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![Subcutaneous Immunoglobulin Replacement Therapy in Patients with Primary
Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study
Alessandra Vultaggio, Chiara Azzari, Cinzia Milito, Andrea Finocchi, Claudia Toppino, Giuseppe Spadaro, Antonino Trizzino, Martire Baldassarr
Aim
To evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with
primary immunodeficiency (PID) in a routine real-life situation.
Methods
In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for
24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human
IgG 16 %, Vivaglobin®, CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume
15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections
(SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization
Results
Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five
SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat
(ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off
school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months.](https://image.slidesharecdn.com/primarydefectinantibodyproduction-231221122708-2e035f7c/85/primary-defect-in-antibody-production-pptx-26-320.jpg)
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- 1. Primary Defects ofAntibody Production PRESENTER : DR. IRA KC MODERATOR: DR. SANTOSH GAUTAM
- 2. IMMUNE SYSTEM: complex networkof organs, cells and proteins that defends the body against infection, whilst protecting the body's own cells Protects against pathogen Check on auto-immunity Cancer surveillance IMMUNODEFICIENCY: Inability to produce an adequate immune response because of an insufficiency or absence of antibodies, immune cells, or both Increased susceptibility to infection Increased risk of autoimmunity/rheumatologic disorder Increased predisposition to malignancy
- 3. Systemic Responses toInfection Host Defenses Skin Mucus Membranes Normal Flora Non-Specific Responses (Innate Immune System) Complement Phagocytes Natural Killer Cells Specific Responses (Adaptive Immune System) Antibody Formation Cellular Immunity
- 4. Cells of theImmune System
- 5. Immune system ofbody
- 6. IMMUNODEFICIENCY Primary Abnormalities in developmentof immune mechanisms 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 Secondary Consequences of disease, drugs, nutritional inadequacies & other processes interfere with proper functioning of mature immune system EG : HIV : Nephrotic syndrome
- 7. December 21, 2023 Disorders ofHumoral Immunity (Antibody production) 1) X-linked Agamma - globulinemia ( Bruton’s Agamma-globulinemia, BTK deficiency, X-LAG) 2) Common Variable Immunodeficiency (CVID) 3) Selective IgA deficiency 4) Transient Hypo-gammaglobulinemia of Infancy 5) Immunodeficiency with hyper-IgM 6) X- linked lymphoproliferative disease
- 8. X-linked (Bruton’s) Agammaglobulinemia 1:200,000 live births, 1st immunodeficiency disease recognised. Described by Bruton ( 1952 ) Genetic features: x-linked recessive inheritance, males. Pathogenesis: abnormal gene XLA maps to q22 on the long arm of the X chromosome, encodes the B-cell protein tyrosine kinase Btk (Bruton tyrosine kinase). Helps in signaling and maturation of pre B cell. No/few B cells (pan hypogammaglobinemia), normal T cells
- 9. Clinical Features Boys,remain well till first 6-9 months of life Infections with extracellular pyogenic organisms , Mycoplasma Chronic fungal infections are seen; Pneumocystis jiroveci pneumonia rarely occurs Viral infections handled normally, except hepatitis viruses and enteroviruses Paralysis after live polio vaccine Failure to thrive A boy with recurrent pneumonia absent tonsils/ no palpable Lymph Nodes + positive family history Order serum immunoglobulin level
