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Immunology & hematology > Immune disorders + onco > Flashcards

Immune disorders + onco Flashcards

1
Q

What is the mechanism of a delayed hemolytic transfusion reaction

A

IgG adhere to RBC (opsonization) -> phagocytosis by macrophages of NK lymphocytes (mostly extravascular), formation of spherocytes -> anemia + hyperbilirubinemia

Anamnestic reaction (re-activated antibody production) or primary alloimmunization to antigen (new antibody production)

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2
Q

What is the mechanism of an acute hemolytic transfusion reaction

A

Type 2 hypersensitivity: pre-formed circulating
IgM react with RBC antigens ->activation of complement (C3a, C5a) -> formation of membrane attack complex -> intravascular hemolysis ->anemia + free hemoglobin (-> AKI)

Complement activation also leads to release of anaphylatoxins, activation of mast cells (-> histamine), monocytes, leukocytes -> release of cytokines (IL-1, IL-6, TNF-alpha, IL-8) -> SIRS

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3
Q

What are the 4 types of hypersensitivity (with clinical examples)

A
  • Type I = immediate hypersensitivity (or IgE-mediated)
    -> anaphylaxis
  • Type II = antibody-mediated cytotoxic hypersensitivity (IgG)
    -> transfusion reactions, neonatal isoerythrolysis
  • Type III = immune complex hypersensitivity (IgG)
    -> immune mediated glomerulonephritis, Leishmaniasis
  • Type IV = delayed-type hypersensitivity (Th1 and Th2 cells)
    -> Mycobacterium (granulomas)
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4
Q

What are the 2 phases of a type I hypersensitivity

A
  1. Sensitization:
    - Encounter of the antigen by an antigen-presenting cell
    - Presentation of the antigen to a naive CD4+ T lymphocyte
    - Differentiation of the lymphocyte into a Th2 cell
    - Stimulation of an antigen-specific B cell b the Th2 cell
    - Production of IgE by the B cell
    - Binding of the IgE to circulating monocytes and tissue mast cells
  2. Re-encounter of antigen
    - Recognition of antigen by IgE-coated mast cells -> cross links 2 IgE on the mast cell surface
    - Mast cell degranulation -> histamine, heparin, serotonin, etc.
    - Synthesis of thromboxane, prostaglandins, and leukotrienes from arachidonic acid
    - Secretion of cytokines (IL-4, TNF-alpha, IL-5)

-> vasodilation, edema, bronchoconstriction, pruritus

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5
Q

What are the shock organs of anaphylaxis in dogs and cats

A

Dogs = liver (portal circulation) + GI
Cats = lungs + GI

(organs where they have the most mast cells)

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6
Q

What type of immunoglobulins are involved in type III hypersensitivity

A

IgG

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7
Q

What is the mechanism of hemolysis in IMHA

A

Type II hypersensitivity: recognition of a RBC antigen by immunoglobulins (IgG or IgM) leading to intravascular hemolysis by complement (membrane attack complex) or extravascular hemolysis by phagocytes

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8
Q

What is the expected delay of response to glucocorticoids in IMHA

A

3-5 days

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9
Q

Give a tapering plan for glucocorticoids following control of IMHA

A

Decrease dose by 20-25% every 3 weeks while monitoring PCV (Hct should stay > 30%) until reaching 0.5 mg/kg q24, then decrease frequency

If there is a relapse during tapering process, dose should be increased back to previous dose if mild relapse or back to original dose if severe relapse

Expected duration of treatment of 3-6 months

If 2nd drug on board, do not change dose while tapering pred (But red tapering can be more rapid ie q2 weeks). Once bred discontinued, continue other drug for 4-8 weeks, the d/c with or without tapering

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10
Q

What is the prognosis for IMHA

A

1-year survival is 65-75% (most deaths within 2 weeks of diagnosis)

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11
Q

What is the reagent used in the Direct agglutination test (= Coomb’s test)

