Precursor Immune Mediated Haemalytic Anaemia and IMHA

[trudiej]

Hi there

I have an 8.5 year old male bearded collie who, just over a week ago became listless and lethargic. Prior to this, he had been having regular anal gland checks following recurring infections which took several courses of antibiotics to shake off (the checks had all been fine). He had also had what we thought was an allergy, with some sneezing and a runny nose, for which we were giving him Piriton - this hadn't totally cleared up, but had seemed to improve.

Following a check at our local vets his bloods showed he was very anaemic and an ultrasound showed a mass on his spleen, so we were referred to a specialist vet, who following a series of tests, have given the diagnosis and treatment plan below:

TESTS PERFORMED:

External blood smear examination: this showed evidence of very mild regeneration, but this was inadequate for the degree of anaemia. A type of red blood cell called spherocytes were observed, which are most commonly seen with IMHA.

Urinalysis: the urine was concentrated and did not contain excessive protein. Some crystals were observed, which occur with storage of urine. Bilirubin with bilirubin crystals were also present (likely secondary to IMHA).

Splenic nodule cytology: evidence of new red blood cell production, with some inflammation (common in conditions which cause systemic inflammation such as IMHA).

Splenic parenchyma cytology: evidence of new red blood cell production, with some inflammation (common in conditions which cause systemic inflammation such as IMHA).

Bone marrow cytology: there was evidence of an increase in the number of red blood cells within the bone marrow, which were then being consumed by white blood cells. This is consistent with precursor immune mediated anaemia.

Bone marrow histopathology: pending.


DIAGNOSIS

Precursor immune mediated haemolytic anaemia (PIMA) and immune mediated haemolytic anaemia (IMHA): these are conditions in which the body attacks its own red blood cells. In the precursor form, this occurs within the bone marrow. With IMHA, this occurs within the circulation.


TREATMENT

Prednisolone 20 mg twice daily

Ciclosporin 100 mg: give one capsule twice daily with a 50 mg capsule. This is an immunosuppressant. Side effects can include a reduction in appetite, vomiting and diarrhoea. We recommend freezing these tablets to reduce these side effects.

Unlicensed medication:
Clopidogrel 18.75 mg: give 2 tablets once daily. This helps prevent the risk of blood clots, which can be seen with Fergus' condition.


FOLLOW-UP

If Fergus remains clinically stable, repeat PCV is advised approximately every 2 weeks to assess for a regenerative response. Once PCV is within the normal range, we would advise sending a blood smear externally to assess for ongoing spherocytosis If resolved, then dose reductions of prednisolone can be commenced. Prednisolone should be reduced by 20-25% every 3-4 weeks, with repeat PCV performed prior to every dose reduction to ensure there is no relapse in anaemia.


QUESTIONS

This was a bit of a shock....., is there anything I should be doing to help Fergus?
Any questions I should be asking of the vet/specialist?
I notice on some posts, a tummy protectant is advised, I asked the specialist vet about this, and she didn't consider it was necessary?

Anything else you think I should be aware of?

Any/all help most gratefully received.

With thanks; Fergus' worried parents

[Catherine]

What was Fergus's PCV amount? If it is quite low I would want to have his PCV tested every few days, certainly more often then every two weeks at first. Also I would definitely want him having something to protect his tummy otherwise he could get more problems.

Here is a good reduction protocol for when his PCV starts to rise:

Immunosuppressive Protocols for Oral Prednisolone in the Dog.
Ref: Clinical Immunology of the Dog & Cat by Michael J Day  – Professor of Veterinary Pathology, University of Bristol, UK and WSAVA - Chairman of Scientific Advisory Committee.

This example is based on a dog receiving an induction dose of 1.0mg/kg/q12hrs (every 12 hours)

Dose                Duration (based on clinical effect)

1.0mg/kg/q12h             10-28 days
0.75mg/kg/q12h            10-28 days
0.5mg/kg/q12h             10-28 days
0.25mg/kg/q12h                         10-28 days
0.25mg/kg/q24h                         10-28 days
0.25-0.5mg/kg/ Every other day      at least 21 days
0.25-0.5 mg/kg/ Every third day       at least 21 days

Azathioprine (a cytotoxic drug) can be used in combination with prednisolone at 2mg/kg/24 or 48 hrs and dose gradually reduced, when remission is achieved, over a period of months.
Clinical response to Azathioprine may take up to 6 weeks. (Plumb's Veterinary Drug Handbook)

Don't forget the gastroprotectant!


