Primary immunodef

Question 1

What are the clinical features of immunodeficiency?

Answer 1

· Recurrent infections (normal: <6-8 URI/year for the 1st 10 years, 6 otitis media and 2 gastroenteritis/year for the 1st 2-3 years)
· Severe infections than expect, or unusual pathogens that do not usually infect (Aspergillus, pnuemocytis), unusual sites (liver abscess, osteomyelitis)
Usually at orifices these are in at different sites which are deeper

Question 2

What is the definition of primary immunodeficiency? what are the 10 warning signs?

Answer 2

Recurrent, unusually persistent, resistant to treatment, unusual organisms, unexpected spread
Other complications: increased predisposition to autoimmune diseases and maligancies (especially lymphoproliferative diseases)
Warning signs of PID
2 or more of the following- suggests that they may have PID
Usually more frequent, severe (i.e need IV AB), fx
10 warning signs of primary immunodeficiency
· 8+ new ear infections w/I 1 year
· 2+ serious sinus infections w/I 1 year
· 2+ months on antibiotics with little effect or none
· 2+ pneumonias w/I 1 year
· Failure of an infant to gain weight or grow normally
· Recurrent, deep skin or organ abscesses
· Persistent thrush (mouth or elsewhere on skin) after 1
· Need for IV AB to clear infections
· 2+ deep seated infections
·A fx of PID

Question 3

How many new ear infections?

Answer 3

8 in a year

Question 4

How many serious sinus infections

Answer 4

2 or more

Question 5

How many months on antibiotics?

Answer 5

2 months with little effect or non

Question 6

How many penumonias within a year?

Answer 6

2

Question 7

How many deep seated infections?

Answer 7

2

Question 8

What are some examples of secondary immunodeficiency? divide into malignancy, infections, extremes of age, nutrition, CKD, splenectomy, and others?

Answer 8

• Infections: viral, bacterial
		○ Viral: HIV, CMV, EBV, Measles 
		○ Chronic bacterial: TB, leprosy 
		○ Chronic parasitic: malaria, leishmaniasis 
		○ Acute bacterial: septicaemia 
	• Malignancy 
		○ Myeloma 
		○ Lymphoma (H and NH) 
		○ Leukaemia (acute and chronic)
	• Extremes of age 
		○ Prematurity: 
			§ Infants <6 months- maternal IgG 
			§ Premature delivery: interrupts placenta transfusion of IgG- infant Ig DEFICEICNY
		○ Old age 
			§ Decline in normal immune function 
	• Nutrition 
		○ Starvation
		○ Anorexia 
		○ Iron deficiency 
		○ Protein loosing enteropathies 
	• CKD
		○ Uraemia 
		○ Dialysis 
		○ Nephrotic syndrome
	• Splenectomy 
	• Others: 
		○ Burns 
		○ Toxic: smoking, alcohol
		○ Drugs: immunosuppression
		○ Trauma/surgery
Transplant

Question 9

What are the features of primary immunodeficiency?

Answer 9

· Usually genetic
· Infrequent but can be life threatening need diagnosis and treatment
Can affect either component
· Adaptive immune system: T and B cells
· Innate immune system: phagocytes and complement
· Frequency: 50% antibody, 30% T cell, 18% phagocytes, 2% complement
· Do not need to know all of them just the most frequent or most severe

Question 10

What would infections with pnuemocystitis or severe fungal and viral infections suggest?

Answer 10

T cell defect

Question 11

What would infections with encapsulated bacteria, streptococcus pneumonia, and haemophilus influenzas suggest?

Answer 11

B cell defect or complement?

Question 12

What would an infection with serratia, staphylococcus, klebsiella, nocardia, asperigillus suggest?

Answer 12

Neutrophil?

Question 13

What would a recurrent neisserial infections suggest?

Answer 13

Complement deficiency?

Question 14

When do the genetic forms of antibody deficiency usually present?

