Immune Deficiency – Primary and Secondary

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