Primary Immunodeficiencies Pediatric Resident Series Part 1

Primary ImmunodeficienciesPediatric Resident SeriesPart 1 Sean McKnight, MD, FAAAAI, FACAAI April 2011

Question #1 A 2 m/o baby boy (with normal birth history) presents to the ER with significant watery diarrhea since birth, diffuse rash, and new finding of left sided pneumonia. An older sibling died when he was 8 months old. What is the most concerning primary immunodeficiency?

Question #2 A previously healthy 14 y/o girl presents to your clinic with severe headaches and a finding of pan-sinusitis. She has labs showing: IgG 227 mg/dL, IgA 12 mg/dL, and IgM of 27 mg/dL, and IgE of 68. What is her most likely Immunologic diagnosis?

Question #3 As an astute pediatric resident, you make the diagnosis of selective IgA deficiency in a 15 y/o boy who has recurrent sinusitis and otitis infections. What is the recommended treatment for this patient?

Question #4 A 6 y/o hispanic boy presents to the ER with his 5th episode of pneumonia, recurrent ear infections despite PE tubes, and a history of failure to thrive. List 5 possible Immunologic diagnoses to consider

Primary Immunodeficiencies • Antibody Disorders • Cellular Disorders/Combined Disorders • Phagocyte disorders (CGD, Chediak-Higashi, LAD, etc.)

Immunodeficiencies E.R. Stiehm, Immunologic Disorders in Infants and Children

Most common forms of immunodeficiency • HIV/AIDS (must specify location) • MBL Deficiency (>> 1/500) • Selective IgA deficiency (1/500-700) • CVID (1/50,000) Board exams will often ask about the most common form of primary immunodeficiency – expecting the correct answer to be selective IgA deficiency. MBL has only come up in the past several years and it’s importance is highly debated.

10 Warning Signs of Primary Immunodeficiency The Jeffrey Modell Foundation: 1-866-INFO-4-PI • www.jmfworld.org

The distribution of lymphocyte subpopulations in human peripheral blood

1994 Revised HIV Pediatric Classification System: Immune Categories Based on Age-Specific CD4 T-cell Count Modified from Centers for Disease Control and Prevention: MMWR 43:1-10, 1994.

Incidence and Prevalence of antibody deficiency • Estimated for all immune deficiencies: • Incidence: 1/10,000-1/2,000 • Prevalence: 8-9/100,000 • For antibody deficiency: • Incidence: 1/20,000-1/4,000 • Prevalence: 4-5/100,000 • Antibody deficiency accounts for 50% of all immune deficiencies

Symptoms of antibody deficiency • Recurrent otitis media, sinusitis, pneumonia • Also can have cellulitis, osteomyelitis, meningitis, etc. • Frequent viral infections • Enteric infections (especially enteroviruses) • Onset may be delayed- protection by maternal Ab acquired during late gestation

Antibody Deficiency Infectious Organisms • Bacteria: pneumococcus, H. flu, meningococcus, Staph aureus, Pseudomonas, Campylobacter • Mycoplasma, ureaplasma • Viruses: enteroviruses, rotavirus • Protozoa: giardia, cryptosporidium • Common organisms are still the most common - but typically more severe and difficult to treat

Infectious Organisms Associated with PID Bonilla FA, Geha RS. JACI 2003: S571-S578

Antibody Deficiencies • Agammaglobinemias (XL,AR) • Common Variable Immunodeficiency • IgA deficiency • IgG subclass deficiency • Specific antibody deficiency • Transient hypogammaglobinemia of infancy

Agammaglobulinemias • X-Linked: Bruton’s tyrosine kinase (BTK) • Autosomal recessive (AR) • IgM mutation/deletion (IGHM) • Surrogate light chain, l5 (CD179B) • B cell linker protein (BLNK) • Leucine rich repeat containing 8 (LRRC8) • All clinically very similar • B cells blocked in the pre-B cell stage in all

