Immune Deficiency – Primary and
Secondary
Dr Liz McDermott
Immunology Department
NUH
Summary
• Different types of Immune Deficiency
• Why it is important to identify immune
deficiency?
• Diagnostic delay
• Antibody deficiency
• Treatment of primary and secondary immune
deficiency
• Immunoglobulin replacement
Primary Immune Deficiency –
genetics +/- environment
• Antibody deficiency
– XLA (X Linked Agammaglobulineamia) - (early)
– CVID (common Variable Immune Deficiency)
Selective IgA deficiency
– Specific antibody deficiency
• Chronic Granulomatous Disease
• Combined immune deficiency
– Ataxia Telangiectasia
• Complement deficiencies
Secondary Immune Deficiency
• Malignancy
• Lymphoproliferative disease
• Uraemia
• Drugs – steroids, immunosuppressants, anti-convulsants,
Biologics
• HIV
• BMT
• Extremes of age
• Asplenia
• Malnutrition
• Burns
• Diabetes
• Protein losing enteropathy
Rituximab
• Anti-CD20 monoclonal antibody
Figure from van Meerten and Hagenbeek. Seminars in
Hematology 2010
Why Is It Important to Identify
Immune Deficiency?
• In acute infections the investigation &
management is different
– Unusual pathogens, persistent infection
• In Primary Immune Deficiency treatment is
available in most cases
– e.g. Immunoglobulin replacement therapy
• Early Diagnosis improves clinical outcome
– Prevents organ damage e.g. bronchiectasis
– Life-saving
Diagnosis of Primary Immune
Deficiency is often delayed - Why?
• Rare
– IgA deficiency 1 : 400-800
– CVID (Common Variable Immune Deficiency)
1 : 25 000-66 000
• Presents in a common way – most patients with
infections do not have immune deficiency
• A new type of immune deficiency identified every
few months! Particularly with Next Generation
Sequencing
How Can Diagnostic Delay Be
Reduced?
• Any thoughts?.......
When to Consider Immune
Deficiency
Need to differentiate between “normal” and
“immune deficiency” pattern of infections
Infections
• S evere
• P ersistent
• U nusual/opportunistic
• R ecurrent
• Associated problems: unusual inflammation,
autoimmunity, granulomata,
Pattern of Infection Indicates Type of
Primary Immune Deficiency
1) Recurrent sinopulmonary bacterial infections
– Antibody deficiency
– (Complement deficiency)
– (Phagocyte deficiency)
2) Recurrent Pyogenic infections +/- Fungal
(Chest, lymphadenitis, skin, abscess)
– Phagocyte deficiency
How do you investigate recurrent
sinopulmonary infections?
– Immunoglobulins
– Functional / Specific antibodies to tetanus, Hib,
pneumococcus (with immunisation history)*
– T & B cell numbers (lymphocyte subsets)
– Complement screening (Immunology input)
– Not IgG subclasses as first choice
– *Sero-specific pneumococcal antibodies
Primary Antibody Deficiency
• 1:25000
• Common Variable Immune Deficiency (CVID)
• X-Linked Agammaglobulinaemia (XLA)
– No mature B cells
• Specific antibody deficiency
– normal Igs, poor response to vaccination
• Selective IgA deficiency
– Most asymptomatic
Presenting Infections in Antibody
Deficiency• Respiratory infections
• Ear
• Sinus
• G I infections
• Cutaneous infections
• CNS/Meningitis
• Septic arthritis/osteomyelitis
• Ophthalmic
What are the roles of
antibodies/immunoglobulins?
The role of immunoglobulins
• Opsonization: Cover microbes to help phagocytes &
APCs to engulf them (extracellular bacteria), mainly
IgG1 & IgG3
• Neutralization: bind to antigen & then stops the antigen
bind to the tissues, IgM>IgG (viruses, toxins)
• Activate the complement system: which assists
phagocytosis, other roles of complement, mainly IgM,
also IgG1 & IgG3
• Antibody dependent cell cytotoxicity: helps cytotoxic
action of NK cells (viral infected cells)
Phagocytosis assisted by IgG and complement
Half-life IgG 21 days IgA 10 days IgM 6 days
T & B cell Interaction
T cell B cell
CD40CD40L
cytokines
Treatment
Treatment in Primary and
Secondary Immune Deficiency
• Prompt antibiotics & prolonged course in
acute infections
• IV or SC Immunoglobulin replacement
therapy (IVIG or SCIG)
• +/- prophylactic antibiotics
• Culture everything!
• Treat complications
SCIG infusion in a Child
Case
• Age 48 male
• Referred with recurrent chest infections
• Well as child/younger person
• Early 40s developed recurrent chest
infections
• Admitted with pneumonia 18/12 ago
• Recent admission pneumonia, Strep Pneum
Case
• Winter months worst
• Often need 2 course of antibiotics to clear
infection
• Weight loss recently (2 Kg)
• No nights sweats
• No family history
• No medications
What immunology tests would you do?