Answer 14

Recurrent infections usually begin around 4 months and 2 years of age as the maternally transferred IGG is passive protection in the first 3-4 months of life

Question 15

What is X linked agammaglobulinaemia (Bruton’s disease)

Answer 15

This is a Major B lymphocyte disorder
· Antibodies/immunoglobins/gammaglobinaemia

Typical history /Clinical Presentation: Male infant presenting with recurrent bacterial infections of lungs, ears, gut etc. between the ages of 4 months and 2 years (as in the first 6 months have mothers IGG and breast mild iGA)

Bruton’s disease
Defect in brutons tyrosine kinase btk gene (X chromosome)
Defect blocks in B cell development (stop at pre-B cells) - stop at the very early stage as this transition relies on tyrosine kinase
If the defect is complete this means that B cells cannot mature- therefore they cannot produce AB- they have agammaglobulinaemia
However may have less severe
Autoimmune diseases (35% of patients) - cannot respond to infection therefore cannot train the IS which is self and which is non self
BTK is needed in this stage in the bone marrow- XLA blocks this and the cells therefore die

Typically: they have no circulating mature B cells but T cells are normal
· FBC- total lymphocytes are low then look at subclasses
· B cells absent/low; plasma cells are absent
· All Igs absent/very low - low IgA, IgG, IgM
Often have no responses to immunisation
· T cells and T cell mediated response normal
Mutation in the Btk gene is found (prenatal diagnosis is now possible)

The treatment 
	· IV Ig (immunoglobulin): 200-600mg/kg/month at 2-3 week intervals 
	· Or subcutaneous Ig weekly 
	· Prompt antibiotic therapy (URI/LRI) 
Do not give live vaccines

Question 16

What is common variable immunodeficiency disorder? When do these people typically present?

Answer 16

These are a heterogenous group of disorders which make up the commonest form of primary antibody deficiency
· Commonest symptomatic Ab deficiency

Presentation: any age childhood to old age not as severe as above
Peak at early childhood/early adulthood
Typical history /Clinical Presentation: Usually a young adult male or female (age may range from childhood to old age) presenting with recurrent bacterial infections affecting lung, sinuses, ears etc
Autoimmune diseases e.g. Idiopathic thrombocytopenic purpura (ITP), Autoimmune haemolytic anemia (AHA) etc. may precede recurrent infections
Recurrent bacterial infections (Chest, sinuses)
Autoimmune problems (20% of patients)
Usually missed (exclusion diagnosis–> late diagnosis–> complications (structural lung/sinus damage))
Investigations:

· Screening tests: request serum immunoglobulins (IgG, IgA, IgM)

Typically have a low IgA often associated with a low IgG, and a low or normal IgM and a normal or low number of B cells. A small group have low T cells as well.
Exclude the other causes of IgG being low (e.g renal protein loss, malabsorption etc causing a secondary hypogammaglobulinemia)

Other tests to be done:
IgG subclasses, specific antibodies to haemophilus, pneumococcus etc
○ Lymphocyte phenotyping: normal numbers of B and T lymphocytes usually
○ T lymphocyte function may be abnormal
B cells are normal or low in blood and lymphoid tissues
B cells cannot different into plasma cells
○ Antibody deficiency (one or more Igs low)
T cells normal; CD4+ T cells can be low
○ Genotyping for various defects causing CVID, but inheritence is very rare

Treatment:
· IV Ig
Antibiotic prophylaxis

Question 17

What is selective IgA deficiency?

Answer 17

Most common 1:400-1:800
IgA is mainly in mucosal secretion- in the gut ,lung, urogenital tracts
Most cases asymptomatic; and diagnosed as incidental finding as young adults however some–> infections of respiratory, urogenital or GI tract
· Low levels of serum and secretory IgA with normal concentrations of IgG and IgM and production of normal antibodies to pathogen
Sometimes: increased incidence of allergic disease may produce IGE e,g coeliac disease
Most are healthy

Question 18

What is severe combined immune deficiency? What is the presentation?

Answer 18

Involves both T and B - adaptive immune response are severely impaired therefore huge risk of infections. There are various different types reflecting the complexity of the cell surface receptors and itnracellular signalling pathways
· Some are locations of X chromosome or autosomal
· 50-60% X linked, rest- autosomal recessive

Presentation:
· Well at birth, problems >1st month
· Diarrhoea, weight loss, persistent candidiasis
· VERY IMMUNODEFICIENCY
· Severe bacterial/viral infections
· Failure to clear vaccines - Develop the disease
· Unusual infections (pneumocystis, Cytomegalgovirus

• Infections are often viral or fungal rather than bacterial
• Chronic diarrhoea is common and often labelled as
‘gastroenteritis’
• Respiratory infections and oral thrush are common
• Failure to thrive, even in absence of obvious
infections, must be investigated
• Lymphopenia is present in almost all affected infants
and is often overlooked
• HIV must be excluded

Question 19

What are the causes of SCID?

