Immune mediated disease Pt. 1 Flashcards
what is a primary immune mediated disease?
Primary (non-associative):
* Defect in immune tolerance
* Antibodies against self
what is a secondary immune mediated disease?
Secondary (associative):
* Non-self antigens ➔ normal cell membrane
> Antibodies ➔ non-self antigens
* Abnormal immune stimulation
* Possible causes: drugs, inflammatory disorders, infection, neoplasia, etc
IMHA - what is it, generally? what types are there?
- Destruction of RBCs
- Primary or secondary IMHA
IMHA - what type of anemia do we see?
- Regenerative anemia (more common):
> RBCs in circulation lysed - Non-regenerative anemia:
> RBC precursors at bone marrow level destroyed
> “Precursor immune mediated anemia” or PIMA
Primary IMHA: Signalment
- Anyage,any breed
- Predisposed:
> American Cocker spaniels, Bichon, poodles, Old English sheepdogs, collies
> Most 2-7 years of age
> Females > males
> Spring & summer (?)
IMHA: Patient Presentation
Clinical signs related to severity of anemia:
* Lethargy, weakness, anorexia
* Collapse
* Tachypnea
* Vomiting, diarrhea
* “Dark” urine (bilirubin, hemoglobinuria)
IMHA: Physical Examination common findings
- Pallor (majority of cases)
- HighHR&RR
- Enlarged spleen, liver (25-50% of cases), abdominal discomfort
- Icterus
- Pigmenturia
- Hemic murmur
Common mechanisms causing anemia
- blood loss
- lack of production
- hemolysis
initial tests for dog presenting with anemia
- Complete blood count**
- Serum biochemical profile
- Urinalysis
why can we sometimes see Mildly elevated ALT in light of marked anemia
- Hypoxic injury to hepatocytes?
why can we sometimes see elevated bilirubinemia and bilirubinuria in light of marked anemia
- Hemolysis
- Hypoxic liver injury
IMHA: Diagnosis
Anemia
* Hct usually <0.25-0.30 L/L
* (Normal ~0.39-0.50)
Evidence of Ab’s against RBCs:
* + Autoagglutination
* + Coomb’s test
* Spherocytosis (80-90%)
Evidence of hemolysis
* Icterus
* Hemolytic serum/urine
Autoagglutination
what is RBC autoagglutination in IMHA? when can we observe it / with what tests?
- May be observed grossly
> In the tube - Slide agglutination test
> Saline to blood 1:49 ratio
> 1 drop EDTA blood
> Check for macro and microscopic agglutination - Slide agglutination test not well standardized
> Some argue it isn’t helpful in the overall case work-up and you’re better off examining the blood smear instead
what is the coomb’s test? what does it look for?
For IMHA
* Detects Ab or complement on RBC surface
* “Coomb’s reagent”
> Anti-canine IgG, IgM, complement
> Added to washed RBCs
> Detect specific RBC agglutination
Spherocytosis - how does it arise? what does it suggest?
- RBC has antibodies on surface
- Recognized by macrophages in spleen or liver
> Phagocytized
> Partial RBC membrane defect - Highly suggestive of IMHA
IMHA: Extravascular vs Intravascular Hemolysis
- what do we see? what is more common and severe?
Extravascular (more common, less severe):
* RBC’s degraded in splenic/hepatic macrophage > Spherocytes
* Hemoglobin released within macrophages
> Processed ➔ bilirubin ➔ icterus
Intravascular:
* RBC’s lysed in circulation
* Hemoglobin released ➔ hemolytic serum, urine
()()()
Both intra and extravascular hemolysis can occur in some IMHA patients
How many criteria needed for diagnosis of IMHA? what is ‘suspicious’?
“Diagnostic” for IMHA:
* Anemia,
* At least 2 signs of destruction (spherocytes, Coombs, SAT)
* And at least 1 sign of hemolysis (icterus, hemolytic serum, urine)
“Suspicious” for IMHA:
* Anemia
* 1 sign of destruction
* 1 sign hemolysis
* No other causes of anemia identified
How and when to rule out secondary IMHA?
