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year 4 CDM 2 > Case 14: Immunodeficiency > Flashcards

Case 14: Immunodeficiency Flashcards

1
Q

Causes of Pan-Hypogammaglobulinemia (i.e. destruction of IgG, IgA and IgM)

A
  • Primary immunodeficiency: CVID, X-linked agammaglobulinemia (more common in males)
  • Medications: Prednisolone, Azathioprine, Methotrexate, Rituximab, anti-epileptics, antipsychotics
  • Malignancy: Multiple myeloma, lymphoma, leukaemia
  • Systemic illness causing bone marrow suppression: severe infection
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2
Q

What investigations should be carried out before starting Azithromycin

A
  • ECG as QT interval can be exacerbated by azithromycin
  • two sputum cultures to rue out acid fast bacilli as azithromycin could mask a bacterial infection
  • medication review as statins can interact
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3
Q

X linked agammaglobulinaemia (XLA)

A
  • Affects male children usually in the first year of life when maternal IgG dwindles
  • Defect in Bruton’s tryrosine kinase gene that leads to a severe block in B cell development resulting in absence of B cells and reduced immunoglobulins
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4
Q

XLA: investigations and management

A
  • Investigations: low immunoglobulins, absent B cells (low CD19 on flow cytometry), confirmed on genetic testing
  • Management: lifelong immunoglobulin replacement, prophylactic antibiotics, consider HSCT, avoid live vaccine
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5
Q

Common variable Immunodeficiency (CVID) criteria

A
  • age >4 years
  • low IgG
  • low IgA and/or IgM
  • poor or absent response to immunisation
  • exclusion of other immunodeficiencies
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6
Q

CVID: investigation results

A
  • low immunoglobulins, esp IgA and IgG
  • poor vaccine response
  • low class switched memory B cells (CD27, CD19)
  • normal CD4 (no T cell deficiency)
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7
Q

Management of CVID

A
  • lifelong immunoglobulin replacement
  • prophylactic antibiotics
  • treat complications e.g. immunosuppression for autoimmune disease
  • monitor for malignancy esp lymphoma
  • consider HSCT
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8
Q

When do you treat patients with low Ig levels

A
  • Reverse underlying cause: reduce immunosuppression, treat infection and cancer
  • Give prophylactic antibiotics: azithromycin, co-trimoxazole
  • Vaccination- but avoid live vaccines
  • Replace immunoglobulins: IV(every month) or SC, only IgG
  • Only replace immunoglobulins if there is a history of infection and prescribe prophylactic antibiotics first
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9
Q

Ig replacement

A
  • 0.4g/kg/month
  • target trough level IgG >6g/L (level it shouldn’t go below)
  • Screen for HIV, hep B and C before starting treatment
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10
Q

Cell mediated immunodeficiency: common infections

A
  • Infections with ordinarily ‘benign’ viruses, opportunistic intracellular pathogens, or fungi
  • Pathogens: CMV, EBV, Herpes, myobacteria, fungi (candida, cryptococcus, pneumocystis)
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11
Q

Specific antibody deficiency

A
  • normal total antibody levels but inadequate antibody vaccine response to polysaccharide antigens
  • Management: Prophylactic antibiotic, immunoglobulin replacement if ongoing recurrent infection
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12
Q

Selective IgA deficiency

A
  • Defect in B cell maturation resulting in absent IgA
  • Associated with coeliac disease: may cause false negative coeliac screen results
  • Can cause severe anaphylactic reactions with blood transfusion due to anti-IgA antibodies
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13
Q

Hyper IgM syndrome (CD40 ligand deficiency)

A
  • Mutations in CD40 gene meaning IgM cannot be converted to other isotopes
  • Infections seen: Pneumocystis pneumonia, hepatitis, diarrhoea
  • High IgM, absent IgA and IgG, reduced CD40 ligand expression, confirmed on genetic testing
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14
Q

Hyper IgE testing

A
  • Mutation in DOCK8 resulting in high IgE antibodies
  • Affects the skin causing eczema and abscesses
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15
Q

X linked lymphoproliferative disease

A
  • Associated with HLH, lymphoma and vulnerable to EBV
  • Investigations: Hypogammaglobulinemia especially low IgG
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16
Q

Cell mediated immunodeficiency causes

A
  • severe combined immunodeficiency (SCID): T cells always affected +/- B cells +/- NK cells. Tend to become unwell as babies and present very quickly.
  • chronic mucocutaneous candidiasis (CMC): Gene deficits contribute (AIRE deficiency, Dectin-1, CARD-9)
  • Di George syndrome: chromosome 22q11.2 deletion (absent thymus)
  • Wiskott-Aldrich syndrome
  • T cell lymphopenia: T cells do not work properly
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17
Q

Common pathogens in T cell deficiency

A
  • Viral: RSV, parainfluenza, rotavirus, noravirus, adenovirus, CMV
  • Protozoam: Pneumocystis carinii, toxoplasma, Cryptosporadium
  • Fungal: Candida, aspergillus, cryptococcus
  • Bacteria: Mycobacteria, Salmonella
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18
Q

