Immunodeficiencies By Angela Migowa Pediatric Rheumatologist Aga Khan University EPLS Instructor RCUK MBCHB UON MMED Pediatrics and Child Health AKUHN Pediatric Rheumatology McGill ID: 909650
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Immunoglobulin Therapy in Primary Immunodeficiencies
By Angela MigowaPediatric Rheumatologist Aga Khan UniversityEPLS Instructor (RCUK) MBCHB (UON), MMED Pediatrics and Child Health (AKUHN), Pediatric Rheumatology (McGill)
Slide2Slide3Objectives
To understand the mechanism of action of Immunoglobulin Therapy in management of Primary ImmunodeficienciesTo describe the indications of Immunoglobulin Therapy in primary immunodeficiencies
To outline the formulations and dosing of immunoglobulins
Slide4OutlineHistorical perspective of Immunoglobulin
TherapyThe status of Immunoglobulin Therapy in Africa and KenyaMode of action of Immunoglobulin TherapyIndications of Immunoglobulin Therapy in PID’sDosing, Formulation and Toxicity of Immunoglobulin TherapyQuestionsSummary
Slide5The Great Overlap
Slide6Definitions
Therapeutic immunoglobulin is a blood product derived from thousands of healthy, pooled donors and preparations are made up of almost exclusively IgG (although commercially available products also contain trace amounts of IgA and IgM).Schwab I et al. Nat Rev Immunol. 2013;13(3):176–189.
Sandomenico A et al. Mol Biotechnol. 2013;54 (3):983–995.
Slide7Historical PerspectiveS
erum from animals or convalescent humans for treatment and prevention by end of the 19 century.Purification of Immunoglibulin G (IgG) in the 1940’s Human Ig
subcut replacement therapy first performed in 1952, by Bruton, in patient with agammaglobulinemia Since
the 1960’s, different
intravenous preparations
S
ubcutaneous
administration
increasingly
used in the last 10 to 15
years
Berger M et al. United States: Academic Press; 2014. pp. 307–377
.
Wasserman RL et al. Allergy
Clin
Immunol.2015;135(2
Suppl
)
Slide8Raising Awareness to improve the current status of PID on the Continent: The A Project
56 African Countries
Gross undiagnosis
and misdiagnosis of PIDs on the continent
Caregivers cannot easily access congresses/resources
Patients have no voice
Urgent need to improve lives of African PID patients
Urgent need to document the African genetic PID landscape
Courtesy Prof J. Chipeta
Slide9Slide10Mode of Action of IVIG
Slide11Slide12Indications of Therapy
Slide13Goal of Therapy
The goal of therapy is to provide levels of functional serum IgG expected in normal subjects, and sufficient amounts of passive antibodies capable of neutralization and opsonization of broad categories of infectious pathogens.Albin S et al. Immunotherapy. 2014; 6(10): 1113–1126
.
Slide14Pre-requisites to IVIG Administration
Improved education among healthcare workersAppropriate patient workup before initiation of therapy. Baseline immunoglobulin levelsSpecific antibodies to prior vaccinations
Screening for potential blood borne infections eg HIV, Hepatitis
Slide15Administration
Currently two routesIntravenous (IVIG), first approved for use in 1979 subcutaneous (SCIG), first approved for use in 2006 [80].Biochemical properties should be considered in the context of unique patient profiles
.Starting in doses between 400 and 600 mg/kg every 3–4 weeks intravenously or twice weekly subcutaneouslyImmune Deficiency Foundation. Immunoglobulin products. www.primaryimmune.org/treatment-information/immunoglobulin-products/
Slide16Indications
Slide17X-Linked Agammaglobulinemia
Caused by a mutation in the gene for Bruton’s tyrosine kinase, which leads to a marked reduction in B cells and agammaglobulinemia.Present with recurrent bacterial infections such as otitis, sinusitis and pneumonia, with physical exam findings of absent or barely detectable tonsillar
lymph node tissue. Immunoglobulin replacement proven successful in preventing infections and allowing patients to lead healthy and productive lives.Debost-Legrand A et al. Gene. 2013;527(1):
426–428
.
