Teaching Clinic - Secodary Immunodeficiency 101 Flashcards
Female 69
Unremarkable PMH
Presented with bilateral SN hearling loss, fleeting lung shadows and postive ANCA (anti-nuclear cytoplasmic antibody)
ANA (anti-nuclear antibody)
What is ANA? How is it detected?
Anti-neutrophilic cytoplasmic Ab Ix
- These Ab stick to neutrophil detected by immunofluorescence involving neutrophils.
§ Find normal cells + fluorescent stain if light up = positive dilute until it is not lighting up = titre
· Titre dilute until its no longer detectable.
· Reflects the concentration, the higher the tire the higher the concentration
· Prone to inter-investigator variability
ANA: Immunofluoresence test, against any nuclei
Titre is more qualitative, 1:160 is significant titre. The higher the titre, the more likely there is autoimmune disease
What is ENA?
- ENA test is often used as a follow-up test after a positive ANA test to identify which autoimmune disease patient has
- ENA test can check the blood for the presence of antinuclear antibodies that are known to be markers of certain diseases
See which specific part of nucleus is detected
What is this immunofluorence pattern?
C-ANCA positive
Cytoplasm is +ve!!!
What is this immunofluorence pattern?
P-ANCA, perinuclear ANCA
What are the 3 staining patterns?
What are the small, medium and large vessels vasculitis?
Types of vasculitis
- Large vessel: Giant cell arteritis, Takayasu arteritis
- Medium vessel: Polyarteritis nodosa, Kawasaki disease
- Immune complex small vessel: Cryoglobulinemic vasculitis, IgA vasculitis
- ANCA- associated small vessel: Microscopic polyangiitis, GPA, EGPA
Giant cell arteritis
- Common presentation
- Dx
- Mx
[Large vessels]
- Older people (F~M)
Background of polymyalgia rheumatica:
o Proximal joint stiffness (girdle disease)
o Constitutional symptoms
o Almost all patients with GCA have PMR, but not a lot of PMR have GCA!!!
Signs & symptoms of GCA:
- Temporal headache, jaw claudication, scalp tenderness, amaurosis fugax
- Risk of permanent blindness
o Arteritic AION (red colour blindness/desaturation) = can be irreversible
Dx
o ESR (3 digit range, sky high), CRP
o Duplex USG of temporal vessel
o Temporal artery biopsy to confirm (page surgeon!)
Mx
o Immediate high dose steroid (AION can be irreversible, need to recognise ASAP)
[Phillip Li said this won’t be assessed]
Polyarteritis Nodosa
- Some overlap with MPA
- Affects large vessel
o Necrosis of skin or pleura
o Renal arteries renal artery stenosis
o Mononeuritis multiplex
What is Kawasaki?
Medium vessel arteritis (coronary artery)
High dose aspirin, IVIg
This is a pure paediatric immunologic condition
Medium vessel vasculitis
Strawberry tongue, peripheral oedema
[Will not be assessed]
Cryoglobulinemic vasculitis
Smokers
Complements are low
Refer to specialist
Henoch Schonlein Purpura (Paediatrics)
PAEDS
IgA-mediated vasculitis
Petechiae of lower limbs
Molecular mimicry
Self-limiting
Petechiae, joint pain
What is reno-pulmonary syndrome?
Vasculature in these structure are effected:
- Glomeruli
- Pulmonary vasculature of lung
Do not miss this in patients with haematuria and haematemesis (not true haematemesis, but rather frank haemoptysis)
FLEETING LUNG SHADOWS ON CXR in EARLY
AKI without symptoms, quickly progress to ESRF
Anti-GBM
- Hematemesis
- Crescentic glomerulonephritis
Symptoms of large vessel involvement
Symptoms of medium vessels
Symptoms of small vessel disease
Man came in coughing blood and peeing
Granuloma
Frank eosinophils
What is dx from below?
Anti-GBM
GPA
EGPA
MPA
EGPA!!!
ANCA+ blood test
Lung biopsy showing granuloma
No eosinophils
What is dx from below?
Anti-GBM
GPA
EGPA
MPA
GPA
AKI
Haematuria
Kidney biopsy shows NO granuloma, NO eosinophils
Pauci-immune glomerulonephritis
Anti-GBM -ve
What is dx from below?