- 10. Diagnosis Serum concentrationsof IgG, IgA, IgM, and IgE are far below 95% confidence limits for appropriate age- and race-matched controls Total Immunoglobulins :<100mg/dl Flow cytometry: Absence of circulating B cells Mature B cells (CD19,CD20,BCR) absent in peripheral blood Under developed germinal centers of lymph nodes
- 11. Common Variable Immunodeficiency Hypogammaglobinemia with phenotypically normal B cells Age : 2nd -3rd decade of life Sex: M=F Recurrent pneumonia /sinusitis/ chronic diarrhea Phenotypic diagnosis with a polygenic inheritance Mutated (< 10 % case) ICOS, SH2DIA, CD19, CD20, CD21, CD81, BAFF-R, TACI similar clinically with XLA (except that enterovirus meningoencephalitis is rare ) Association with other autoimmune disease : high
- 12. Clinical Features Lungs:Pneumonia, Bronchiectasis, Acute or chronic Bronchitis Head and Neck: Rhinosinusitis, Otitis media, Conjunctivitis GIT: Acute Infectious Diarrhea(C.jejuni, Salmonella), H.pylori Infections Urinary Tract: Infections Joints: Septic Arthritis Skin: Herpes zoster, Molluscum CNS: Meningitis Systemic: Bacterial Sepsis
- 13. Approach SUSPECT PRIMARY IMMUNODEFICIENCY/HUMORAL DEFECT HYPOGAMMAGLOBULINEMIA B- CELLS ABSENT PRESENT X-LINKED AGAMMAGLOBULINEMIA COMMON VARIABLE IMMUNODEFICIENCY IG PROFILE
- 14. Transient Hypogammaglobulinemia ofInfancy Represents developmental delay in the production of immunoglobulin Most infants begin to produce IgG in the 1st 3 months, increases throughout infancy Small number either begin late or do not increase their production as expected Characterized by Frequent sinopulmonary infections Low serum immunoglobulins Condition may last into pre-school years Diagnosis can only be made definitively in retrospect key distinction : responses to vaccines preserved. Source of Diagnostic confusion
- 15. 15 Care and Treatmentof the Child with Suspected Transient Hypogammaglobinemia Serial monitoring of immunoglobulins and antibody titers Re-immunization may be necessary Awareness 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 child have a CBC, blood culture and physical exam Live viral vaccines should be held until immuno-competency is demonstrated
- 16. Selective IgA Deficiency MostCommon in this group incidence 0.33% in normal populations. Immunological features: Serum IgA<5mg/dl but normal IgM and IgG Genetic features : IgA Deficiency and genetic factors: associated with HLA-A2, B8 and DW3 or A1 and B8 Pathogenesis: failure in terminal differentiation of B cells due to intrinsic B cell defect or abnormal T cell help (TGF-B,IL-5) or in B cell responses to these cytokines
- 17. Selective IgA Deficiency ClinicalFeatures: Majority are asymptomatic Anaphylactic transfusion reactions Atopic disorders Recurrent infections in respiratory tract, Gastrointestinal tract, urogenital tract. Diagnosis cannot be made until about 4 years of age, when IgA levels should be matured to adult levels Treatment: Washed erythrocytes (frozen blood would have this done routinely) or blood products from other IgA- deficient individuals should be administered to patients with IgA deficiency. IVIG not recommended Not very severe life threatening
- 18. Hyper IgM syndrome Genetically heterogeneous Characterized by Normal/Elevated serum IgM levels associated with Low/Absent IgG, IgA, and IgE serum levels defect in the class switch recombination (CSR) process Causative mutations identified in the CD40 ligand gene ( X chromosome) and 3 genes on autosomal chromosomes: AID(Activation induced cytidine deaminase), UNG(Uracil DNA glycosylase) and CD40 gene on chromosome 20. All patients should undergo molecular analysis to ascertain the affected gene for purposes of genetic counseling, carrier detection, and decisions regarding definitive therapy.