Investigations
• IgG 1.02 ( 5.3-16.5) mg/l
• IgA 0.20 (0.8-4) mg/l
• IgM 0.12 (0.5-1.9) mg/l
• No paraprotein
• No Bence Jones protein
Functional Antibodies
• Pneumococcal abs <1.50 mg/L (>40)
• Tetanus abs 0.15 IU/mL (>0.15)
• H. influenzae b (Hib) abs 0.03 mg/L (>1.0)
Pneumo & Hib very low
Pneumovax II & Hib immunisations given & then
retest after 4 weeks
“Test Immunisation”
Post-Vaccination Levels
• Pneumo abs <1.50 → 3.56 mg/L
• Hib abs 0.03 → 1.02 mg/L
• Should see about 3 fold increase and be in
normal range
Other Investigations
• Lymphocyte subsets (markers): normal T &
B cell numbers but low class switched
memory B cells (CD19/IgG/CD27)
• HRCT scan chest: bronchiectasis RLL
• Bone Marrow: normal
• CT chest/abdo/pelvis: few small abdominal
lymph nodes, nil suspicious of lymphoma
Diagnosis
• Primary antibody deficiency
• Most likely CVID (Common Variable Immune
Deficiency)
• Diagnosis of exclusion - Negative genetic tests
for other causes: X Linked
Agammaglobulinaemia, X Linked Lympho-
proliferative disease, etc.
Treatment
• Treat IVIG replacement
• Chest physio
• Prompt antibiotics for acute infections &
double usual length course
• Microbiology specimens wherever possible
IVIG
• Mechanism of action
– Replacement therapy
– Immuno-modulatory
• DOH demand management plan
– Prescribing IVIG
– IVIG database
Immunoglobulin replacement therapy
• IgG purified from plasma pool from 6000-10,000
donor units
• Highly processed to reduce blood borne infection
• Replacement: 0.4-0.6g/Kg/month, adjusted to
response
• IVIG given 3 weekly, SCIG given weekly
• No clonal expansion, so no focussing to current
infection
• Immunomodulatory: high doses, one off
How does it work?
• Complex!
• In Immune deficiency – replaces
absent/poor quality IgG
• High dose has immuno-modulatory effects
on adaptive & innate immune system
Clinical Indications Priority
Red Highest Priority
Blue Reasonable evidence base
but other treatment options
available
Grey Lowest priority. Weak
evidence base
Black Evidence to suggest
immunoglobulin is not
appropriate
DOH National Guidelines for the
appropriate use of Immunoglobulin
BLUE Priority - MEDIUM
BLACK IVIG Not Indicated
Available at all times
Automatic approval
Reduced use in times of shortage Panel approval
required
Case by case basis. Panel and
PCT funding approval required
Automatic rejection by
panel
IVIG given
IVIG given
IVIG given if Panel and
commisioners’ approval
IVIG is NOT given
RED Priority-
HIGH
GREY & UNLISTED
Priority -LOW
Selection Criteria
Outcome Measures identified
Selective IgA Deficiency
• Absent IgA but normal IgG & IgM
• Normal functional antibodies
• Common, 1:500-600
What problems are associated?
• Majority asymptomatic
• Increased risk autoimmunity & atopy
• Rarely, recurrent respiratory/GI infections
Selective IgA Deficiency
• IgA based tests for Coeliac disease are non-informative
– IgA anti tissue transglutaminase
– IgA anti endomysial antibodies
• IgG based tests for Coeliac disease less sensitive or specific so less helpful
• Serology alone may miss Coeliac disease in IgA deficiency
Chronic Granulomatous Disease
(CGD)• Rare inherited disorder of phagocytes
– 1 in 200 000
• Failure of “respiratory burst” due to
defect/deficiency of component of NADPH oxidase
complex in phagosome
– Membrane-bound components gp 22 & gp91
– Cytosolic components p47, p67, p40 & p21
– X-linked or Autosomal recessive
Leads to ineffective intracellular killing
Phagocytosis assisted by IgG and complement
CGD• Susceptible to serious, life-threatening infections
• Problems with
– Catalase-positive bacteria e.g. Staph aureus, Salmonella, Klebsiella
– Fungi e.g. Aspergillus
• Main sites of infection: lungs, skin, lymph nodes
• Chronic granulomatous inflammation
– Colitis, mimics Crohn’s disease
• Obstruction of hollow organs
– Oesophageal/Urinary tract/Gastric outlet obstruction
Diagnosis
• NBT (Nitro blue tetrazolium) Test
– Yellow dye
– Turns purple when reduced
1. Activate neutrophils and add dye
→ neutrophils ingest dye and produce superoxide radicals
2. View down microscope to see colour change (absent in CGD)
Unstimulated
Stimulated
Control CGD Patient CGD Carrier
Unstimulated
Stimulated Stimulated
Unstimulated
Treatment CGD
• Prophylactic CoTrimoxazole
• Prophylactic antifungals
• BMT / gene therapy – better outcome in
younger age
• Acute infections – use antibiotics with good
cell penetrance e.g. Cipro, Tazocin
Summary
• Think Immunodeficiency – primary
or secondary
• Secondary Immune deficiency
becoming more common
• Infections: SPUR
• Look for unusual pathogens
• Treat more aggressively
• Discuss with Immunologist early
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