A

Serum anti-IgG, IgM, and complement

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12
Q

What are signs of hemolysis accepted as diagnostic criteria for IMHA

A
  • Spherocytosis in dogs
  • Hyperbilirubinemia without liver dysfunction / cholestasis = icterus / increased bilirubin concentration / bilirubinuria in cats or at least 2+ bilirubin in dogs
  • Hemoglobinemia / hemoglobinuria without artifactual sample hemolysis
  • Erythrocyte ghosts
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13
Q

What are signs that RBC destruction is immune-mediated accepted as diagnostic criteria for IMHA

A

On pre-transfusion samples ideally:

  • Spherocytosis at least 1+ in dogs
  • Saline agglutination test
  • Direct antiglobulin test = Direct agglutination test = Coomb’s test
  • Flow cytometry
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14
Q

Describe how to do a saline agglutination test

A

Mix 1 drop of blood with 4 drops of saline at room temperature or 37°C and observe for agglutination microscopically and macroscopically
–> specificity of 100%

Washing the RBCs 3 times before can increase specificity

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15
Q

List trigger factors of IMHA

A
  1. Infection
    Dogs:
    - Babesia (mostly B gibsoni) (intermediate to high evidence)
    - Anaplasma phagocytophilum (low evidence)
    - Low evidence for Leishmania, Dirofilaria, Bartonella

Cats:
- Mycoplasma haemofelis (high evidence)
- Babesia felis
- FeLV (low evidence)
- Low evidence for FIP, FIV, Leishmania

  1. Neoplasia (lymphoma, sarcoma, carcinoma, multiple myeloma, etc.) - low evidence in dogs and cats
  2. Inflammatory disease (theoretically any, but low evidence)
    * IMHA associated inflammation can cause pancreatitis
  3. Drugs and toxins: antimicrobials, vaccines - overall lack of evidence
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16
Q

What are the criteria to diagnose IMHA

A

Confirmed = at least 2 signs of immune mediated destruction (spherocytosis in dogs, Coomb’s test, saline agglutination test, flow cytometry) OR positive saline agglutination test with washed RBCs + at least 1 sign of hemolysis (hyperbilirubinemia, hemoglobinemia / hemoglobinuria, erythrocyte ghosts)

Otherwise supportive of IMHA if at least 2 signs of immune-mediated destruction but no sign of hemolysis, OR only 1 sign of immune-mediated destruction and at least 1 sign of hemolysis. If no other cause of anemia identified.

Suspicious for IMHA if only 1 sign of immune-mediated destruction but no sign of hemolysis if no other cause of anemia identified.

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17
Q

What is the recommended age of pRBC units to be used in IMHA patients

A

7-10 days

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18
Q

What are indications for TPE in IMHA

A
  • Requirement of 3 or more transfusions
  • Severe hyperbilirubinemia with risk of bilirubin encephalopathy
  • Before adding a 3rd immunosuppressant or human IV immunoglobulins
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19
Q

What are the chances of remission in patients undergoing TPE for IMHA? How many TPE sessions does it typically require

A

~70%

About 3-5 sessions needed

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20
Q

What are the different mechanisms of anaphylaxis

A
  1. IgE-mediated: type I hypersensitivity
  2. Non-IgE immune mediated: mast cell activation by other immune mechanisms (complement anaphylatoxin, T-cell activation, neutrophil activation, IgG, etc.)
  3. Non-immune mediated: activation of mast cells by heat / cold / drugs
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21
Q

What are the major mediators of anaphylaxis and what phases do they participate in

A
  1. Early phase
    - Histamine
    - Tryptase
    - Chymase
    - Heparin
  2. Mid-phase
    - Prostaglandins - mostly PGD2 (arachidonic acid cascade)
    - Leukotriene (arachidonic acid cascade)
    - Platelet activating factor (major contributor!)
  3. Late phase
    - Cytokines
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22
Q

