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Small Animal Final Year > Immune Mediated Disease > Flashcards

Immune Mediated Disease Flashcards

1
Q

Do immune mediated diseases occur more in dogs or cats?

A

Dogs

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2
Q

What does the initial presentation tend to be like?

A

•Vague initial presentation often pyrexia of unknown origin (PUO) which waxes and wanes for a number of weeks

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3
Q

Name a multi system involvement immune mediated disease (2)

A

–Systemic lupus erythematosis (SLE)

–Sjogren’s syndrome

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4
Q

Name 2 cutaenous immune mediated diseases (3)

A

–Canine dermatomyositis

–Discoid lupus erythematosus (DLE)

–Pemphigus-pemphigoid complex

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5
Q

Name 2 musculoskeletal/neuromuscular immune mediated disease (3)

A

•Musculoskeletal/neuromuscular

–Polymyositis/polyneuritis

–Myasthenia gravis (neuromuscular)

•Focal vs. generalised

–Polyarthritis (erosive and non-erosive)

•Feline progressive polyarthritis

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6
Q

Name 2 haemolymphatic immune mediated diseases (3)

A

–Immune mediated haemolytic anaemia

–Immune mediated thrombocytopaenia

–Immune mediated neutropaenia

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7
Q

Name a renal immun mediate disease

A

Glomerulonephropathies

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8
Q

Name a CNS immune mediated disease (2)

A

–Steroid responsive meningitis/encephalitis

–Granulomatous menigoencephalitis

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9
Q

Name a GI immune mediated disease

A

IBD

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10
Q

What can cause primary immune mediated disease (2)

A

–MHC class (accounts for some breed predispositions)

–May be true auto-immunity

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11
Q

Name 5 secondary causes of immune mediated dissease (7)

A

–Vaccination (variable evidence for this….)

–Neoplasia (particularly lymphoproliferative diseases)

–Inflammatory disease (pancreatitis, prostatitis etc)

–Infection (Mycoplasma, Salmonella, GI parasites, etc)

–Drugs/toxins (TMPS, carprofen, cephlosporins, griseofulvin, Zinc, etc)

–Hormones (oestrogen)

–Seasonality (some evidence for seasonal influence and recrudescence)

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12
Q

What is the aetiology of immune mediated disease?

A

•Due to loss of self-tolerance, allowing formation of antibodies to a subset of normal proteins in the body

–Lack of regulation leads to development of progressive inflammation and damage

–Usually NOT global immunodeficiency

–Specificity of loss appears to be determined in part by genetic background

–Role of hormonal factors unclear in animals

–Can present at any age, but some more common at specific times of life

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13
Q

How can we diagnose immune mediated disease?

A

•Recognition of the signalment and evaluation of history and physical examination findings

–Careful analysis of laboratory tests and biopsy results

–When available, fulfilment of specific diagnostic criteria, e.g. those used for SLE

–Several of the diseases do not have a specific “lab test”; diagnosis on identifying problems and prioritising differentials list, followed by supporting clinical data

–Often follow a waxing and waning course

  • Determined by the problem list for each individual patient
  • Should include haematology, biochemistry and urinalysis in all cases as part of the minimum database
  • Diagnostic tests should be carried out before institution of therapy wherever possible

–If not retain samples for submission at a later time point

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14
Q

What are the different ways you can have IMHA? (6)

A
  • Alloantibody: blood transfusion reaction,neonatal isoerythrolysis
  • Autoantibody to RBC membrane antigen
  • Cross-reacting antibody against infectious agent
  • Antibody against drug adherent to RBC
  • Drug or infection modifies RBC antigen or exposes a hidden antigen
  • Idiopathic
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15
Q

What are the main causes of IMHA?

What can it cause?

A
  • Idiopathic in majority (60-75%) dogs and cats that and neoplasia
  • May be due to auto-reactive T cells, but unclear
  • Phagocytosis of opsonized red blood cells predominantly in the spleen (extravascular), but also by blood monocytes (intravascular)
  • Usually IgG, sometimes IgM or C3 complement implicated

–IgM more likely to be intra-vascular haemolysis

  • In rare cases can be in bone marrow only
  • Causes death can also be through thrombus formation, DIC and marked systemic immune response
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16
Q

How can immune mediated diseases be characterised?

A

–Primary (idiopathic)

–Secondary (underlying cause)

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17
Q

What is the diagnostic criteria for SLE?