Anti-GBM
GPA
EGPA
MPA
MPA
ANCA-associated vasculitis
How to diagnose?
GPA
EGPA
MPA
Gold-standard for Dx is BIOPSY, blood test often inaccurate (e.g. EGPA is notorious for -ve ANCA)
Need to use biopsy to Dx
- Adult-onset asthma
- Eosinophila
- Vasculitic phase: Renopulmonary symptoms
What does this patient have?
EGPA
Wegner’s GPA features?
Mid-line lesion
Sinopulmonary symptoms
SN hearing loss
Female, 69 years old Unremarkable past medical history Presented with bilateral sensorineural hearing loss, fleeting lung shadows and + ANCA Diagnosed with Granulomatosis with polyangiitis
How to treat GPA?
- Induction
- Induction: high dose prednisolone and rituximab (antibody mediated disorder)
o Rituximab anti-CD20 kill cells expressing CD20
§ ADCC mechanism
§ Kills off pre-B cell, transitional B cell, activated B cell and memory cell
§ Does not kill off plasma cells but eventually it will be depleted
· myeloma not treated with rituximab, but daratumumab instead (anti-CD38)
o Given co-trimoxazole
§ Need to give as we are worried about Pneumocystis carinii in immunocompromised individuals
§ Alternative: pentamidine
§ G6PD
· 5% men, 0.5% women
· X-linked recessive (but still common for a woman to have)
o Reasons for women to have:
§ Turner
§ Skewed lyonisation (X-inactivation)
§ Extreme mosaicism
Maintenance: MMF
o Anti-metabolite
o Anti-lymphocyte agent
Patient with GPA has severe pneumonia
If you see diaphgram in pneumonia, which lobe can you exclude? If there is silhouette sign, which lobe is involved?
If you see see diaphgram, it is not lower lobe
Silhouette sign: RML is consolidated. then its density becomes same as that of heart and it cannot be seen separately from the heart.
(right lower lobe is not normal/atypical)
Patient’s respiratory culture showed:
o PJP
o CMV
o Alpha-haemolytic streptococci, Pseudomonas aeruginosa, Neisseria species
What type of immunodeficiency does this patient have?
o Combined immunodeficiency § Patient IgG only 216 (N: 600)
Combination of bacteria, fungi and virus
The patient was given high-dose steroid, rituximab and MMF:
§ Rituximab leads to B cell deficiency
· Does not alone explain the PJP and CMV
§ (+ MMF and steroid T cell deficiency)
How do we manage this patient?
Patient’s respiratory culture showed:
o PJP
o CMV
o Alpha-haemolytic streptococci, Pseudomonas aeruginosa, Neisseria species
Mx:
§ IV meropenem, ganciclovir, co-trimoxazole
§ Withold MMF
§ No need G-CSF because neutrophil count is normal (4.47)
§ Give IVIg due to low IgG · Can switch to subcutaneous Ig later on
How do we differentiate the PIDs?
Innate vs acquired immunity >60% are due to antibody deficiency
Most common secondary immunodeficiencies:
Predominantly antibody or cellular deficiencies
B-cells [MORE COMMONLY EXAMINED]: Encapsulated bacterias (NHS)
Giardia lamblia is almost pathognomonic of B-cell issue
T-cells: smaller bacteria which gets inside cells (intracellular), viruses (enter the cells)
Secondary antibody deficiency / hypogammaglobulinemia
Usually multi-factorial
- esp disease vs. medications
- B-cell lymphoproliferative diseases:
chronic lymphocytic leukemia, multiple myeloma, lymphoma
- B-cell depleting therapies / conventional immunosuppression
> 30x more common than primary antibody deficiencies
- But fewer studies and available data
- Practice mostly based from experience in PID
Unlike primary immunodeficiencies…may be reversible!
Antibody quality probably more important than quantity
- Defect in production > antibody loss
Disease phenotype similar to primary antibody deficiency
- Frequent sinopulmonary / gastrointestinal infections
- Encapsulated extracellular organisms
Secondary: born with intact immune system. Either it is disease (blood disorder, leukaemia, MM), iatrogenic (chemotherapy, rituximab) or combination of both
Not congenital
Sinus, pulmonary, gut, CNS (when you colonise throat for too long, it may go to the prain)
What are common causes of antibody deficiency?