Answer 19

Causes:
Some to do with development and maturation of B and T cells
Must recombine genes for Ab and T cell receptors- to recognize foreign and self
Genes that are involved in this process - cannot develop or stay alive
○ Common cytokine receptor y-chain defect (signal transducing component of receptors for iL2, IL4, IL7, IL9, IL11, IL15, IL21); IL7 needed for the survival T cell precursors- defective T cell development- lack in B helper cell (low AB)
○ RAG1/RAG2 defect- no T and B cells
○ ADA (adenosine deaminase deficiency)- accumulation of deoxyadenosine and deoxy-ATP- toxic for rapidly dividing thymocytes

Question 20

What investigations are done for SCID?

Answer 20

Investigations:
· FBC- low total lymphocytes decrease
· Lymphocytes subsets: T, B, NK (% and numbers)- low lymphocytes
· What type:
○ Pattern: very low/absent T; normal/absent B, sometimes also absent NK (y chain defect affecting IL15 receptor)
○ Igs low without B cells
○ T cell function low (proliferation, cytokines)

Question 21

What is the treatment for SCID?

Answer 21

Treatment:
· Bubble boy- isolation- to prevent further infection used to be the case
· Do not give live vaccines
· Blood products from CMV negative donors as cannot protect themselves
· IV Ig replacement
· Treat infections
· Bone marrow/haematopoietic stem cell transplant
· Gene therapy (for ADA and y-chain genes)
Outcome:
· Dependent on promptness of diagnosis
· Survival >80% (Early diagnosis, good donor match, no infections pre transplant)
· Survival <40% (late diagnosis, chronic infections, poorly matched donors)
Regular monitoring post BMT- engraftment

Question 22

What is DiGeroge syndrome?

Answer 22

· Syndrome- therefore may have various development consequences
· 22q11 deletion- failure development of pharyngeal pouches
· Complex array of development defects
· Dysmorphic face: cleft palate, low set ears, fish shaped mouth
· Hypoparathryoidism- convusions, tetancy
· cardiac abnormalities
· Variable immunodeficiency (Absent/reduced thymus- affects T cell development
Thymus is abnormal, CD3 cells are low but rise with age

Question 23

What is Wiskott Aldrich syndrome?

Answer 23

Syndrome- therefore may have various development consequences
X linked
Defect in WASP (protein which is involved in actin polymerisation- defect in signalling) affects recognition of Ab
1. Thrombocytopaeni-bleeding
2. eczema
3. Infections
· Progressive immunodeficiency (T cell loss)
· Progressive, loss of T cells, loss of T cell proliferation
· Ab production (low IGM, IGG, high IgE, IgA need cytokines)

Question 24

What is Ataxia telangiectasia?

Answer 24

· Autosomal recessive
· Defect in cell cycle checkpoint gene (ATM)- sensor of DNA damage- activates p53, apoptosis of cells with damaged DNA
· ATM gene stabilises DNA double strand break complexes during v(d)j recombination- defect in generation of lymphocyte antigen receptors and lymphocyte development
Clinical features:
1. Progressive cerebellar ataxia (abnormal gait)
2. typical telangiectasia (ear lobes, conjunctivae)
3. Immunodeficiency
· Combined immunodifiency (B and T)
· Defects in production of switched AB (IgA/G2)
· T cell defects (less pronounced)– thymic hypoplasia
· Upper and lower RTI
· Increased incidence of tumours later in life - malignant disease
· Autoimmune phenomena

Question 25

What is chronic granulomatous disease? What is the defect in, how does it present?

