Immunodeficiency

Question 1

what are some important investigations once you discover hypogammaglobulinaemia?

drug history has been taken and excluded,

Answer 1

in the investigation of immunodeficiency, the goal is to exclude secondary disease

in adult medicine, it is much more likely that we’re encountering a secondary phenomenon

the major players in secondary im/def are:

1. haematological (lymphoid stuff) - do a SEPP, cryoglobs
2. poor production related to malnutrition, sepsis or chronic inflamm - check albumin, ESR, CRP
3. renal or digestive loss - urine PCR/24 hr albuminuria, faecal alpha1 antitrypsin

Question 2

what is CVID?

what is Goods syndrome?

Answer 2

this is a catch bag of immune def with B cell deficiencies

Good syndrome is thymoma with B cell deficiency and some T cell deficiency

Question 3

what is Bruton’s agammaglobulinaemia?

Answer 3

this is an X-linked immunodeficiency

(aka XLA = X-linked Agammaglobulinaemia).

there are no B cells in the peripheral blood

there is a deficiency of the Btk protein

randomly, there can be an association with neutropenia

Question 4

what is the clinical presentation of IgA deficiency?

Answer 4

mostly this is asymptomatic

when they get blood transfusions, their body can have a reaction to an IgA that is sent across

the best way to determine functional defects is with response to bacterial vaccines

IVIg is indicated if there is significant infection and a defect in functional response to vaccine

Question 5

what is Di George syndrome?

Answer 5

this is a paediatric condition

it is about T cell deficiency, and also assoc with facial malformation and heart defects

can present in extremis with no thymus and severe T cell defects

Question 6

what is idiopathic CD4 lymphopenia?

Answer 6

low CD4, NOT HIV

associated with cryptococcal infection, but also some of the AIDS illnesses like MAC, CMV

Question 7

What is the story with chronic granulomatous disease?

Answer 7

it is a defect in the way that neutrophils kill bacteria.

it is a defect in the oxidative burst
can lead to chronic infections of lung, skin and abscesses

particularly look for fungi and staph

Question 8

tumours developing in patients with immune dysregulation due to immune deficiency are most likely to arise from which lineage?

Answer 8

it is B cells. The poor immune regulation is most likely to affect cells which have high replication (affinity maturation in a germinal centre, for eg)

the best example is EBV related tumours

Question 9

what is the role of CD40 and CD40L?

what does mutations in this pathway lead to?

Answer 9

this has a big role in isotype class switching.

leads to hyper IgM syndrome

Question 10

which is the most common immunodeficiency to be assoc with transfusion reactions

Answer 10

IgA deficiency

because the accidental transfusion of these leads to a response from the host

Question 11

which Ig activates classical pathway

which activate alternate?

Answer 11

classical is IgG and IgM

alternate is IgA

Question 12

what is the halflife of:

IgG

IgM

Answer 12

IgG is the longest at 21 days
The way to remember this is that MAb are deliberately chosen to be IgG because they last longest

IgM has 7 day half life

Question 13

which Ig in breast milk is most useful for baby’s protection?

Answer 13

it is the IgA because it protects the baby’s mucosa

but it’s a bit of a weird question from the college

Question 14

what is the immune deficiency associated with findings on methenamine silver nitrate staining of a biopsy?

Answer 14

well, this is a stain for yeast forms

particularly PCP

therefore, it’s associated with T cell deficiency

Question 15

Which infections are typical of an immunodeficiency syndrome due to: lack of an antibody response?

Answer 15

Infections in Immunodeficiency: Lack of Ab Response.

1. Recurrent sinopulmonary and GIT infections:
   Sinusitis, bronchitis, tonsillitis, OM, bacterial pneumonia, bronchiectasis (long-term), skin infections, infectious diarrhoea
2. Polysaccharide-encapsulated pyogenic organisms:
   S. pneumonia, H. influenza type B, S.pyogenes, M. catarrhalis
3. S. aureus
4. G. lamblia
5. C. jejuni

Question 16

Which infections are typical of an immunodeficiency syndrome due to: Lack of T-cells?