Once supportive evidence of IMHA found, consider ruling out secondary causes:
* Client interview to review previous medical history
* Infectious agents – 4Dx snap test, serology depending on area
* Imaging for neoplasia, infections, inflammation
> Thoracic radiographs
> Abdominal ultrasound
infectious causes of secondary IMHA
Anaplasma
Babesia
Mycoplasma
Heartworm
drug causes of secondary IMHA
Sulfas
Beta lactams
Certain toxins
when can we see direct hemolytic anemia (not immune mediated)
- Zinc ingestion (some pennies, toys, diaper
cream, dog tags) - Hypophosphatemia
- Onion & garlic
- Acetaminophen
> check patient history to rule out
IMHA: Treatment goals
- Stabilize the patient
- Stop the immune-mediated destruction
- Prevent complications
> Thromboembolism
Initial Stabilization strategies for IMHA if we see Signs of dehydration, hemodynamic instability?
> IV catheter, start IV fluids
“Transfusion triggers” or signs of
insufficient oxygen delivery
> Tachycardia, tachypnea, increased work breathing
Dull mental attitude
Very marked anemia
Immunosuppressive Medications that can be used for IMHA
- Few studies with high quality evidence to inform clinicians
Corticosteroids:
* Used alone will result in successful outcome for many patients
* No good consensus if/when a second-line immunosuppressive should be added
IMHA: Combination Therapy benefits and risks?
Possible benefits:
* Improved survival (?)
* Better treatment for more severe cases(?)
* Ability to wean corticosteroid earlier
Risks:
* Side effects of medications
* Increased risk of secondary infections
* Overall lack of evidence
Mainstay of IMHA treatment? how fast does it work?
Corticosteroids
* Can see improvement within 7 days
* Single-agent treatment often sufficient
* Common options:
* Prednisone @ 2 mg/kg PO q24h
* Dexamethasone @ 0.25 mg/kg IV q24h
Corticosteroids pros and cons
PROS:
* Inexpensive, available
* Rapid onset of action
* Several mechanisms of impairing the immune system
CONS:
* PU/PD, polyphagia
* Panting
* Muscle wasting
* Gastric ulceration
* Immunosuppression
Azathioprine - what does it do?
- Antimetabolite
- Inhibits T cell proliferation
Azathioprine - potential side effects? when not to use? requires what?
- GI upset
- Pancreatitis
- Liver toxicity
- Bone marrow suppression
> Especially cats – do not use - Requires regular monitoring of bloodwork
Cyclosporine - what does it do? does it work for IMHA?
- Inhibits T-cell function
- Anecdotal efficacy, expensive
- Ideal to monitor [drug] levels
- Note: different dose / frequency than for skin disease
Cyclosporine side effects
- GI upset
- Alopecia
- Gingival hyperplasia
- Opportunistic infections
- Neoplasia (?)
Mycophenolate - what does it do, what patients is it used in?
- Inhibits T- and B-lymphocyte production
- Used in dogs or cats
Mycophenolate adverse effects?
- Diarrhea most common
Mycophenolate advantages over azathioprine:
- Lack of myelosuppression or hepatotoxicity
what % of canine IMHA patients develop thromboembolic complications? pathogenesis?
Up to 80% canine IMHA patients develop thromboembolic complications
* Pathogenesis unknown
> Activated platelets
> Disseminated intravascular coagulation
Thromboprophylaxis Options
Platelet inhibition
* Clopidogrel
* Low dose aspirin (less effective than clopidogrel, typically no longer used alone)
Anticoagulants
* Heparin
* Rivaroxaban
Usually just use one of the above options
overall example treatment plan for IMHA
- Stabilize the patient
> IV Fluid therapy (dehydration / not eating), monitor for transfusion triggers - Immunosuppression
> Dexamethasone IV or prednisone PO if
taking oral meds - Prevent TE complications
> Clopidogrel PO
IMHA chronic treatment - how to manage
- Decrease 1 immunosuppressive at a time
> Often prednisone first (due to PU/PD, etc) if there are >1 immunosuppressives - Recommend decreasing 1 med by ~25-50%, every 2-4 weeks
IMHA: Relapses rate?
- Relapse rate ~15-30%
when treating IMHA for the long term, what do we do if Hct has declined compared to last recheck:
- Back to previous doses when Hct was normal
- Check Hct frequently (1x/week depending on patient’s condition)
- May need to increase back to full immunosuppressive doses
- Can try tapering more slowly once normal Hct again
- Some need chronic medication for life
> Usually low-dose
Canine IMHA:
Prognosis
- Overall, guarded to poor prognosis for long-term survival
- 50% or more mortality rate in some studies
> Referral bias? - Majority of deaths/euthanasia within first 2 months
> Ongoing disease
> Complications
Canine IMHA: treatment Summary
- Supportive care (e.g., transfusion, ICU if
needed) - Immunosuppression (steroid +/- other agent)
- Anti-thrombotics