A

Diagnostic criteria:

Definite SLE: Two major signs with positive serology OR one major and two minor signs with positive serology

Probable SLE: One major sign with positive serology OR two major signs with negative serology

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18
Q

What serology can we do for SLE?

A

Anti nuclear antibody (ANA)

Lupus erythematous cell preparation

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19
Q

What are these?

A

Lupus erythematosus cells

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20
Q

What does this show?

A

Antinuclear Antibody reaction (ANA)

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21
Q

What is the signalment for IMHA?

A
  • Cocker spaniel, Min Schnauzer, Springer spaniel, poodle, old English sheepdogs and others at increased risk, probably from DLA haplotype
  • Usually young-middle aged, F>M dogs
  • May be more prevalent in summer months
  • Unconfirmed link with vaccination
  • If none of these apply, may be secondary to infectious disease or neoplasia
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22
Q

What is the clinical presentation of IMHA?

A

•Presentation variable in both severity and chronicity

–Primarily relate to reduction in oxygen carrying capacity of the blood

  • Lethargy, depression, tachypnoea, tachycardia, weakness, anorexia
  • Collapse, Pallor of mucus membranes seen in >75%

–Haemic heart murmur due to altered blood viscosity

–Jaundice (pre-hepatic due to increased bilirubin from RBC breakdown) usually from extravascular form

•Intravascular IMHA leads to haemoglobinaemia (red plasma not orange)

–Hepatosplenomegaly seen in many cases

–may have concurrent IMTP (Evans’ syndrome)

  • Affects prognosis
  • More difficult to stabilise due to bleeding tendency with IMTP
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23
Q

How can we diagnose IMHA?

A

•Characterised by a regenerative anaemia

–Degree depends on the magnitude of the anaemia

–Pre-regenerative if per-acute presentation

•Spherocytosis (hard to see in cats)

–Partial phagocytosis by cells of RES

•Auto-agglutination:

–Add one to three drops of saline to one drop of EDTA blood and mix by rocking. Look under microscope for RBC clumping (distinguish from rouleux – stacked coins)

•Concurrent leucocytosis, hyperbilirubinemia and elevated liver enzymes common

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24
Q

What are these smears characteristic of?

A

IMHA

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25
Q

What is the coombs test?

A

Identify RBC which have AB attached to them

In vitro agglutination

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26
Q

How can we treat IMHA and IMTP?

A
  • Treatment for IMHA and IMTP is similar in principle
  • Aim to induce rapid remission from ongoing haemolysis (or platelet destruction and haemhorrage)
  • Slower aim to enable recovery from anaemia
  • (treatment details later slide Treatment will induce a neutrophilia from steroids but is hard to distinguish beetween the neutrophilia cause by IMHA and then the neutrophilia then caused by treatment so CRP is used instead as is more sensitive marker as it is a Acute Phase Protein APP)
  • How do we know if disease is controlled?
  • Absence of spherocytes, lack of reticulocytosis once PCV normalised, APPs?
27
Q

How do we know if IMHA is controlled?

A

–Absence of spherocytes, lack of reticulocytosis once PCV normalised, APPs?

–Unknown what the cause of neutrophilia is- steroids will cause this as well as wdisease

–Measure CRP and get a reference point – check CRP at each drug change

–CRP – more sensitive inflammation marker

28
Q

What is the outcome and prognosis of IMHA?

A
  • 50-88% survival to discharge from hospital
  • Death/euthanasia from ongoing IMHA or complications

–Major complication is thromboembolic disease

–If survive past 14 days prognosis improves with most dogs then surviving to a year

•variable median survival times

–Therefore use prognostic indicators

  • Relapse common
  • Negative prognostic factors

–Icterus, severe autoagglutination, thrombocytopenia, hypoalbumaemia, elevated urea

29
Q

What usually causes IMTP?

A

•Usually results from destruction of circulating platelets

–Occasionally immune mediated attack at the level of the precursors in the bone marrow (amegakaryocytic thrombocytopaenia)

30
Q

Which breeds are over represented with IMTP?

A

•Cockers, poodles, Old English Sheepdogs over-represented

–CKCS often (~50%) have a low platelet count

  • Due to mutation in β-tubulin gene
  • Counts can be between 50-120x109/l
31
Q

What classifies IMTP?

A
  • Thrombocytopaenia any platelet count lower than normal range (160-500x109/l)
  • Platelet count can vary but usually is <30x109/l with IMTP

–Spontaneous bleeding usually occurs below this level

–Occasionally above if thrombopathia present as well

32
Q

What signs are seen with IMTP?