Have you checked out the information here?: http://cimda.co.uk/smf/index.php?topic=11.0 and here: http://cimda.co.uk/smf/index.php?topic=16.0

[trudiej]

Hi Catherine

Thanks for the reply; Fergus's PCV was 21, 19 and 22 - the 22 being the result of a test done on Wednesday 2 June.

Would you consider this low enough to warrant another blood test during this coming week (he's booked in at vets for next blood test on 15 June), and should we consider a biochemical test, as well as the PCV test, to check liver and kidney function?

I will speak to the vet regarding a tummy protectant - is there one you'd particulary recommend for Fergus's condition?

On reading the articles you linked to; should Fergus be on a broad spectrum anti-biotic? And should we consider a low fat food; he is currently on a grain free salmon, trout, asparagus and sweet potato kibble (it says the crude fat content is 11%).

Many thanks.

Trudie

[Catherine]

The normal range approximately in the UK for PCV (HCT) is 37 -55 so even allowing for variations 22 is quite low. So yes I personally would want to test Fergus as soon as possible. Hopefully the PCV will have started to increase again but I would still test more regularly. It would not hurt to keep an eye on his kidneys and liver but the liver enzymes will rise anyway with the steroids so do not be too shocked.

Omeprazole is one gastroprotectant but it did not agree with my dog but I found Zitac (Cimetidine) was good. Some you have to give apart from other medication.

I can not see any reason for an antibiotic unless Fergus has other issues. Also if he has been fine on his normal food I would stay with it - you do not want to change too much at once.

[Jo CIMDA]

Hi and welcome

I am sorry that Fergus has non-regenerative anaemia.  Unfortunately this is a known inherited condition that can be seen in beardies. 

Catherine has given you the information that you need, so there is not a lot more than I can add,  just to reiterate that Fergus should be on 1mg/kg/12hours prednisolone and it is best to give a low fat diet and give perhaps four smaller meals than one or two larger ones.  This makes it easier for this pancreas to deal with and may prevent pancreatitis.  Also, as far as I am concerned, there is no good reason not to give a gastroprotectant because if it isn't given there is a risk of the stomach becoming ulcerated and  if an ulcer develops then it may bleed which will cause regenerative anaemia.    As Fergus' immune system is significantly suppressed you should be careful about taking him to a popular dog walking area where he may pick up infections.  Often a course of antibiotics is given at the start of treatment as a precaution. 

I do hope Fergus  is starting to feel better. 

Jo

[trudiej]

Hi there

As of a blood test last week Fergus PCV was 42 so vets were very pleased. We have another blood test tomorrow and if results have remained stable then a blood smear will be done, and pending those results we may be able to reduce steroids.

I have spoken to specialist twice about the tummy protectant, she was of the view that there was no medical evidence to support giving this to Fergus, and as Fergus has a sensitive tummy and has been prone to bouts of colitis she was loathe to prescribe one. Should I raise this again?

Am noticing loss of weight, possibly muscle tone and fur, drinking is increased (though we were told increased thirst/hunger is a side effect of the steroids), is there anything else we can do to help support our boy?

[Jo CIMDA]

Hi

A PCV of 42 is good news and I hope the vet will start to reduce the preds very soon.

Dog that have not been on a gastroprotectant and have been on high doses of steroids for a while can develop gastric ulcers. 

Jo


Here is some information about what to expect when your dog is on immunosuppressive therapy with prednsiolone.