Answer 25

Certain step of phagosome mechanism - they have a mutation in NADH components- defective oxidative killing of phagocytosed microbes- mutation in the phagocyte oxidase components - various genes can be defect
There is an inability to do intracellular killing- ingested bacteria survive and proliferate in intracellular enviroemtn free from AB and most antibiotics. Here there is a failure to produce high concetrations of ROS

Clinical features:
· Present with granulomas on the skin (wall of pathogens) 
Infections are recurrent and prolonged
Clinical features may be minimal despite severe infection
Infections are:
• poorly responsive to antibiotics
• commonly staphylococcal
• involve skin and mucous membranes
• complicated by lymphadenopathy

Diagnosis:
· NBT test (nitroblue tetrazolium reduction)- uses phagosomes of the blood then compare with control- treat with NBT- if they produce ROS-t if they do it produces blue but in CGD remain blue
Flow cytometry assay dihydrohodamines - activate neutrophils if they produce ROS- the molecule is cleared
‘Treatment: prophylaxis AB (usually co-trimoxazole) and antifungal agents
Some studies show IFNy reduces infections, allogenic BM transplant offer only long term hope

Question 26

What is Chediak Higashi syndrome

Answer 26

· Rare genetic disease Autosomal recessive
· Defect in LYST gene (regulates lysosome traffic) - enzymes to do with lysosomes not fuses
· Defetc in phagosome- lysosome fusion- defective killing of phaogyctosed microbes- leading to recurrent infections
· Therefore can only use ROS
· Neutrophils have defective phagocytosis
· Repetitive severe infections

Diagnosis:
· Decreased number neutrophils
· Neutrophils have giant granules b/c lysosomes fuse with each other as they cannot fuse with phagosomes

Question 27

What is leucocyte adhesion deficiency?

Answer 27

· One of the class of the molecules that is important for the movement of neutrophils rom blood into the tissue- intergrins and selectins ligands are impaired- therefore neutrophils cannot leave
· Defect in B2 chain integrins (LFA-1, Mac1) 
· Defect in sialyl lewis X (Selectin ligand)
· Delayed umbilical cord separation- the stump takes longer to fall off- need phagocytes to clear the debris- diagnosis defect in B2 chain integrins (LFA-1, Mac1) 

Clinical presentation:
· Skin infection, intestinal and perianal ulcers, and ginigivitis
Deep abscesses, peritonitis, osteomyelitis

Investigations:
· Decreased neutrophils chemotaxis - can do this in vitro
· Reduced integrins on phagocytosis (flow cytometry)

Question 28

What is complement deficiency?

Answer 28

Depending on the component that is affected- affects the symptoms- either lyse them or promote inflammatory response
· Recurrent infections Neisseria group- deficiency terminal complex (MAC- membrane attack complex): C5-C9
· Severe fatal pyrogenic infections (C3 deficiency) which is Key in all activation of complement
· SLE like syndrome (C1q, C2, C4 deficiency) this is involved in activation of vesicle forming pathway - milder presentation
·Hereditary angioneurotic odema: failure to inactive complement (deficiency in C1 inhibitor) intermittent acute odema skin/mucosa- vomiting, diarrhoea, airway obstruction

to investigate:
CH50 complete function
Measure individual components

Question 29

What is the presentation and treatment of Hereditary angioneurotic odema?

Answer 29

Deficiency of the inhibitor of the first component of complement (Cī inhibitor) (Cī INH)

It is the commonest known deficiency of a complement component.
Patients suffer from recurrentattacks of skin, laryngeal or intestinal oedema. In contrast to urticaria, localized oedema of the face, limbs and trunk is neither painful nor itchy. Sometimes, however, oedema occurs in the intestinal tract, causing severe abdominal pain and vomiting when the jejunum is involved, or watery diarrhoea if the colon is affected. Laryngeal oedema may be fatal because of airways obstruction. The attacks develop over a few hours and subside spontaneously over 1–2 days

· Measure individual components
· Complement function: CH50 (haemolysis)
· A total complement measurement, also known as a total hemolytic complement or a CH50 measurement, checks how well the complement system is functioning.
· Screening tests: C3 & C4
· Typically the C4 is low, C3 is normal (low C4 and low C3 is seen in immune complex disease due to complement consumption)
· Confirm diagnosis by C1 esterase inhibitor: low level confirms HAE type 1 which makes up 85%
· 15% have normal C1 esterase inhibitor level, but it is non functional (type ii HAE)

Treatment: replace C1est. inhibitor by infusions and/or bradykinin receptor blocker (subcutaneous injection (as the angioedema/sweeling is mediated by bradykinin not histamine
· Cannot to turn off- use up all of the complement in their blood therefore do not have any left for infection- too much inflammation
· We have various inhibitors which stop this

Complications: laryngeal odema

Question 30

What are the principles of management of primary immunodeficiency?