T cell deficiency: investigations and conditions

A
  • Conditions: SCID, ataxic telengiectasia, Wiskott-Aldrich syndrome, DiGeorge syndrome
  • Investigations: lymphocyte surface markers, T cell proliferation assays, immunoglobulins
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19
Q

SCID (severe combined immunodeficiency)

A
  • Absent T cells
  • B cells may be present or absent (may fail as no T cells to activate)NK cells may be present or absent
  • Most common cause: X linked, defect in common gamma chain (protein used in IL2 receptor)
  • Presents in children <1
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20
Q

SCID: Investigation results

A
  • absolute lymphocyte count below 2.5
  • decreased CD3, CD4 and CD8 (T cells)
  • may be decreased CD19 (B cells)
  • decreased PHA (indicates low lymphocyte proliferation)
  • Decreased immunoglobulins
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21
Q

Omenn syndrome

A
  • Indeterminate SCID
  • Due to hypomorphic mutations (unlike complete mutation in SCID) meaning some T cells form but they are abnormal
  • Characterised by: erythroderma, lymphadeopathy, hepatosplenomegaly
22
Q

Ataxic telangiectasia

A
  • Defects in DNA repair enzymes (autosomal recessive)
  • Associated with cerebellar ataxia, telangiectasia, recurrent chest infection
  • Associated with malignancy esp lymphoma or leukaemia
23
Q

Wiskott-Aldrich syndrome

A
  • Defect in WASP gene (X linked recessive)
  • Characterised by: eczema, thrombocytopenia, recurrent bacterial infections
  • Associated with autoimmune disease and malignancy
24
Q

DiGeorge syndrome

A
  • Chromosome 22q11.2 deletion
  • Causes an absent thymus
  • Characterised by: congenital heart disease, learning difficulties, cleft palate, hypocalcaemia, recurrent viral and fungal infections
25
Q

Deficiencies in the innate immune system

A
  • Phagocyte disorders: reduced number or function
  • NK cell defects
  • Cytokine deficiencies
  • Toll like receptors defects
  • Complement deficiency
  • Phagocyte and Complement are the most common deficiencies
26
Q

Overview of complement pathway

A
  • Part of the innate immune system- groups of plasma proteins
  • Has 3 main functions:
  • The ability to lyse cells
  • The ability to opsonize particles (making them easier for phagocytes to engulf)
  • The ability to produce proteins generated by the complement cascade which generate fragments that have potent inflammatory activity
27
Q

3 main pathways: complement

A
  • Classical pathway: Triggered by antibodies that are bound to their antigens
  • Alternate pathway: Activated by the presence of pathogen (antibody independent)
  • Lectin pathway: Activated by lectin-type proteins that are already bound to pathogens
28
Q

Outcomes of the complement pathway

A

All pathways ultimately lead to the activation and binding of C3. The pathways then proceed together (terminal pathway) producing a membrane attack complex that forms a transmembrane pore in the pathogen causing cell lysis.

29
Q

Complement deficiencies: classical pathway

A
  • Development of systemic Autoimmune diseases especially SLE development
  • Deficiency in C1, C2, C4
  • Increased risk of infection with encapsulated bacteria: S. pneumoniae, Haemophilus influenzae, and Neisseria meningitidis.
30
Q

Complement deficiency: alternative pathway

A
  • Properidin deficiency: Properidin stabilizes C3 and C5 convertase, deficiency causes reduced activity.
  • X-linked inheritance
  • Present: recurrent severe bacterial infections in childhood. Meningitis due to Neisseria meningitides should raise suspicion
31
Q

Complement deficiency: Lectin pathway

A
  • Deficiency in Mannan binding Lectin (MBL)- first protein in the Lectin pathway
  • Can cause increased risk of encapsulated bacterial infections in children <2, however, after then the adaptive immunity compensates
  • Associated with cystic fibrosis
  • You get very low MBL levels in asymptomatic patients. MBL deficiency is insufficient to cause disease in the absence of other host-defence problems
32
Q

Complement deficiency: Common pathway

A
  • Life-threatening recurrent infections staring in early childhood
  • Particularly susceptible to encapsulated organisms (Commonly Strep. Pneumoniae, H.influenza and N. Meningitides)
  • Associated with immune complex diseases i.e. renal disease and autoimmune disease (SLE)
33
Q

Complement deficiencies: Membrane Attack complex (MAC)

A
  • Deficiency in one of the terminal components of the complement cascade. Causes infections with gram negative bacteria (Neisseria)
  • PNH: CD59 (MAC- inhibitory protein) neutralises MAC when attach to self cells. PNH (paroxysmal nocturnal haematuria) presents CD59 expression on certain cells causing cell death. Rare and life threatening condition. Present with Haemoglobinuria (first thing in the morning from haemolysis and haemosderin), anaemia, increased thrombosis risk
34
Q

How to investigate complement deficiencies

A
  • First line: CH100 and AP100
  • Radial immunodiffusion assays: CH100 shows the classical pathway and AP100 shows the alternative pathway
  • Normal complement: both clear
  • Measure individual complement components: C3 and C4 are measured routinely. More specific ones are measured in specialist laboratories (second line)
  • Genetics: known genetic mutations in each factor
35
Q