What are B-cell targeted therapies? How long does B cell depletion last for? What cells are spared? What may hypogammaglobulinemia be caused by?
B cell targeted therapies -
- Rituximab – chimeric monoclonal Ab against CD20
- B cell depletion lasts 6-12 months even though the drug is no longer used
o Variable: disease and patient dependent
o Plasma cells are main source of IgG but do not express CD20
- Stem cells, pro-B cells, plasma cells do not express CD20 spared B cell recovery after anti-CD20 therapy
- Hypogammaglobulinemia due to prolonged depletion of plasma cell precursors (rmb 40 and 1/4)
o 40% in lymphoma
o 1/4 in autoimmune diseases o Due to production problem!
Lymphoma patients were already quite immunocompromised – rituximab will further increase the immunosuppression
o Also due to combination therapy offered to these patients e.g. RCHOP kill off more cells
When to suspect immunodeficiency?
- Severe infections
- Persistent infections despite therapy
- Unusual sites of infection or microbes
- Recurrent infections
- Family history
- Unusual clinical presentation
- Unusual phenotype suggestive of syndrome associated with immunodeficiency (DiGeorge Syndrome)
- Infectious after biologics
SPUR = Serious, Persistent, Unusual, Recurring
Jeffrey Modell Foundation 10 Warning Signs of Primary Immunodeficiency
How do we workup for suspected immunodeficiencies?
- Think of non-immunological causes (anatomical lesions, functional disorders, i.e. cystic fibrosis)
- Exclude secondary immunodeficiency
- HIV
- Chronic kidney disease, DM
- Malignancy, lymphoproliferative diseaes (esp. CLL/MM)
- Protein-losing states, malnutrition
- Chemotherapy or immunosuppresive therapy (Rituximab)
Administer live vaccinations with caution (Ask Dr Li before giving it in immunocompromised individuals)
How to ask a family hisotyr?
X-linked recessive disorder: Ask at least 3 generations
Plot a family tree
Square for male
Circle for female
Patient and siblings, auntie’s and uncle’s siblings (one generation)
Mom, dad, aunties, uncles (second generation)
Patient’s sibling’s children (third generation)
Absolute lymphocyte count is low = Probably T-cell problem
How do we interpret A/G ratio?
Don’t just look at A/G ratio → need to look at absolute values for both
a. Both AG very low, AG ratio still very low → protein losing state? Liver failure?
b. Albumin very low, globulin very high → paraproteinemia
c. Both very high → acute inflammatory states
d. If globulin low → 99% IgG low (IgG 70% of total Ig)
What is normal cut-off for ESR?
M = age/2
F = age + 10 / 2
Must learn to calculate!!!
Reflects acute-phase reactants
ESR unit is mm/H
ESR is very high in: GCA (high platelet, globulin, fibrinogen = clot clumps together, heavy = falls faster), polycythaemic
ESR will be falsely low in anaemia, hypogammaglobulinemia
CRP (acute phase reactant)
APR made by liver
- ESR high CRP normal ⇒ LUPUS
- Fibrinogen (e.g. consumed in HLH)
- CRP super high and ESR inappropriately normal → think of hypogammaglobulinemia
What immunglobulins will we need to check?
GAME: IgG, IgA, IgM, IgE
do not check D
Ig replacement: IV vs SC
SCIg ⇒ EVERY WEEK CAN DO AT HOME
● Replacement Ig start at 0.4-0.6 g/kg/month
● Either IVIg or SCIG
○ Weekly infusions (infusion pump) vs ‘daily push’ (no pump) at home
● More stable troughs, better patient (?± clinical) outcomes
○ Rate of adverse reactions (headache, muscle aches), infections, thrombotic risk (viscous blood)
○ C.f. IVIG less physiological, fluctuating total serum IgG concentration, extreme concentrations (too high/low) can have detrimental effects
● Flexibility and freedom for patients
● Cost saving (for patients & hospital)
○ Admissions/ bed occupancy
○ Manpower
○ Follow-up
○ Days off/productivity
○ QoL
○ (Risk of infections)
Only do IVIg if patient has severe infection and you need to boost up immunoglobulins ASAP