Answer 16

Infections in Immunodeficiency:
Lack of T-cells

Infections with INTRACELLULAR organisms (as in AIDS)

a. Fungi eg. mucosal candida
b. Viruses: CMV, VZV, HSV,
c. Protozoa eg. pneumocystis
d. Listeria

Question 17

Which infections are typical of an immunodeficiency syndrome due to: Lack of neutrophils / monocytes?

Answer 17

Infections in Immunodeficiency:
Lack of neutrophils / monocytes

1. High grade bacterial infections
   - S. aureus
   - Gram neg bacteria
   - E. coli, P. mirabilis, Serratia marcescens (ESCAPPM), P. aerugninosa & cepacia
2. Fungi
   - Invasive Aspergillus
   - Systemic Candidiasis

Question 18

Disorders due to lack of complement components:

Answer 18

Lack of complement components:

CLASSICAL Pathway:
C1q, C1r, C1s → SLE
C4 → SLE, GN
C2 → SLE, vasculitis, GN
C3 → recurrent pyogenic infections, GN, immune complex diseases
C3, C3 Factor B, Factor I, Factor H, Thrombomodulin → Atypical HUS

ALTERNATIVE Pathway:
Properdin, Factor D → Neisseria infections, other pyogenic infections

TERMINAL Components:
C5-9 → Disseminated Neisseria infections (meningitidis, gonorrhea).

Question 19

Live vaccines are relatively contraindicated in those who are immunocompromised.
Which vaccines should be avoided?

Answer 19

Live Vaccines = “MOBY-VRT”:

• MMR
• Oral polio (Inactivated Polio Vaccine is ok)
• BCG
• Yellow fever
• Varicella (and varicella zoster)
• Rotavirus
• Oral Typhoid (Inactivated Parenteral Typhoid Vaccine is ok)

Question 20

When are live vaccines contraindicated?

Answer 20

> 20mg prednisolone / day

HIV positive with CD4<200

anti-TNF meds

+ Some primary immunodeficiencies (vaccines avoided varies by deficiency).
+ Consider risk in haematological malignancy.

Other immunosuppressants (eg. azathioprine, MTX) - risk unclear.
Suggest being off all these Rx for at least one month (best 3 months) before giving

Note: other inactivated vaccines may be safe but ineffective - patient may not make protective antibody response

Question 21

Pathophysiology of IgA deficiency?

Answer 21

Absence of IgA +/- IgG subclasses.

Due to dysregulation in Ig isotype class switching during B-cell activation

Causes:

• sporadic genetic (sometimes familial – or sometimes in families with CVID);
• drug-induced (phenytoin, penicillamine);
• intra-uterine infection (TORCHS)

Question 22

Presentation of IgA deficiency?

Answer 22

• Onset at any age
• Many patients asymptomatic (may only become symptomatic when a second immune defect is present)
• Mucosal infections (like with CVID, XLA) – sinopulmonary, giardiasis

Question 23

IgA deficiency is associated with a number of other disorders related to immune dysregulation. What are some of these?

Answer 23

IgA deficiency associated with:
• atopic disease
• cow’s milk allergy
• GI disease (coeliac disease, IBD, nodular lymphoid hyperplasia)
• AI disorders (RA, SLE, DMS, SS, JRA; ITP; Pernicious anaemia, thyroiditis, Addison’s AI-CAH)
• Anaphylaxis: transfusion of IgA-containing blood products (require blood from IgA-deficient donor or triple-wash cells); due to anti-IgA Abs
• Lymphoreticular malignancy

Question 24

What investigation results would be consistent with IgA deficiency?

Answer 24

Ig levels: Absent IgA
- may have low IgG subset

sEPP: normal
B-cell count: normal

Question 25

Management of IgA deficiency?

Answer 25

Prompt Ab therapy for acute episodes. NOT IVIG as is mucosal defect, not systemic (only considered if associated IgG subclass deficiency – but need IgA-deficient preparation). Medic alert bracelet for Ig-A deficient / triple wash cell PRBCs.