X-Linked Agammaglobulinemia (XLA) • 85% of agammaglobulinemia • Presentation in infancy/childhood with recurrent sinopulmonary pyogenic infections • Enteroviral meningoencephalitis, vaccine strain poliomyelitis (oral vaccine), mycoplasma or ureaplasma arthritis • 25% with neutropenia, infection related • Generally improve with IVIG and antibiotics

XLA (continued) • 50% positive family history • IgG usually < 100 mg/dL • B cells < 2% of lymphocytes (usually 0.05-0.3%) • Normal T cell number and function • Almost all mutations lead to absence of BTK protein • 84% maternal, 16% grand maternal carriage rates

Common Variable Immunodeficiency (CVID) • Hypogammaglobulinemia (IgG, IgA, IgM, IgE) • Impaired antibody response • Recurrent sinopulmonary infections, bronchiectasis • Chronic enterovirus, arthritis, giardiasis • Autoimmunity • Lymphoproliferative disease • Gastric CA and lymphoma (300 fold increased risk)

CVID Overview • Marked reduction in serum IgG and IgA • IgM reduced in approx 50% of pts • 2 peaks in onset of infection • 1-5 y/o • 16-20 y/o • Diagnosis often not made until the 3rd or 4th decade of life! • Male=Female • Familial inheritance observed in approx 25% of cases • Possible environmental (infectious?) agent as triggering factor

Clinical findings in CVID • +++ Sinusitis(Hemophilus influenza, Streptococcus pneumoniae, Moraxella catharralis) • +++ Pneumonia(Hemophilus influenza, Streptococcus pneumoniae) • ++ Bronchiectasis • + Gastrointestinal infections (Giardia lamblia, Campylobacter jejuni) • + Meningitis(ECHO virus) • + Splenomegaly, lymphadenopathy, conjunctivitis, autoimmune disease, and increased risk of cancer

Reference range for serum immunoglobins based on age From the laboratories of Children’s Hospital, Boston, Mass.

Trends in immunoglobulins • There is a physiologic nadir in serum IgG concentration at 4-6 months • Among the IgG subclasses, IgG2 & IgG4 are lower in childhood and increase gradually to adult values • Serum IgA concentrations are the last to rise to adult values and are the first to decline in most primary immunodeficiencies

IgG Antibody Levels Vary with Age

IgA Deficiency • Absence of IgA (< 7 mg/dL) • 1:700 caucasians, usually asymptomatic • Associated with: • Chronic lung disease • Atopy • Rheumatoid arthritis, lupus, Sjogren’s, diabetes, pernicious anemia, hemolytic anemia, autoimmune hepatitis • Gastric CA, lymphoma

IgA Deficiency (Continued) • May be similar to CVID or IgG subclass deficiency • IgA deficiency “locus” (IGAD1) at MHC class II/III boundary (also implicated in CVID)

IgG sublcass deficiency • One or more IgG subclasses >2 SD below the age adjusted mean • Increasingly controversial as a diagnosis of immunodeficiency • Demonstration of an associated impairment of specific antibody formation is important

IgG subclass def. (Cont’d) • Normal in majority • Recurrent bacterial infections • Recurrent severe viral illnesses • Diarrhea, may be food related • Atopy • Vasculitis/autoimmune disease • Epilepsy • HIV infection/AIDS • Following BMT

IgG subclass def. (Cont’d) • IgG2 deficiency is common in young boys • IgG2 def also associated with +/- IgG4 and +/- IGAD • IgG4 deficiency is rarely associated with recurrent infections. Very commonly seen in certain populations. • Treatment is symptomatic, prophylactic antibiotics, but not IVIG unless also have functional antibody def.