Answer 30

Aims:
· Minimise/control infection
· Replace defective/absent component of IS
· Prompt treatment of infection
· Prevention of infection: isolation, AB prophylaxis, vaccination (not live)
Nutrition

Question 31

What are the tests you want to study for immune system (quantitiative and functional)

Answer 31

Important to find out:
• How much of a component of the immune system is present/deficient (quantitative tests)?
• How well do the components of the immune system function (functional tests)?

Question 32

What are the serological functional and quantitative tests you can do?

Answer 32

Serological tests: These tests measure serum proteins (e.g. antibodies, complement)
1. Quantitative tests:
Immunoglobulins:
• The three main immunoglobulin classes IgG, IgA, and IgM are measured
• Deficiency raises suspicion of immunodeficiency and needs further investigation.
IgG subclasses:
• IgG can be subdivided into IgG1, IgG2, IgG3, and IgG4, all of which have slightly different functions, so deficiency can cause susceptibility to certain infections.
• It’s possible to be deficient in an IgG subclass and still have a normal total IgG level.
Complement:
• Any complement component including mannose binding lectin (MBL), may be deficient
• Deficiency in terminal complement components may result in an increased susceptibility to meningococcal infection, MBL deficiency may result in increased frequency of chest infections and C2 deficiency is associated with autoimmunity.
• Deficiency in C1 esterase inhibitor results in hereditary angioedema.

2. Functional Tests.
   Specific antibody responses.
   This measures specific IgG antibodies directed against:
3. Common pathogens/environmental microbes e.g. E.coli, isohaemagglutinin.
   • Absence of these specific antibodies may suggest a more general failure to respond appropriately to infection.
4. Tetanus, H. influenza type B and pneumococcus (“functional antibodies”).
   • A pre and post vaccination level can be measured. Failure to respond to vaccination (i.e. a less that four-fold increase in titres) can be found in immunodeficiency.

Total haemolytic complement: This measures the function of the classical pathway (CH50 test) or alternative pathway (AP50 test).

Opsonisation (heat inactivated serum): Detects deficient antibody function to a certain organism.

Question 33

What cellular tests can you do (quantitive, T lymphocyte, phagocyte)

Answer 33

Quantitative tests: The white cell count and differential will identify deficiency of lymphocytes and neutrophils. A “lymphocyte subsets” test (done by flow cytometry) will count numbers of CD4, CD8, NK and B cells.
T lymphocyte functional tests: stimulating cultured T lymphocytes with a variety of antigens (e.g. candida, PHA, MLR) can help to identify exact functional defects.

Phagocyte functional tests:
1. Dihydrorhodamine test (DHR) or nitro blue test (NBT). This identifies failure of the neutrophil oxidative burst/intracellular killing mechanism
2. Mobility tests identify cells which are unable to move properly/transmigrate from the blood stream to tissues
3. Opsonisation tests detect abnormal phagocytosis
4. Cell surface markers: it is known that abnormal phagocytes lack certain cell
surface markers (CD18, CD11a etc). This can be measured by flow cytometry.

Question 34

A male infant born at full term by normal delivery developed otitis media at the age of 7 months followed by frequent chest infections and an episode of pneumonia due to Haemophilus influenzae (encapsulated). On examination, there was no lymph node enlargement or evidence of candida infection.
The mother was extremely worried as she had lost one of her younger brothers aged 10 months following severe pneumonia. He has 2 healthy sisters, and his parents were not consanguineous.
What is the likely cause? List the relevant points to help you make the diagnosis