What is the pathophysiology of shock in anaphylaxis in dogs

A

Histamine release (+ other mediators)
-> arterial vasodilation -> distributive shock

-> simultaneous liver venous congestion -> portal hypertension, pooling of blood in liver +/- abdominal effusion -> hypovolemic shock

-> increased vascular permeability (worsened by prostaglandins and PAF) -> hypovolemic shock

-> action of histamine on cardiomyocytes -> possible cardiogenic shock

Release of PAF (platelet activating factor) by mast cells also found to be very important, causes severe vasodilation via NO pathway

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23
Q

What are diagnostic criteria of anaphylaxis

A
  • Acute onset of cutaneous signs AND respiratory compromise / hypotension
  • OR Exposure to likely allergen and at least 2 of the following: cutaneous signs / respiratory compromise / hypotension / GI signs
  • OR hypotension after exposure to known allergen
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24
Q

What are the actions of epinephrine when used as a treatment for anaphylaxis

A
  • Alpha1-adrenergic -> vasoconstriction -> improves distributive shock, improves BP and coronary flow
  • Beta1-adrenergic -> improves inotropy and cardiac output
  • Beta2-adrenergic -> bronchodilation + stabilization of mast cells (prevents further degranulation)
  • Inhibits PAF receptor
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25
Q

What is the recommended dose of epinephrine for anaphylaxis

A
  • 0.01 mg/kg IM (preferably) or IV
  • then CRI ~0.05 mcg/kg/min weaned over 6-12h
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26
Q

What are indications to start a second immunosuppressant in IMHA

A
  • Life threatening disease on presentation
  • OR need to decrease steroid dose due to severe adverse effects
  • OR no response to steroids in 7 days (PCV decreases by >5% in 24h or dog is still transfusion dependent)
27
Q

Name 2 intracellular pathways activated in mast cells during anaphylaxis

A
  • Phospholipase C -> IP3 -> Ca2+ release in cytoplasm -> degranulation
  • Phospholipase A2 -> arachidonic acid cascade + Platelet activating factor (PAF) secretion
28
Q

Are steroids indicated in anaphylaxis? If administered, what do they target?

A

Not routinely indicated as no proven benefit.

Could try to avoid delayed phase reaction (but still no proven benefit), does nothing for acute phase

29
Q

What are signs of anaphylaxis in cats

A
  • Respiratory distress
  • Hypersalivation
  • GI signs
  • Possible cardiovascular collapse
  • Increased Hct
30
Q

What is the mortality for severe anaphylaxis in dogs

A

15%

31
Q

What parameters are associated with mortality in dogs with severe anaphylaxis

A
  • Lower temperature
  • Increased PT (more prognostic than PTT)
  • Hypoglycemia
  • Hyperphosphatemia
32
Q

What is the prevalence of abdominal effusion in severe anaphylaxis? What are the mechanisms behind it?

A

65%

Combination of increased permeability (histamine, cytokines, PAF), portal hypertension / hepatic congestion, and possible hemorrhage due to coagulopathy

33
Q

What type of hypersensitivity is associated with IMHA / allergic contact dermatitis / myasthenia gravis / anaphylaxis / tuberculosis / leishmaniasis / immune-mediated glomerulonephritis

A
  • IMHA: type II
  • Allergic contact dermatitis: type IV
  • Myasthenia gravis: type II
  • Anaphylaxis: type I
  • Tuberculosis: type IV
  • Leishmaniasis: type III
  • Immune-mediated glomerulonephritis: type III
34
Q

What is detected by a direct Coombs test?

A

Determine if a patient’s RBCs have been coated in vivo with immunoglobulin, complement

35
Q

In anaphylaxis, the IgE antibodies bind to which receptor on the mast cell?

A

Fc-ε-R1

36
Q

The biological effects of histamine and mediated by G-protein coupled receptors H1-H4. What are the functions of H1 and H2?