Slide18Common Variable Immunodeficiency
Hypogammaglobulinemia with a variety of T cell abnormalitiesClinical manifestations include infections, autoimmunity and cancer.Infections from encapsulated, atypical bacteria and parasites eg GiardiaImmunoglobulin replacement may be used in conjunction with prophylactic antibiotics
.Immunoglobulin does not primarily treat the noninfectious manifestations of CVIDCunningham-Rundles C et al. Blood. 2010;116(1):7–15.
Slide19Hyper IgM Syndromes
Hyper IgM syndromes (HIGM) are a group of antibody deficiencies characterized by defective CD40/CD40L interactionsImmunoglobulin therapy is indicated for all forms Additional treatments include prophylactic antibiotics GCSF for neutropenia and bone marrow transplant
Quartier P et al. Clin Immunol. 2004;110(1):22–29.
Slide20Wiskott Aldrich Syndrome
Wiskott-Aldrich syndrome is a triad of recurrent infections, microthrombocytopenia and eczemaPatients also are predisposed to autoimmune disorders and malignancies
It is an X-linked disease caused by mutations in the WASP gene. WASP protein is involved in the transduction of signals from receptorsBone marrow transplant is the only cure Supportive treatment includes immunoglobulin therapy, antimicrobials, platelet transfusions
Massaad
MJ et al.
Ann NY Acad Sci. 2013;1285:26–43.
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is a heterogeneous group of genetic disorders characterized by significant T-cell deficiency, with variable production and function of B and NK cells [67].Infants born are normal at birth, but infection and failure to thrive manifest as passively transferred maternal antibodies begin to waneConsidered
a pediatric emergencyWhile awaiting transplant, patients are given prophylactic antibiotics and immunoglobulin replacement.Bousifa A et al. Front
Immunol
. 2011;2:54
.
Dvorak CC et al. J
Clin
Immunol
. 2013;33(7):1156–1164.
The Bubble Boy
Slide22When to be cautious with IVIG therapy
Slide23Selective Ig A Deficiency
Asymptomatic patients with selective IgA deficiency do not need immunoglobulin treatmentRecurrent infections should be treated as neededSelective IgA deficiency is not an indication for immunoglobulin, and administration may lead to anaphylaxis or similarly severe reactions for IgA-deficient patients who have IgG or IgE
anti-IgA antibodies Burks AW et al. N Engl J Med. 1986;314(9):560–564.
Slide24Toxicity
Slide25Adverse Effects
Symptoms and signs
FrequencyRelated to infusion rate
Chills
Frequent
Headache
Frequent
Dyspnea
Frequent
Chest pain or tightness
Frequent
Back pain
Frequent
Fatigue and malaise
Frequent
Fever
Frequent
Hypotension or hypertension
Frequent
Myalgia
Frequent
Nausea and vomiting
Frequent
Pruritus
Frequent
Skin rash and hives
Frequent
Flu-like symptoms
Frequent
Tachycardia
Frequent
Types and frequency of adverse effects associated with administration of intravenous immunoglobulin
https
://
www.ncbi.nlm.nih.gov/pmc/articles/PMC5823061
Slide26Adverse Effects
Symptoms and signs
FrequencyTachycardiaFrequent
Central nervous system
Aseptic meningitis
Rare
Severe headache
Rare
Renal
Acute renal failure (acute tubular necrosis)
Rare (usually associated with sucrose as a stabilizer)
Azotemia
Rare
Thromboembolic events
Thrombosis and cerebral infarction
Rare
Myocardial infarction
Rare
Pulmonary thromboembolism
Rare
Posterior leukoencephalopathy syndrome
Rare
Types and frequency of adverse effects associated with administration of intravenous immunoglobulin
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823061/
Slide27Imperatives 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
prescribe
work?)
Slide28Questions?
Slide29Summary
Slide30Slide31Thank you
Slide32Summary