A
  • Can suffer with pyrexia prior to overt thrombocytopenia
  • Often initial signs seen by owner are due to haemorrhage

–Mucosal and skin haemorrhage - petechiae and ecchymoses

–Hyphaemia/retinal haemorrhage/ epistaxis

–GI haemorrhage - melaena and haematemesis

33
Q

How do you diagose IMTP?

A

•Diagnosis on low platelet count and exclusion of other potential causes

–Need to determine between primary and secondary IMTP

–Diagnosis of exclusion once infectious, drug induced and neoplastic causes ruled out

34
Q

What may a dog with IMTP have also?

A

IMHA

35
Q

What is the aim of immune mediated disease therapy?

A

•Halt ongoing immune mediated damage to allow recovery

–e.g. red cell production/platelet production

–(along with nutritional, nursing and analgesic requirements)

–2 fold – stop disease, and support the animal to suppress the diease

–Stopping the disease is not enough on its own

36
Q

What is the main therapy option for immune mediated disease?

A

Corticosteroids +/- adjuncts

37
Q

What are the actions of corticosteroids in immune mediated disease? (6)

A

–Reduced egress of inflam cells into tissues

–Reduction in inflammatory mediators

–Suppressed macrophage and neutrophil function

–Lymphocytotoxic

–Reduced macrophage Fc receptor expression

–Inhibition of complement

38
Q

What side effects are there with corticosteroids in immune mediated disease?

A

–Some mild and others less so

–PUPD, polyphagia, muscle wastage, HPA suppression, GI ulceration and depression common

–Rarely thromboembolic complications

39
Q

What are the potencies of immunosuppressive corticosteroids?

A
  • Effects usually seen within 24-36 hours
  • Dexamethasone thought to be significantly more ulcerogenic than prednisolone

–longer half life therefore cumulative effects need to be considered if using this

–often used as IV preparation

–However prednisolone is rapidly absorbed after oral administration therefore questionable need for IV route

  • Effects usually seen within 24-36 hours
  • Dexamethasone thought to be significantly more ulcerogenic than prednisolone

–longer half life therefore cumulative effects need to be considered if using this

–often used as IV preparation

–However prednisolone is rapidly absorbed after oral administration therefore questionable need for IV route

40
Q

Discuss the use of azathioprine

A
  • Purine analogue, metabolised in liver to active form which prevents cellular proliferation
  • Tablets (do not split), typically dosed q48h
  • Side effects more in dogs than humans due to the metabolites
  • Usually well tolerated in dogs
  • irreversible myelosuppression if used at higher than recommended dosage
  • progressive hepatopathy therefore monitor live enzymes
  • Not recommended in cats (rapid lethal bone marrow suppresssion)
  • Delayed onset of activity therefore is invariably used as adjunct

–Start early for optimal onset of activity use in combination with corticosteroids (preds)

41
Q

Discuss the use of cyclosporine

A
  • Becoming more common
  • Licensed in the cascade for the species for another condition
  • Calcineurin inhibitor: Suppresses formation of cytokines in innate and adaptive immune system and blockade G0 transition to G1

–Stop lymphocyte proliferation – suppressed lymphocytes especically T cells

  • Various formulations now available
  • Microemulsion capsule (do not split)
  • Liquid preparations (easier to dose)
  • Probably no need for therapeutic monitoring when using atopica – can measure whole blood levels
  • May increase risk of infection, and linked with increased incidence of lymphoma
  • Anecdotally useful in many immune mediated diseases
42
Q

Discuss the use of cyclophosphamide?

A
  • Alkylating agent: interferes with DNA and RNA transcription
  • [Part of lymphoma COP/CHOP therapy]
  • Associated with neutral or negative impact on survival in IMHA

–therefore recommend this is NOT used in immune mediated disease

43
Q

Discuss the use of chlorambucil

A
  • Alkylating agent: interferes with DNA and RNA transcription
  • Slow acting, low toxicity
  • Give on empty stomach as food reduces absorption

–Need to be stored in the fridge

•Can use as an adjunct to steroids in IMHA, IMTP, PA, IBD

44
Q

Discuss the use of Mycophenolate mofetil?