- 21. X-linked Autosomal Recessive Genemutation CD40 ligand gene AID, UNG, CD40 Lymph node Abortive germinal centers with with depletion of follicular dendritic cells cells Giant germinal centers filled with highly proliferating B cells Susceptibility to P.jiroveci pneumonia marked No Treatment HLA identical Hematopoietic Stem Cell Transplantation, Granulocyte- CSF IVIg infusion, Antibiotics
- 22. X-linked Lymphoproliferative Disease Also known as Duncan Disease Two types namely ; XLP Type I AND XLP Type II XLP Type I: mutation in SH2D1A gene (encoding SAP) Can lead to uncontrolled cytotoxic T-cell response to EBV XLP Type II: mutation in XIAP gene
- 23. Clinical Presentation Fulminant InfectiousMononucleosis: Excessive proliferation of EBV-infected B cells, cytotoxic T cells and macrophage in various tissues including hematopoietic cells, brain, liver and heart massive infiltration of these cells into lymphoid and other organs extensive parenchymal damage including hepatic necrosis and bone marrow failure Thrombocytopenia, Anemia, hepatic dysfunction, meningoencephalitis, fulminant hepatitis Dysgammaglobulinemia: Decreased levels of IgG1 and IgG3 with elevated levels of IgM and IgA progress over time to include deficiencies of all isotypes of Immunoglobulins Lymphoma: Due to impaired immune surveillance and elimination by T cells
- 24. Mean yearof presentation: <5 yrs Affected males are usually healthy until they acquire EBV infection Asymptomatic until onset of complications Unfavorable Prognosis
- 25. Treatment of humoraldefects Immunoglobulin administration (IVIG or SCIG) at a dose of 400 mg/kg per month EXCEPT FOR THE CD40 LIGAND DEFECT AND XLP stem cell transplantation Judicious use of antibiotics to treat documented infections
- 26. Subcutaneous Immunoglobulin ReplacementTherapy in Patients with Primary Immunodeficiency in Routine Clinical Practice: The VISPO Prospective Multicenter Study Alessandra Vultaggio, Chiara Azzari, Cinzia Milito, Andrea Finocchi, Claudia Toppino, Giuseppe Spadaro, Antonino Trizzino, Martire Baldassarr Aim To evaluate the shifting from intravenous immunoglobulins (IVIGs) replacement therapy to SCIG in patients with primary immunodeficiency (PID) in a routine real-life situation. Methods In a multicenter prospective observational study, we enrolled 50 patients suffering from PID who were monitored for 24 months; 44 patients switched from IVIG and six from different SCIG preparations. The study preparation (human IgG 16 %, Vivaglobin®, CSL Behring GmbH, Germany) was subcutaneously infused weekly (maximum volume 15 mL/site; maximum infusion rate 22 mL/h). The study endpoints were: annual rate of severe bacterial infections (SBIs), local adverse reactions, quality of life, days off school/work, and days of hospitalization Results Thirty-three of 39 (84.6 %) patients who completed the study experienced an infection or signs thereof. Only five SBIs were observed, corresponding to an annual rate of 0.056 episodes per patient in 44 subjects [intention-to-treat (ITT) population]. A significant decrease in both days of hospitalization (1.93 ± 4.08 vs. 0.64 ± 2.94) and days off school/work (15.27 ± 23.17 vs. 2.26 ± 4.45) was recorded at 24 months.
- 27. Local reactions wereobserved in 14/50 (28 %) patients, mainly consisting of skin manifestations at the injection site. Only three (6.8 %) patients discontinued due to infusion site reactions. In patients shifting from IVIG to SCIG, the total mean score of Life Quality Index (LQI) improved from 76.9 ± 16.8 to 90.7 ± 11.6 (P < 0.01) at 6 months; there was an improvement also in the overall patients’ evaluation. Conclusions A total of 93.2 % patients tolerated the new route of administration and reported a significant improvement in their LQI. Our results from a routine clinical practice in a real-life population are consistent with those of phase III clinical studies.
- 28. Bibliography Nelsons Textbookof Paediatrics, 21st edition Uptodate 2023 Medscape Pubmed Thank you
Editor's Notes
- #12 ICOS (inducible co-stimulator) deficiency, SH2DIA (responsible for X-linked lymphoproliferative disease [XLP]), BAFF-R (Bcell– activating factor of the tumor necrosis factor family of receptors, , TACI (transmembrane activator, calcium modulator, and cyclophilin ligand interactor)
- #19 activation-induced cytidine deaminase (AID ) gene, the uracil DNA glycosylase gene (UNG ), and the CD40 gene on chromosome 20..