(e.g. CVID, SCID)

Complement Deficiencyor Asplenia

Phagocytic Defect(e.g. CGD)

• Need to avoid: -outside play near mulch -swimming in fresh water -being around new construction or remodeling projects

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