A

H1 activates smooth muscle contraction and endothelial changes resulting in vasodilation and increased vascular permeability

H2 modulates gastric acid secretion and regulation of cardiac myocytes

37
Q

What is the sensitivity and specificity for increased ALT and gallbladder wall edema in anaphylaxis?

A

Increased ALT:
- Sens: 85%
- Spec: 98%

Gallbaldder wall edema:
- Sens: 93%
- Spec: 98%

38
Q

What chemotherapeutic agents are considered less, moderately and highly immunosuppressive?

A

Low:
- Corticosteroids
- L-asparaginase
- Chlorambucil
- Blemycin

Moderate:
- Vincristine
- Vinblastine
- Cyclophsophamide
- Mephalan

Highly:
- Lomustine
- Carboplatin
- Doxorubicin
- Mitoxantrone

39
Q

When does neutropenia generally occur with common chemotherapeutic drugs?

A

Vinc, vinblastine, doxo, cyclo, lomustine: 6-8 days

Carboplatin: 14 days in dogs & 14 - >25 days in cats

40
Q

3 risk factors of developing sepsis in dogs following chemotherapy

A
  • Lower body weight
  • Dx of lymphoma
  • Administration of doxo or vinc
41
Q

Ddx for hypercalcemia of malignancy

A
  • Lymphoma (most common cause in dogs)
  • Anal sac apocrine gland adenocarcinoma
  • Multiple myeloma
  • Thymoma
  • Thyroid carcinoma
  • Squamous
  • Mammary carcinoma
  • Melanoma
    …
42
Q

Which cancer is almost always associated with acute tumor lysis syndrome?

A

High stage lymphoma

43
Q

Consequences to tumor lysis syndrome

A
  • Hyperkalemia
  • Hyperphosphatemia
  • Hypocalcemia
  • Hyperuricemia
44
Q

Fluid of choice for management of tumor lysis syndrome

A

NaCl 0.9%

45
Q

Name 8 paraneoplastic syndromes

A
  • Hypercalcemia
  • Hypoglycemia
  • Polycythemia
  • Anemia
  • Thrombocytopenia
  • Coagulopathies/DIC
  • Hypertrophic osteodystrophy
  • Fever
46
Q

True or false: hematocrit is more reliable than PCV for diagnosis of IMHA

A

False - HCT may be unreliable when agglutination is present

47
Q

Percentage of dogs with IMHA that have non regenerative anemia at presentation

A

30%

48
Q

What quantity of spherocytes is supportive of IMHA?

A

> 5 spherocytes/x100 oil immersion field

49
Q

Other than IMHA, give 5 Ddx for spherocytosis

A
  • Oxidative damage (zinc, acetaminophen)
  • Envenomation
  • Hypersplenism
  • Pyruvate kinase deficiency
  • Endocarditis, hemangiosarcoma –> erythrocyte fragmentation
50
Q

What is the new nomenclature for categorization of IMHA?

A

Associative (a comorbidity is identified) vs non-associative (comorbidity not identified in the diagnostic evaluation)

51
Q

The recommendation for pRBC transfusion in dogs with IMHA is to administer a unit of what age?

A

7-10 days old

52
Q

Dose recommendation for immunosuppressive drugs in IMHA

A
  • Prednisone: 2-3 mg/kg/day or 50-60 mg/m2/day for dogs > 25kg
    *If starting with dose > 2 mg/kg/day recommend decreasing < or equal to 2 mg/kg/day within the first 1-2 weeks

Second immunosuppressive:
- Azathioprine 2 mg/kg PO q24h, after 2-3 weeks can decrease to EOD
- Cyclosporine 5mg/kg PO q12h
- Mycophenolate mofetil 8-12 mg/kg PO q12

53
Q

What are side effects of azathioprine?