Question 26

Why is a low level of one or more IgG subclasses "consistent with, but not diagnostic of, immune deficiency"?

Answer 26

A low level of one or more IgG subclasses, but with a NORMAL TOTAL IgG level, is not uncommon and may or may not be of "clinical significance" (ie. associated with increased susceptibility to infections). Usually it is IgG2 or 3 that are low. As IgG1 normally accounts for approx 75% of IgG, an IgG1 deficiency would usually result in CVID. The subclasses do have different functions, but many people with IgG subclass deficiency will not have an increased rate of infections. Furthermore, defining normal ranges of the subclasses is difficult.

Question 27

IgG subclass deficiency is most commonly associated with which other immunodeficiency syndrome?

Answer 27

IgA deficiency.

Question 28

What is the treatment for IgG subclass deficiency?

Answer 28

May not require if not clinically significant. Supportive (eg. antibiotics, etc). IVIg not funded for IgG subclass deficiency in Australia, but may consider if frequent infections.

Question 29

Hyper IgM Syndrome: genetic defect and inheritance pattern?

Answer 29

Mutation in gene for CD40 Ligand --> CD40L deficiency on Tcells. Absent CD40-CD40L signal (Bcell to Tcell) → failure of B cell isotype switching and memory B cell generation. Usually X-linked Recessive. Some AR forms.

Question 30

Hyper IgM Syndrome: Presentation

Answer 30

- Paediatric disorder: onset usually 1-2yo - Recurrent bacterial infections – respiratory, PCP (b/c APCs activate T cells via CD40-CD40L also) - Acute / chronic diarrhea – cryptosporidium, oral ulcers, proctitis - Complicatons: AI disease, malignancy, neutropaenia (cause unclear)

Question 31

Hyper IgM Syndrome: Investigations and Treatment

Answer 31

Dx: Immunofixation: markedly low IgA, G, E; normal or increased IgM. Normal B cell levels. Flow cytometry for surface CD40L. ``` Tx: IVIg Bactrim prophylaxis G-CSF ??BMT ```

Question 32

CVID: clinical presentation

Answer 32

Heterogenous group of disorders characterized by lack of immunoglobulin 10% familial, so most will not have a FHx Onset at any age: peaks at 1-5yo and 18-25 yo Clinical: • Recurrent sinopulmonary infections • GIT infections • Skin infections • T-cell infections uncommon but increased (eg. mycobacterial, fungal, PCP) • Autoimmunity: ITP, AIHA, thyroid disease, pernicious anaemia, polyarthropathy, polymyositis, vitiligo • Neoplasia: lymphoma, pseudolymphoma, stomach Ca • Lymphoproliferation: lymphaedenopathy, splenomegaly, granulomatous disease • Allergic disease (food allergies) • Bronchiectasis and respiratory failure (RFT surveillance) • Chronic infection → amyloidosis

Question 33

CVID: Investigations and Diagnosis

Answer 33

IgG low and either/both IgA and IgM also decreased * B cell count roughly normal * EPP: hypogamma * Impaired vaccination response Exclude secondary causes of hypogamma: drugs, myeloma, lymphoma, nephrotic syndrome, GI protein loss.

Question 34

CVID: Complications

Answer 34

- Bronchiectasis - Respiratory failure - Chronic infection (--> amyloidosis) Increased risk of cancer and AI conditions.

Question 35

CVID: Treatment

Answer 35

* Gammaglobulin: IVIg monthly or subcut infusion * ABs for infections: start early, treat for longer, identify organism, prophylaxis * Avoid live vaccines!

