The use of Immunology The use of Immunology tests in clinical practicetests in clinical practice

Dr Charu ChopraDr Charu ChopraSpR ImmunologySpR Immunology30th June 201030th June 2010

Learning ObjectivesLearning Objectives5 clinical case histories, with lab test data. MRCP part 2 style format questions

Complement

Acute antibodies

Cryoglobulins

Anti-nuclear antibodies

Immunoglobulins

Q1. A 19 year old man presents to A&E with swelling of his lips and tongue. He is quite anxious and short of breath. You establish that his saturations are 100% on 20% oxygen and there is no stridor. His blood pressure is 120/85 mmHg. He was given a single dose of 10 mg iv chlorpheniramine and im adrenaline (0.5mg) by the paramedics. There is no skin rash. His father died many years ago after a sudden collapse.

What one diagnostic test would you perform?

A) Total immunoglobulinsB) Serum IgE levelsC) Mast cell tryptaseD) C1 inhibitor level and functionE) C3 and C4 levels

What is the diagnosis?

Answer: D

Hereditary Angioedema (HAE)Hereditary Angioedema (HAE)

Prev 1 in 50,000 (USA)

Recurrent well circumscribed swellings affecting skin, intestine and airway

NO urticaria

Mortality 20-30% in the past

Autosomal Dominant; C1 inh gene chromosome 11

Tests: C1 inhibitor level and function

PathophysiologyPathophysiology

TreatmentTreatment

C1 inhibitor concentrate (20 units/ kg) iv over approx 30 mins

Adrenaline/ anti-histamines do NOT work

Fig 1 Immunofluorescence with patient Fig 1 Immunofluorescence with patient serum applied to Ethanol fixed neutrophilsserum applied to Ethanol fixed neutrophils

Q2. A 55 year old Caucasian man presents with haemoptysis, shortness of breath and malaise. He is a non smoker and has had these symptoms for 4 months during which he has lost 6kg in weight.

What does the slide demonstrate?

A) Anti-nuclear antibodies B) Anti-GBM antibodies C) Macrophage Activation Syndrome D) C-ANCA positivity E) None of the above

Answer: D

What is the diagnosis?

What further test would you do?

Q3 A 47 year old man (previous IVDU) presents with a 2 year history of joint pains, purpuric rash and Raynaud’s phenomenon. His urine dipstick is positive for protein + and blood ++.

What test would be most likely to yield a diagnosis? A) Complement levels B) Immunoglobulins C) Liver/kidney autoantibodies D) Anti-nuclear antibody E) Cryoglobulins

Answer: E

What further tests would you do?

Answer: Viral hepatitis serology, rheumatoid factor, C3/C4

Presence in the serum of one (monoclonal) or more (mixed cryoglobulinaemia) immunoglobulins which precipitate at temperatures< 37 C and redissolve on warming

Symptoms: Skin Joints Kidneys

hyperviscosity

Igs deposition / complement activation/ vasculitis

CryoglobulinaemiaCryoglobulinaemia

CryoglobulinsCryoglobulins

Type 1 monoclonal immunoglobulin: Haematological malignancies (CLL, CML, NHL, MM, Hodgkin’s, Waldenstrom’s)

Type 2 (mixed) monoclonal and polyclonal components. Rheumatoid factor +

Type 3 (mixed) polyclonal immunmoglobulins. Rheumatoid factor +

Type2/3 : HIV, Hep C/B, Sjogren’s, SLE, PAN, Scleroderma, Anti phospholipid syndrome, Familial

Fig 2 Immunofluorescence with patient Fig 2 Immunofluorescence with patient serum applied to Hep 2 cellsserum applied to Hep 2 cells

Q4 What does this image show?

What conditions are associated with this serological profile? A) SLE B) Drug induced Lupus C) Rheumatoid arthritis D) Infection E) All of the above

Answer : E

Fig 3 Immunofluorescence to detect ds Fig 3 Immunofluorescence to detect ds DNA antibodies (Crithidia luciliae DNA antibodies (Crithidia luciliae

kinetoplast)kinetoplast)

ds DNA antibodies highly specific for SLE

Q5. A 48 year old lady presents in outpatients clinic with a history of chronic shortness of breath, daily cough productive of pale coloured phlegm and recurrent chest infections. There is no history of haemoptysis. She has had 3 episodes of pneumonia over the last 2 years, requiring hospital admission. Sputum cultures from these grew Streptococcus pneumoniae on one occasion and Haemophilus influenzae on another. An HRCT scan of her chest showed bilateral diffuse bronchiectasis with evidence of a few granulomata in both lung fields. She is a non-smoker. There is no other significant medical history

Bloods: IgG 3.5 g/L (6-16)IgA 0.2 g/L (0.8-2)

IgM <0.17 g/L (0.5-2)No paraprotein detected

Which diagnosis would be in keeping with these clinical

and laboratory findings?

A) TuberculosisB) SarcoidosisC) Chronic Granulomatous DiseaseD) X-linked AgammaglobulinaemiaE) None of the above

Answer: E (None of the above)

Lymphoproliferative Disease: check urine BJP, serum EL (? paraprotein), serum free light chains, LDH/beta-2-microglobulin, Ca profile, ? bone marrow biopsy

Drugs: steroids, cyclophosphamide, gold salts/ DMARDs, anti-epileptics

Protein losing states (enteropathy, nephrotic syndrome) - but usually just low IgG

Hypercatabolism of Igs in sepsis

Common Variable Immune Deficiency (CVID)

Rare: genetic causes (Trisomy 8, Trisomy 21, metabolic disease, myotonic dystrophy, other PIDs)

Rare: Congenital infections (congenital Rubella/CMV/Toxo/EBV)

The differential diagnosis of The differential diagnosis of panhypogammaglobulinaemiapanhypogammaglobulinaemia

The immunoglobulins are repeated and are found to be accurate values. The patient has mild splenomegaly on examination.

How do you explain this patient’s signs and symptoms?

CVIDCVID

Other clinical manifestations: hepatospelnomegaly, granulomatous disease, anaemia, diarrhoea (?giardiasis), arthralgia (?mycoplasma septic arthritis), bowel changes (villous atrophy)

Autoimmune thyroidits, AIHA, AI thrombocytopenia

Treatment: vigilance and treatment of infx immunoglobulin replacement therapy

Prognosis: pretty good! Surveillance for tumours (lymphoma and gastric ca)

Ref: Park et al., Lancet 2008; 372: 489-502

Common Variable Immune Deficiency Common Variable Immune Deficiency (CVID)(CVID)

Form of Primary Antibody Deficiency, heterogeneous group of disorders

Prevalence: variable 1 in 50,000

Age:bimodal: mid childhood early adulthood

Recurrent sinopulmonary infections, bronchiectasis

Genetics: No clear inheritence, ICOS, CD19, BAFF-R and TACI mutations linked to only 10% cases

Summary of learning objectivesSummary of learning objectivesUnderstanding of the use and interpretation of certain tests with reference to relevant clinical conditions

Immunoglobulins

Complement

Acute antibodies / C-ANCA

Cryoglobulins

Anti-nuclear antibodies

Thankyou