CH100 and AP100

A
  • Lysis in the CH100 assay with no lysis in the AP100 assay: alternate pathway (such as Properdin) deficiency
  • Absence of lysis in the CH100 assay with normal lysis in the AP100: classical pathway (C1, C4, C2) deficiency
  • Absence of lysis in both assays (red): terminal component (C3, C5-C9) deficiency
36
Q

Granulocytes (commonly neutrophil) deficiencies presentation

A
  • Recurrent invasive skin and soft tissue infections
  • Focal abscesses requiring incision and drainage Esp. liver and lung (high level of suspicion)
  • Granulomas / granulomatous diseases
  • Common pathogens: S. aureus, gram-negative bacilli, aspergillus, nocardia
37
Q

Causes of Granulocyte (neutrophil) deficiencies

A
  • Primary: Chronic granulomatous disease (most common but still rare), Leukocte adhesion defects, Chediak Higashi syndrome, Griscelli syndrome
  • Secondary: Medications (immunosuppression, steroids, azathioprine, chemo), infection
38
Q

Chronic granulomatous (CGD) key features

A
  • FBC- neutrophils can be normal just don’t work properly
  • Typically X-linked (affects men) but can be autosomal recessive
  • Early presentation (children) – usually
  • Abscess of skin and deep seated infections of lungs, lymph nodes, liver and bones
  • Catalase positive bacteria – Staphylococcus, Kebsiella, Serratia & Burkholderia
  • Fungal infections – Aspergillus (historically leading fatal cause of death)
  • IBD
39
Q

CGD investigations

A
  • Negative blue tetrazolium test on microscopy
  • Abnormal dihydrorhodamine flow cytometry test
  • Investigation: Neutrophil oxidative burst
  • FBC will show normal neutrophil count
40
Q

Chronic Granulomatous disease treatment

A
  • Prophylactic antibiotics
  • Prophylactic anti-fungals
  • Interferon Gamma
  • Bone marrow transplantation
41
Q

Chediak Higashi syndrome

A
  • Microtubule polymerisation defects leading to decreased phagocytosis
  • Characterised by: partial albinism (light skin, eyes, hair), peripheral neuropathy, recurrent bacterial infections
42
Q

Leukocyte adhesion deficiency

A
  • Defects of LFA-1 intern (CD18) protein on neutrophils which causes defective adherence mechanisms meaning leukocytes don’t localise to sites of infection
  • Presents with: recurrent bacterial infection, delay in umbilical cord sloughing, absent of neutrophils/pus at infections
43
Q

Cancers immunodeficiencies are associated with

A
  • Lymphoma: CVID, SCID, Wiskott-Alrich syndrome, ataxic telengiectasia, X-linked lymphoproliferative disease
  • HCC- hyper IgM
  • Leukaemia- Ataxic telengiectasis
44
Q

General treatment for immunodeficiencies

A
  • Treat infection (prophylaxis): antibiotics, antivirals, replacement IgG etc
  • Treat autoimmunity: steroids, Ciclosporin
  • Treat malignancy
  • Curative treatment: HSCT, Gene therapy
45
Q

Curative treatment for immunodeficiencies

A
  • Haematopoietic Stem Cell Transplant
  • Gene Therapy: Gene addition, Gene editing, Stem cells, Target cells
  • Thymic Transplant
  • (Enzyme Replacement Therapy)
46
Q

Features in primary immunodeficiency

A

lifelong history of infections, younger age of onset, concurrent autoimmunity or malignancy, family history.

47
Q

Features in secondary immunodeficiency

A

Use of chemotherapy or immunosuppressant medications, radiation, malignancy, protein loss from gut or kidneys, malnourishment, HIV.

48
Q

Immunodeficiency: initial bloods and investigations

A
  • Bloods: FBC, U&Es, LFTs, B12, Thyroid function, HBA1c, serum immunoglobulins and electrophoresis, HIV, lymphocyte subsets, specific antibodies against viruses (e.g, varicella, MMR) and bacteria (tetanus and pneumococcus.
  • Blood film
  • HRCT: to look for any structural damage, i.e. presence of Bronchiectasis, a thymoma or malignancy
49
Q

Immunodeficiency: second line investigations

A
  • Changes in Immunoglobulin: serum free light chains and immunofixation
  • Serum electrophoresis
  • Complement assays
  • Response to immunisation- if low response to Pneumovax offer Prevenar
  • Flow cytometry: Lymphocyte subsets, Neutrophil oxidative burst, T cell proliferation assay, NK Cell Granule Release Assay
  • Monitoring post bone marrow transplant: T cell proliferation assay
50
Q

Immunodeficiency management

A
  • Prophylactic antibiotics i.e. Azithromycin (ECG before starting to check for QT elongation, and check for TB as can be masked by Azithromycin)
  • Immunoglobulin replacement therapy: test for HIV, Hep B and Hep C before starting and IgM antibodies against blood group antigen (must be absent). Blood tests post treatment aren’t valid.
51
Q
A

year 4 CDM 2 (39 decks)

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