Answer 34

Discuss the likely causes of his recurrent infections
B cells or complement

List the relevant points in the above history that may help make a diagnosis
LN NOT enlarged: not responding to infection!!!!!
Candida would suggest T cells
Could be X linked!
Antibody deficiency
• X linked agammaglobulinemia (male, fx)
• Transient hypogammaglobulinemia of infancy (when the period when the material IGG goes down, and infant starts to make own antibodies) (male or female, prematurity)
Complement deficiency is rare

What investigations may help arrive at a diagnosis?
• Serum immunoglobulins are very low
• Lymphocyte genotyping: absent B cells and normal T cells
• BTK gene mutations- this helps makes the firm diagnosis
Diagnosis: X linked agammaglobulinaemia confirmed by tyrosine kinase gene mutations (BRUTONS)

Question 35

A 2-month old baby, born at full term was admitted to the children’s ward with a chest infection that had not responded to two courses of antibiotic therapy given by his GP. He has faltering growth, persistent diarrhoea and severe candidiasis affecting the mouth and diaper areas. His parents are consanguineous but healthy.
What is the likely cause? List the relevant points to help you make the diagnosis

Answer 35

Discuss the likely causes of his recurrent infections
Chest infections- B cells
Fungal infection and antibiotics not working - T cells
Faltering growth
Parents consanguineous
Infection suggests combined T and B cell defect

Primary: combined B and T cells e.g SCID
Secondary: HIV and AIDs

What investigations may help arrive at a diagnosis?
• Lymphocyte count low
• Lymphocyte phenotyping: T and B cells are low
• Immunoglobulins low (due to B cell and T cell being low)
○ There is a bit of IGG- they still have the mothers

Severe combined immunodeficiency
Types of SCID- present similarly within the first 6 months of life (infections, faltering growth)
Learning:
• Lymphopenia <2 x 109 in baby <6 months SCID until proven otherwise
• Suspected SCID should be referred urgently
• AVOID LIVE VACCINES
• Iridate all cell products to avoid engraftment of donor lymphocyte

Question 36

A 17 year old woman presented to A&E with acute, swelling of the face and anterior tongue. She spoke with difficulty, and was having trouble swallowing saliva. She had undergone a minor dental procedure earlier that day.
Since the age of 16 years the patient has had recurrent episodes of swellings affecting the hands, feet and sometimes the trunk, occurring about once a month and lasting 3 – 4 days at a time. She was investigated for abdominal colics when she was 12 years old. What is the likely cause? List the relevant points to help you make the diagnosis

Answer 36

What are the likely causes for her symptoms?
Complement deficiency- C1 esterase inhibitor
Anaphylaxis is she reacting to anaesthetic
Ask if there itching with the swelling
Drug induced (analgesics, ACE i)
What investigations may help arrive at a diagnosis?
• C3 is normal
• C4 is low
• C1 esterase inhibitor LEVEL: is low
• C1 esterase inhibitor function Is low
Diagnosis: HAE- swelling is deeper therefore do not get itching

Question 37

A 2 year boy was referred to the Immunology clinic for investigation of frequent hospital admissions with axillary and perianal abscesses. A recent Staphylococcal abscess on the anterior abdominal wall was drained surgically, and there was delayed healing of the surgical wound.
On examination, he was a thin pale child, below the 10th centile for height and weight and had hepato-splenomegaly.

Answer 37

Discuss the possible causes of his symptoms and signs
• Chronic granulomatous disease–> neutrophils are affected!
• Antibody deficiency (B cells)
What investigations may help arrive at a diagnosis?
• Full FBC/DC
○ Low HB, normal lymphocyte, elevated neutrophil, elevated ESR (showing inflammation)
• Serum immunoglobulins elevated
○ IGG is high trying to fight infection
• CRP is high
• Neutrophil phagocytosis: normal - they are encapsulated and then they get respiratory burst to kill
• Neutrophil respiratory burst (DHR): absent
Encapsulated bacteria
Delayed healing- neutrophils re not performingwell
Chronic granulamatous disease

Chronic granulomatous disease (CGD)
Fx, consanguityy (X linked, AR)
HX of bacterial/fungal infections
Review of systems: deep seated infections (live abscess, lymphadenopathy, osteomyelitis), granuloma in bowel (malabsorption)
Diagnosis is missed unless test for respiratory burst is asked for