Specific antibody deficiency with normal immunoglobulins (SADNI) • Recurrent sinopulmonary infections • Normal IgG, IgA, IgM, and IgG subclasses • Impaired vaccine response (polysaccharide) • Impaired antibody response to natural infection with encapsulated bacteria • Normal B cell number • Normal T cell number and function • Also called “functional antibody deficiency”

Functional tests of specific antibody production • Measurement of serum isohemagglutinins (anti-A and anti-B titers) in patients who are not blood type AB (Looks at IgM to polysaccharide blood group antigens A and/or B) • Children <1 y/o don’t have predictable isohemagglutinins • Isohemagglutinin antibodies should be greater than 1:10 titer in normal patients (except AB patients who have none!) • Measurement of a 4-fold or greater rise in titer of antibodies to protein antigens (diptheria or tetanus toxoid) after booster immunization • Measurement of antibodies produced in response to immunization with purified pneumococcal polysaccharide vaccine (Pneumovax)

Functional tests of specific antibody production - II • Normal antibody production would include a rise in specific antibody levels within 2 weeks for protein antigens and within 4-6 weeks for polysaccharide antigens • Very challenging to assess patient who has already received intravenous immunoglobin (IVIG) therapy • Bacteriophage FX174– novel antigen used to assess primary and secondary antibody response. Still considered experimental! Hans D. Ochs, MD at Univ of Washington is PI for this study.

Transient hypogammaglobinemia of infancy (THI) • Onset around 6 months of age • Resolves by 4 y/o • Recurrent sinopulmonary infections • Low IgG, normal specific antibodies • Normal lymphocyte number and function • Delay in maturation of T cell help for antibody production? • Defect unknown • Familial cases

IVIG therapy • The primary goal with IVIG is to prevent infections and to minimize damage to the lungs (Bronchiectasis) • Therapy should be started as soon as the diagnosis is made • Initial target therapy of 400-500 mg/kg every 2-4 weeks • Target to keep trough IgG levels >800 mg/dl (some studies suggest >1,000 mg/dL- Orange J, Clin of Immuno 2010)

IVIG Therapy - II • “The only indication for provision of IVIG to a patient with immunodeficiency is severe impairment of the ability to produce antibody” • Indicated for CVID, XLA, HIM, SCID, or functional antibody deficient patients with significant infections • Numerous manufacturers for IVIG • Relative contraindication is antibodies to IgA • Anaphylactic infusion reactions can occur in the rare patient who has IgE antibodies against IgA • Gammagard and Polygam both contain trace amounts of IgA, whereas others can have large quantities of IgA

IVIG Therapy - III • Has also been given via subcutaneous infusion – generally weekly w/ few side affects (Vivaglobin & Hizentra) • Produced from pools of plasma from plasma donations • Lots can contain plasma from 10,000 to 200,000 donors • Each donation is tested for hepatitis B surface antigen, HIV-p24 antigen, and antibodies to syphilis, HIV-1, HIV-2, and hepatitis C

Adverse reactions to IVIG • Can commonly see the following: • Back and abdominal aches/pain • Chills/fever • Myalgias • Headache • Less common: • Anaphylactic reaction • Aseptic meningitis • Renal dysfunction (sucrose?/osmolality) • Not reported: • HIV • Hepatitis A • Parvovirus B19

Question 1 4 y/o female with recurrent sinus and ear infections and history of pneumonia. Most likely diagnosis? • XLA • CVID • IGAD • IgG subclass deficiency

Question 2 5 m/o female with recurrent ear infections. IgG level is 283 mg/dL. What do you do next? • Repeat in 2-4 months • Start IVIG • Start prophylactic antibiotics and IVIG • Nothing

Reference range for serum immunoglobins based on age From the laboratories of Children’s Hospital, Boston, Mass.

Question 3 6 y/o boy with h/o pneumonia (2 episodes) and now diagnosed with bilateral maxillary sinusitis and nasal polyposis. What is in your differential diagnosis?

Nasal polyps in child • Think Cystic Fibrosis!!! • Sweat chloride test • Ask about diarrhea and foul smelling stool • Birth history: time to pass meconium • Family history: anyone else with CF?

Primary Immunodeficiencies Pediatric Resident Series Part 1