current concepts in investigation of immune deficiency & … · approach to adult with...
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Current concepts in investigation
of Immune deficiency &
Immunoglobulin replacement
therapy - Adults
Stan Ress
Emeritus Assoc Professor of Medicine, UCT
UCT Private Academic Hospital
Email: [email protected]
Approach to adult with
Recurrent Infections:
? IMMUNE DEFICIENCY
3 Important clinical rules
• Recurrent regional infections mandates
exclusion of anatomical defects.
• Secondary causes of Immune deficiency are
commonest.
• Primary immune deficiency can present for
the first time in Adults.
SECONDARY IMMUNODEFICIENCY
• HIV
• DIABETES
• ETHANOL
• IMMUNOSUPRESSIVE
DRUGS
• LIVER CIRRHOSIS
• MALIGNANCY
-myeloproliferative
-lymphoproliferative
-carcinoma
• GAMMAGLOBULIN LOSS
- nephrotic syndrome
- protein losing enteropathy
Diagnostic Challenge - PID
• May present for 1st time as adults - common
underlying problems - sinusitis and associated
bronchial hyper-reactivity & Allergy
• Early diagnosis important, to prevent
permanent sequelae such as bronchiectasis,
yet diagnostic delay common
Patient with Recurrent Infections:
? Immune deficiency
IMMUNE CLINICAL
1. B-cell Recurrent URTI/Pneumonia
2. T-cell Viral/Protozoa/fungus/mycobact
4. Phagocytosis Sup. skin or systemic infections:
low grade organisms
5. Complement Infections/autoimmunity
3. NK cell Recurrent viral
• Immune deficiency - Clinical Correlations outline
• Common Variable Immune Deficiency (CVID)
• IgA deficiency
• IgG subclass deficiency
• Selective IgG deficiency
• B -cell subsets & memory B-cells
• Ig replacement options & ASE
Outline of Topics
Common Variable Immune Deficiency - CVID
• Commonest primary, intrinsic disorder of anti –
body production in both children & adults.
• Markedly reduced serum IgG with low level IgA
and/or IgM together with:
i) proven lack of specific IgG production – test
immunizations.
ii) exclusion of other B-cell defects
& hematological conditions such as
multiple myeloma, CLL etc.
Specific IgG ELIZA
Baseline
• Strep. Pneumonia
• H. Influenza 0.80
• T. Toxoid 0.09
Post-vaccination
18.63 > 270
> 9
> 4
Induration - chin & nodules on lip & forehead - amyloidosis
71 Year-Old Lady
Lab Results
• Protein electrophoresis - monoclonal peak 3.6
g/L in Gamma region
• Low Serum IgA & IgG = immune paresis
• Serum Kappa light chains very elevated in
Free light chain assay
• Diagnosis - Myeloma
Patient with Recurrent Infections:
? Immune deficiency
The case of recurrent lung
infection & rapid onset
bronchiectasis in a 28 year
old man
• March 04: mediastinal biopsy Thymoma
• May 04: Radiotherapy
June 04 – Ig levels requested
IgG 4,61 g/l (7 -16)
IgA 0,32 g/l (0,7 - 4)
IgM <0,25 g/l (0,4 – 2,3)
Thymoma and hypogammaglobulinaemia
= Good syndrome (Robert Good –1954)
Rare, (5-6% thymomas) adult onset (29-75)
immune deficiency @:
hypogammaglobulinemia, variable T-cell defect
with OI’s, lymphopenia, eosinopenia, other
hematological disorders.
Common Variable Immune Deficiency - CVID
• Commonest primary, intrinsic disorder of anti –
body production in both children & adults.
• Markedly reduced serum IgG with low level IgA
and/or IgM - exclusion of other B-cell defects
& haematological conditions such as myeloma.
• Exclude cystic fibrosis, immotile cilia syndrome, PLE
• Recurrent sinusitis & URTI’s bronchiectasis.
• Autoimmunity, enteropathy, lymphoid malignancy.
• Heterogeneous, clinically diverse disorder.