A
  • Anti-metabolite agent, inhibiting purine synthesis in lymphocytes
  • Increasingly popular as a steroid adjunct in some centres
  • Capsule and injectable forms, moderately expensive
  • Limited evidence for efficacy

–studies show efficacy in myaesthenia gravis and IMHA

•Can get some severe GI side effects

45
Q

Discuss the use of Intravenous immunoglobulin

A

•Purified preparation of polyspecific IgG from human blood donors

–Ethics over use in vet species

  • £££££ and inconsistent availability
  • Multiple actions including blockade of Fc receptors and neutralise auto Abs
  • Used in IMHA, IMTP and some skin diseases as an adjunctive therapy
  • Variable reports on efficacy, may reduce days of hospitalisation in some cases – further clinical trials needed
46
Q

Discuss the use off vincristine

A

•Vincristine is also used for IMTP

–it’s effects are thought to be

–Stimulate thrombopoeisis in the bone marrow

–Inhibition of platelet phagocytosis by monocytes

•Platelets containing high concentrations of vincristine?

47
Q

Name intervention therapies for immune mediated disease (other than drugs)

A

–Blood transfusion (packed cells vs whole blood)

–Oxyglobin

–Thromboprophylaxis indicated in management of IMHA

•Aspirin or clopidogrel

–Splenectomy can reduce mortality rates in IMHA and IMTP

–Therapeutic plasmapheresis (if you can afford)

–Gastroprotectants not shown to be of value prophylactically when using glucocorticoids

•Indicated if suspect GI ulceration however

48
Q

How can we monitor immune mediated therapy?

A

•Usually start with single agent prednisolone at 1-2mg/kg PO q24h dogs, cats 2mg/kg q12h

–Must have ruled out infectious disease prior to introduction

–Care with dosing in large dogs – better to use mg/m2 dose schedule (same as chemo)

  • Muscle weakness notable in large dogs
  • Generally dose is maintained until induction of remission, often this is maintained for 3-4 weeks

–Dose reduction/addition of adjunctive therapy when side effects excessive

•If poor response, add additional therapy

–Often this is introduced at beginning depends on severity and clinician preference

•Recent review suggested prednisolone alone should be sufficient in the majority of cases

–Once remission achieved, taper corticosteroids over 3-4 months at 20-25% per month.

  • Again depends on side effects and maintenance of remission
  • Guided by APP (Acute Phase Protein and CRP) too
  • Owners often don’t want to pay for this – go on signs
  • Reduce dose monthly – take blood 2 week later
  • Monitor for recurrence – common.
49
Q

What is alloimmune haemolytic anaemia?

A

Within a specific species which stops it surviving due to other things in that species

Specific antibodies directed against erythrocyte antigens (blood types) from the same species but not from the individual producing the antibody

Occur naturally (cats)

Produced through sensitization by birth of foal with mismatched blood group (horses)

Produced through sensitization with mismatched blood transfusion (dog)

50
Q

What is neonatal isoerythrolysis?

A

Caused by the transfer of maternal antibodies in the colostrum. Kittens & foals are born healthy, NI develops several hours – days after colostrum ingestion

Haemolysis is the main mechanism in the pathogenesis of disease; agglutinating antibodies are less important

Cats – natural alloantibodies (don’t need sensitisation)

= first mismatched litter at risk

Horses – alloantibodies aquired through sensitization

= 2nd and subsequent mismatched foals at risk

(except if sensitization occurred prior to pregnancy through blood transfusions, or the administration of vaccines containing equine tissue products)

51
Q

What is feline neonatal isoerythrolysis?

A

=Caused by maternal anti-A alloantibodies in colostrum of blood group B queens.

=Immune mediated haemolysis of type A and type AB erythrocytes

=major cause of the fading kitten syndrome; kittens dying quickly. Take urine and if it has hemoglobin in – high chance of NE

= breed variation in the proportion of type B queens: UK

British shorthaired population - high prevalence of type B queens.

Domestic shorthaired population low prevalence of type B queens (Knottenbelt and others 1999).

CANT PREDICT THE BLOOD – MUST KNOW

52
Q

What are the clinical signs of feline neonatal isoerythrolyis?

A

develop within hours of feeding or after a few days.

hemoglobinuria

= Every effort should be made to obtain a urine sample from kittens presented with fading kitten syndrome.

53
Q

How can you treat feline neonatal isoerythrolysis?

A
  • Blood transfusion
  • Fostering by type A queen or milk replacer
  • Supportive therapy
54
Q

How can you present feline neonatal isoerythrolysis?

