Immunodeficiency Flashcards
what are some important investigations once you discover hypogammaglobulinaemia?
drug history has been taken and excluded,
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:
- haematological (lymphoid stuff) - do a SEPP, cryoglobs
- poor production related to malnutrition, sepsis or chronic inflamm - check albumin, ESR, CRP
- renal or digestive loss - urine PCR/24 hr albuminuria, faecal alpha1 antitrypsin
what is CVID?
what is Goods syndrome?
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
what is Bruton’s agammaglobulinaemia?
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
what is the clinical presentation of IgA deficiency?
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
what is Di George syndrome?
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
what is idiopathic CD4 lymphopenia?
low CD4, NOT HIV
associated with cryptococcal infection, but also some of the AIDS illnesses like MAC, CMV
What is the story with chronic granulomatous disease?
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
tumours developing in patients with immune dysregulation due to immune deficiency are most likely to arise from which lineage?
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
what is the role of CD40 and CD40L?
what does mutations in this pathway lead to?
this has a big role in isotype class switching.
leads to hyper IgM syndrome
which is the most common immunodeficiency to be assoc with transfusion reactions
IgA deficiency
because the accidental transfusion of these leads to a response from the host
which Ig activates classical pathway
which activate alternate?
classical is IgG and IgM
alternate is IgA
what is the halflife of:
IgG
IgM
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
which Ig in breast milk is most useful for baby’s protection?
it is the IgA because it protects the baby’s mucosa
but it’s a bit of a weird question from the college
what is the immune deficiency associated with findings on methenamine silver nitrate staining of a biopsy?
well, this is a stain for yeast forms
particularly PCP
therefore, it’s associated with T cell deficiency
Which infections are typical of an immunodeficiency syndrome due to: lack of an antibody response?
Infections in Immunodeficiency: Lack of Ab Response.
- Recurrent sinopulmonary and GIT infections:
Sinusitis, bronchitis, tonsillitis, OM, bacterial pneumonia, bronchiectasis (long-term), skin infections, infectious diarrhoea - Polysaccharide-encapsulated pyogenic organisms:
S. pneumonia, H. influenza type B, S.pyogenes, M. catarrhalis - S. aureus
- G. lamblia
- C. jejuni
Which infections are typical of an immunodeficiency syndrome due to: Lack of T-cells?
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
Which infections are typical of an immunodeficiency syndrome due to: Lack of neutrophils / monocytes?
Infections in Immunodeficiency:
Lack of neutrophils / monocytes
- High grade bacterial infections
- S. aureus
- Gram neg bacteria
- E. coli, P. mirabilis, Serratia marcescens (ESCAPPM), P. aerugninosa & cepacia - Fungi
- Invasive Aspergillus
- Systemic Candidiasis
Disorders due to lack of complement components:
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).
Live vaccines are relatively contraindicated in those who are immunocompromised.
Which vaccines should be avoided?
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)
When are live vaccines contraindicated?
> 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
Pathophysiology of IgA deficiency?
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)
Presentation of IgA deficiency?
- 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
IgA deficiency is associated with a number of other disorders related to immune dysregulation. What are some of these?
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
What investigation results would be consistent with IgA deficiency?
Ig levels: Absent IgA
- may have low IgG subset
sEPP: normal
B-cell count: normal
Management of IgA deficiency?
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.
Why is a low level of one or more IgG subclasses “consistent with, but not diagnostic of, immune deficiency”?
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.
IgG subclass deficiency is most commonly associated with which other immunodeficiency syndrome?
IgA deficiency.
What is the treatment for IgG subclass deficiency?
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.
Hyper IgM Syndrome: genetic defect and inheritance pattern?
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.
Hyper IgM Syndrome: Presentation
- 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)
Hyper IgM Syndrome: Investigations and Treatment
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
CVID: clinical presentation
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
CVID: Investigations and Diagnosis
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.
CVID: Complications
- Bronchiectasis
- Respiratory failure
- Chronic infection (–> amyloidosis)
Increased risk of cancer and AI conditions.
CVID: Treatment
- Gammaglobulin: IVIg monthly or subcut infusion
- ABs for infections: start early, treat for longer, identify organism, prophylaxis
- Avoid live vaccines!
CVID: genetic DDx to rule out
CVID is a diagnosis of exclusion.
DDx:
- X-linked agammaglobulinaemia ("Bruton's" agamma)
- X-linked lymphoproliferative disease
- Hyper IgM syndromeWhat is the presentation of CMC (Chronic Mucocutaneous Candidiasis)?
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
What is the presentation of SCID?
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
Investigations for suspected immunodeficiency
- Full blood count and serum immunoglobulin IgG, IgA, IgM, IgE
- 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).
- Antigen specific antibody response (eg. to HBV vaccine) and IgG subclasses
- More detailed immunophenotyping.
eg. CD40 and CD40L for Hyper IgM.
eg. switched memory B cells CD27 with surface IgM in CVID. - Specific genetic testing
Is immune replacement therapy (=IRT - ie. IVIg) useful in secondary causes of antibody deficiency?
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
Conditions associated with secondary antibody deficiency (either due to condition or treatment)?
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
Drugs associated with immune deficiency?
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
How is IVIg administered and monitored / adjusted?
What are the potential ADRs to know about?
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).