A

GI, hepatotoxicity, myelosuppression

CBCs and biochem (especially ALT) monitoring q2 weeks during first 2 months of treatment and then q1-2 months until discontinuation of treatment

54
Q

What are side effects of cyclosporine?

A

GI effects and gingival overgrowth + biochem q2-3 months due to risk of hepatotoxicity (idiosyncratic and uncommon)

NOT myelosuppressive

55
Q

What are side effects of mycophenolate?

A

GI + myelosuppression

CBC every 2-3 weeks for first month of Tx, then every 2-3 months

56
Q

Therapeutic algorithm for IMHA management

A

See picture

57
Q

Relapse algorithm

A

See picture

58
Q

How should an immunosuppressive drug associated myelosuppression be managed?

A
  1. Recommend discontinuing causative agent as soon as myelosuppression documented
  2. Asymptomatic neutropenic patients
    a. If neut between 1000-3000 cells/uL –> no ATB unless other risk factor for infection
    b. If neut < 1000 (some references suggest 750) –> prophylactic ATB
  3. Symptomatic neutropenic patients (fever)
    a. Identify source of infx
    b. Start parenteral broad spectrum ATB
    c. IV fluids and hemodynamic monitoring
    d. Recombinant granulocyte colony stimulating factor to be considered
  4. Suggest a different drug once patient has recovered and if further immunosuppressive needed
59
Q

How is neutropenia defined in dogs vs cats

A

Dogs: neutrophils < 2.9x10^9/L
Cats: neutrophils < 2.0x10^9/L (because have more marginated neutrophils)

60
Q

When should thromboprophylaxis be initiated with IMHA and what protocol should be used?

A

Initiation at time of diagnosis

61
Q

What are some hypotheses for the development of hemoperitoneum in anaphylaxis?

A
  • Coagulopathy and DIC
  • Rapid splenic or liver engorgement and subsequent vascular rupture
  • Widespread mast cell degranulation with release of heparin and tryptase, along with significant hepatic venous congestion, could contribute to hemoperi- toneum due to diapedesis of blood and plasma
62
Q

What are the different mechanisms possibly leading to neutropenia

A
  1. Increased utilization: recruitment of circulating neutrophils to the tissues, increased release of neutrophils from bone marrow but can become exhausted
  2. Depletion of granulocyte progenitor cells in the bone marrow (bone marrow hypoplasia)
    - Infectious diseases: Parvo, FIV, Ehrlichia canis)
    - Drug-induced: chemotherapy, radiation, anti-epileptics (pheno), antimicrobials (chloramphenicol, fenbendazole, TMS), methimazole, estrogens
    - Myelophthisis: neoplasia (leukemia, lymphoma, multiple myeloma), myelofibrosis, osteosclerosis, osteomyelitis
    - Cyclic hematopoiesis (gray Collie syndrome)
  3. Ineffective granulopoieisis in the bone marrow (dysgranulopoiesis)
    - Myelodysplastic syndrome (eg. FeLV)
    - Secondary dysgranulopoiesis: secondary to IMHA, ITP, lymphoma, drugs (same as the ones leading to bone marrow hypoplasia)
    - Trapped neutrophil syndrome in Border Collies
  4. Immune-mediated destruction (primary or secondary - similar to IMHA)
63
Q

Why is it challenging to find the source of an infection secondary to neutropenia

A

Most visible signs of infection (on physical exam, imaging, cytology) are caused by the inflammatory response, which is suppressed in cases of neutropenia with secondary infection

64
Q

What drug can be considered for treatment of febrile neutropenia (other than antimicrobials)

A

Recombinant G-CSF -> increases differentiation of progenitor cells into neutrophils, increases release of neutrophils in circulation, increases chemotaxis of mature neutrophils, increases respiratory burst and improves IgA-mediated phagocytosis

Available as human or canine recombinant

*Not recommended in parvo as it could actually increase mortality

Immunology & hematology (3 decks)

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