A

Blood typing queen & tom and only mating type B queens with type B toms (keep Bs and Bs together)

Foster nursing type A and AB kittens born to type B queen

55
Q

What is equine neonatal isoerythrolysis?

A

Sensitization of mare to the stallion’s RBC antigens that differ from her own RBC antigens via blood leakage through the placenta during pregnancy or delivery = producing of alloantibodies

Sensitization after initial exposure (usually after the first pregnancy) is usually minimal. Repeated exposure to the same RBC antigens (ie after mating with same stallion) occurs with subsequent pregnancies, = alloantibody production increased

90% of all NI cases are associated with antibodies to blood groups Aa and Qa; it has not been associated with Ca antigen in the horse.

56
Q

What are the cliical signs of equine neonatal isoerythrolysis?

A
  • progressively lethargic, weak, and depressed.
  • Pale mucous membranes and later icteric (degree of icterus is dependent upon time and the amount of hemolysis that occurs)
  • severe anemia Æ marked hemoglobinemia and hemoglobinuria
  • breathing may become shallow, rapid, and labored (reduced oxygen carrying capacity of the anemic blood
  • +/- Tachycardia

severe hypoxia Æ convulse or become comatose and die.

shock Æ rapid death (within 6-8 hours postpartum) before icterus can occur.

57
Q

How do you treat Equine Neonatal Isoerythrolysis?

A
  • Immediately stop the further ingestion of colostrum
  • Supportive care is needed until the foal recovers
  • Intravenous fluid therapy
  • Transfusion – whole blood if suitable donor available or washed RBCs from the dam
58
Q

How do you prevent equine neonatal isoerythrolysis?

A
  • Avoid mismatched matings
  • If NI is a potential problem that may develop from the ingestion of colostrum, then colostrum can be withheld from the foal until a crossmatch is performed between the mare’s serum and the offspring’s RBCs (Jaundice Foal Agglutination (JFA) test)
  • Feed stored (frozen) suitable colostrum
59
Q

discuss bovine neonatal pancytopaenia

Including the signs and what it is

A
  • Total loss of all cells in the bone marrow
  • 1st case reported in EU in 2006, in UK April 2009; 445 calves (Feb’11)
  • Clinical signs; pyrexia, signs of unexplained haemorrhage from the nose, gum margins, ear tag sites, injection sites and GI tract (melaena), beading of blood on the skin (insect bites?), petechial haemorrhages on the ventral tongue
  • Initially bright calves quickly become recumbant, pale mucous membranes, dyspnoae, colic, sudden death
  • Mortality ~90%
60
Q

What is the aetiology of Bovine Neonatal Pancytopaenia (BNP)?

A
  • Correlation with BVD vaccine
  • Destruction of bone marrow cells (megacaryocytes, as well as granulocyte & erythrocyte precursors)
  • Aetiology still under investigation – some evidence for immunopathological reaction due to alloreactive antibodies, which are transferred to the calves via colostrum
  • Thought to be in older cows which have had multiple vaccines
  • Greater risk for 2nd and 3rd partum cows with multiple vaccinations
61
Q

How can you definitively diagnose bovine neonatal pancytopaenia?

A

Definitve diagnosis:

  • Multiple internal and external haemorrhages
  • Thrombocytopaenia
  • Leucocytopaenia
  • Bone marrow depletion
  • <4 weeks in age
62
Q

How can you treat bovine neonatal pancytopaenia?

A
  • Gentle handling to prevent further haemorrhage/ haematoma formations
  • Blood transfusion (whole blood) often only transient improvement of clinical signs
63
Q

How can you prevent bovine neonatal pancyotpaenia?

A
  • Avoid the use of pooled colostrum (especially pooled colostrum containing colostrum from any cow which has produced a BNP calf),
  • newborn calves, born to cows which have previously produced a BNP calf, should receive adequate colostrum from other cows which have not produced BNP calves,
  • no colostrum or blood from cows on farms with a BNP history should be used for commercial purposes, e.G. Production of commercial colostrum replacers, other feed additives, or pharmaceuticals.
64
Q

What is fell pony immunodeficiency?

What causes it?

What are the signs?

A
  • autosomal recessive,
  • Majorly impaired adaptive immune system, molecular basis unknown
  • Foals appear normal at birth but fail to thrive, fatal disease (3 months)
  • profound anaemia, B-lymphopenia and failure to produce immunoglobulins.
  • Common in UK, DNA test being developed

Small Animal Final Year (317 decks)

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