Severe IgA deficiency
• 15 year-old girl with Asthma, recurrent respiratory
tract & Sinus infections since age of 3, with severely
reduced IgA of 0.07 g/L & normal IgM , IgG & IgG
subclasses. Mild bronchiectasis, impaired baseline AB
memory, but a good response to vaccination:
Baseline Post-Vaccination
• Strep. Pneumonia 23.78 151
• H. Influenza 0.25 >9
• T. Toxoid 0.01 1
IgA deficiency - management
• Optimal management of allergic rhinitis & asthma
• Diagnose bacterial RTI’s & Rx antibiotic therapy
• Wean off excessive steroid use & dependency
• Prophylactic ABs in view of recurrent infections
& established bronchiectasis
• No Immunoglobulin replacement therapy at this
stage - vaccination response demonstrates good
functional antibody production
• Total or Partial IgA deficiency
• Recurrent sinopulmonary infections
• Autoimmune disorders: cytopenias & SLE
• GIT infections, Celiac disease & IBD
• Allergic disorders: rhinitis & Asthma
• Anaphylactic transfusion reactions - anti-IgA Abs
• Many asymptomatic, severity & complications seen in
total IgA or associated IgG subclass deficiency
2 Faces of IgA deficiency
IgG Subclass Deficiency
54 year-old lady with recurrent respiratory tract &
sinus infections, & reduced IgG 2 & 3 subclasses, was
actually treated with IVIG on this basis. However,
antibody response to vaccination was intact.
Total IgG 7.04 g/L
IgG1 4.69
IgG2 1.23 (1.69 – 7.86)
IgG3 0.10 (0.11 – 0.85)
IgG4 0.08
% Distribution (N)
76 ( > 60)
20 ( > 10-15)
1.6 (> 5)
1.3
98.9
Valuable QC - check result validity JACI 2013
1. 1 or more significantly reduced IgG subclasses (~10%)
with near normal total serum IgG.
2. Inadequate response to vaccination.
3. Recurrent Infections.
3 Criteria to Diagnose Clinically
Significant IgG Subclass Deficiency:
Management consists of aggressive treatment of predisposing
allergic rhinitis & asthma, appropriate AB Rx, Prophylactic
Abs if sinopulmonary infections still persist despite these
measures, & IVIG if strict criteria for this are met.
Selective IgG deficiency
• Patients with recurrent infections who present with
modest reduction of serum IgG 5-7 g/L.
• Frequently have Allergic Rhinitis & recurrent Sinusitis,
often Asthmatic with significant steroid use as a cause.
• Hypogammaglobulinaemia due to steroid use can be
diagnosed by preservation of functional antibody production:
adequate baseline memory or a good response to vaccination
with pneumovax , H. Influenza and Tetanus Toxoid.
• Poorly defined “chronic infections”, fatigue, borderline IgG.
• Progression to immune deficiency may be predicted by
analysis of B-cell memory subsets by Flow Cytometry.
B-cell Subsets
• Naïve B-Cells IgD+ CD27-
• Non-Class-switched Memory B-cells IgD+ CD27+
• Class-switched Memory B-cells* IgD- IgM- CD27+
• IgM+ Memory B-cells* IgD+ IgM+ CD27+
(spleen marginal zone)
* Reduction in Class-switched & IgM+ memory B-cells
are most commonly seen in primary immune deficiency
& associated with complications such as pneumonia.
Indications for IVIG
1. Primary Antibody deficiency.
2. Immune modulation of autoimmune &
immune dysregulation syndromes.
3. Prevention & treatment of infectious
diseases.
4. Miscellaneous, eg. Kawasaki’s disease &
severe, uncontrolled Asthma.
Primary Antibody Deficiency
• Selective IgA Deficiency
• Selective IgM Deficiency
• Selective IgG Deficiency
• IgG Subclass Deficiency & SAD/SPAD
• Common Variable Hypogammaglobulinaemia
With recurrent infections, proven lack of response to test
vaccinations, and exclusion of other causes of reduced serum Ig.
Options & Preparations
Available
1. IV Ig preparations:
i) Polygam - NBI 2-3 % sucrose
ii) Octagam - Octopharma 5% maltose
2. SC Ig
Beriglobin CSL Behring (Mirren) 16%
Dose clinically or treat to target?
• Pneumonia incidence declined by 27% with each g/L increment.
• Pneumonia incidence with 5 g/L IgG trough was 5-fold that
with maintenance of 10 g/L ( N. Range 7-16 g/L)
• Alternate view is to treat according to clinical infections –
must individualize therapy.
• Acute Kidney Injury: osmotic nephrosis and ARF due to sugar
containing preparations (especially sucrose ) damaging
proximal renal tubules (cf Mannitol osmotic nephrosis )
• Risk factors are pre-existing renal disease, diabetes,
dehydration, age >65, sepsis, hyperviscosity due to
paraproteinemia, & concomitant use of nephrotoxic meds
• AKI can resolve on stopping IVIG but may be irreversible
• Prevent by ensuring adequate hydration, infusion rate
maximal 3mg sucrose/kg/min
• Monitor renal function soon after IVIG initiation, &
regularly thereafter
Renal Failure - IVIG
Polygam NBI 2-3% Sucrose
Sect 21
adults: A scoring system to guide decisions on immunoglobulin
replacement -J ALLERGY CLIN IMMUNOL