Question 36

CVID: genetic DDx to rule out

Answer 36

``` CVID is a diagnosis of exclusion. DDx: - X-linked agammaglobulinaemia ("Bruton's" agamma) - X-linked lymphoproliferative disease - Hyper IgM syndrome ```

Question 37

What is the presentation of CMC (Chronic Mucocutaneous Candidiasis)?

Answer 37

Chronic Mucocutaneous Candidiasis (CMC): Onset in childhood Often lack Th17 cells May have gain of function (eg. increased Th1 → AI thyroid disease) Chronic / recurrent candida infection – skin, nails, mucosae (oesophageal & pulmonary) Other infections, eg. HSV

Question 38

What is the presentation of SCID?

Answer 38

SCID: Paediatric Lack of a component essential for T-cell function eg. lack of response to IL-7 FTT, chronic diarrhea Recurrent opportunistic infections: fungal, viral, protozoal (PCP) B cell dysfunction (lack of help) Variable severity +/- AI disease, malignancy

Question 39

Investigations for suspected immunodeficiency

Answer 39

1. Full blood count and serum immunoglobulin IgG, IgA, IgM, IgE 2. Serum, urinary and faecal proteins [rule out other causes of hypogamma]. ``` 3. Lymphocyte subset markers: CD3+ CD4+ [T helper cells], CD3+ CD8+ [T cytotoxic cells], CD16+ CD56+ [NK cells], CD19+ CD20+ [B cells] (eg. B cell deficiency in XLA). ``` 4. Antigen specific antibody response (eg. to HBV vaccine) and IgG subclasses 5. More detailed immunophenotyping. eg. CD40 and CD40L for Hyper IgM. eg. switched memory B cells CD27 with surface IgM in CVID. 6. Specific genetic testing

Question 40

Is immune replacement therapy (=IRT - ie. IVIg) useful in secondary causes of antibody deficiency?

Answer 40

The first priority is to treat the underlying disorder causing the antibody deficiency where possible * Opinions vary on the use of IRT for these secondary causes of antibody deficiency * IRT may be considered in patients with severe recurrent infection and profound hypogammaglobulinemia * In HIV infection in children, antiretroviral therapy should be used as the first line treatment prior to considering IRT * IRT is usually not helpful in protein losing states such as nephrotic syndrome and protein losing enteropathy * Evaluation of specific antibody responses to vaccine antigens may assist in decision to commence IRT

Question 41

Conditions associated with secondary antibody deficiency (either due to condition or treatment)?

Answer 41

``` Haematological / Lymphoproliferative conditions • CLL • MM • Lymphoma • Acute leukaemia ``` Infections • HIV • Congenital Rubella Drugs Transplantation • Solid organ • Haemopoietic stem cell ``` Protein losing states • Nephrotic syndrome • Protein losing enteropathy • Lymphangiectasia • Chylothorax • Severe burns ```

Question 42

Drugs associated with immune deficiency?

Answer 42

Idiosyncratic effect: carbamazepine, phenytoin, gold salts, sulfasalazine, antimalarials, penicillamine, captopril. Drugs with known immunosuppressive effects: • Glucocorticosteroids • Cytotoxic immunosuppressives • Cancer chemotherapy • B cell depleting monoclonals eg rituximab • Combination transplant rejection regimens

Question 43

How is IVIg administered and monitored / adjusted? | What are the potential ADRs to know about?

Answer 43

IV or subcut. Usually once monthly. Trough doses are measured. Target above LLN of age-related reference range. Dose adjustments based on clinical parameters and trough levels. Patients require regular clinical review. PFT monitoring for bronchiectasis. ADRs: Serious adverse events are very uncommon. Immediate transfusion reactions mild – severe. As for other blood products, incl. haemolysis, TRALI, anaphylaxis. May be able to manage by slowing / breaking infusion, or pre-medicating with paracetamol or oral antihistamine or IV hydrocortisone prior. Delayed reactions: Most common is headache (treat with ibuprofen). Aseptic meningitis. Hyponatraemia / pseudohyponatraemia (due to hyperproteinaemia). Transient neutropaenia. Thrombosis (rare). ARF. Autoimmunity. Viral infections – risk remote due to inactivation steps, as for other blood products. Note: maltose in some IVIg gives pseudohyperglycaemia (risk of iatrogenic hypoglycaemia).