WHAT TO EXPECT ONCE IMMUNOSUPPRESSIVE TREATMENT HAS STARTED
If a dog has a serious autoimmune disease, then the sooner treatment commences the better chance the dog has of survival.  The main delay to starting treatment is obtaining a diagnosis or at least your vet being sure that he hasn't missed anything that could be made worse by giving high doses of steroids.  Achieving a diagnosis can be a fight against time. 
If your vet has decided that in all probabilities your dog has an autoimmune disease, then to a certain extent, which autoimmune disease your dog has, as far as treatment is concerned, is irrelevant because with the exception of a few diseases, they are all treated the same, that is, with immunosuppressive drugs.  The main objective is to 'knock out' the immune system and virtually stop it from working (or near enough) so the destruction will cease and give the body a chance to recover.  As previously stated, this treatment regime works in most cases, that is, if it has been given early enough and the dosage is correct.  All dogs are different and some can tolerate the drugs better than others. In proportion to their size, small dogs seem more able to tolerate higher doses of steroids than large ones. Some diseases are more serious than others and carry a poorer prognosis. So the initial crisis is a crucial time, however anecdotal evidence shows that many more dogs survive than die if correct treatment is administered in good time.
It is hoped that a positive response can be seen within 4-6 hours of starting treatment (depending on the disease), but in a serious, life threatening situation, the first 2-7-14 days can be a very worrying time.  Assuming the dog has stabilised he will quickly feel much better, and if he is in hospital may be allowed home within a week.
When he comes home he will probably have a 'goody bag' full of drugs.  He will be on a high dose of steroid, usually prednisolone, and he may also be on another immunosuppressive drug, such as Azathioprine.  Your dog will be weaned off in a controlled manner according to his wellness and clinical observations. 
Note: High doses of steroids must not be stopped abruptly.  Your dog could go into an adrenal crisis if the medication is withdrawn too quickly. 
In addition to immunosuppressive drugs he should have something to protect his stomach from excess acid.  The last thing your dog needs when he is feeling poorly is a bleeding stomach ulcer caused by the drugs.  Sometimes, Antepsin is given to coat and protect the stomach (but this must not be given within two hours of other medication otherwise it will stop the drugs from being absorbed. Another gastroprotectant used is Omeprazole. To minimise irritation to the stomach it is usual for the daily dose of steroid to be split into two doses and given with food, one dose in the morning with breakfast and the other dose with his evening meal. I have known several dogs, who did not receive a gastroprotectant as a part of their treatment regime, and went on to develop anaemia. This is not autoimmune haemolytic anaemia but iron deficiency anaemia caused by bleeding stomach ulcers. Using a gastroprotectant is a good preventative measure. When the steroids have been significantly reduced to a low dose, a gastroprotectant may not be necessary.
Excess acid, produced because of the drugs, may make a dog prone to developing pancreatitis. A dog with pancreatitis will appear in pain and his back may be arched as if he can't straighten up.  He may be lethargic, seem bloated and have a tender abdomen. Dogs usually go off food and water, may vomit and look depressed.  If you suspect that your dog has pancreatitis, don't try to feed him because it will make the condition worse. Take him to the vet as soon as possible as he may require treatment or need to go on an intravenous drip to stop him dehydrating.  Again, the risk of pancreatitis should be minimal once the dog is on a lower dose of steroids.   A low fat diet is best when your dog is on high dose steroids or prone to pancreatitis. 
As your dog's immune system is being significantly suppressed, he will be more likely to pick up infections, and will not have the ability to fight against them.  As a precaution a broad spectrum antibiotic is often prescribed. Also it is sensible not to exercise him in areas where he is more likely to encounter infections, for example, a park or a popular dog walking area. 
Whilst your dog is on high dose steroids he will want to eat and drink excessively. However, this also means that he will want to urinate more and this can sometimes cause temporary incontinence.  You may have to get up to let him out during the night and if you leave the garden door open during the day, it may save some mopping up!  He cannot help it and won't like it either, so don't be too hard on him, it's only temporary. You will notice as he is weaned off the drugs the unwanted side effects will subside and he should return to normal habits and behaviour.  Urinary tract infections and/or bacterial skin pustules are not uncommon when a dog's immune system is suppressed, and this is often the reason for a dog to be off colour during this time.  Note: Always consider a urine infection if your dog seems under par.  A course of antibiotics will usually sort this out quickly.
Depending on what autoimmune disease your dog has, he will probably need to have regular blood tests.  Biochemical blood tests will also keep an eye on other body functions, such as those of the liver and kidneys, which is important at this stage.
Assuming good progress is being made, the clinical signs of his illness are diminishing and positive signs of improvement are apparent, your vet will want to start weaning him down from the high doses of steroid.  This process can take 3-6 months or more, and usually begins any time after 10 - 28 days from the start of treatment, depending on the results of his blood tests and his clinical signs.
Relapses are not uncommon, especially in diseases that are difficult to control, for example SLE.  A relapse may mean that initially, your dog needed to be on a higher dose of immunosuppressive drugs for a longer period of time, or your dog may have been weaned off a little too quickly and then the dose withdrawn too soon.
If a relapse occurs he will probably show similar clinical signs to his initial crisis.  He will have to go back on an immunosuppressive dose of prednisolone, but it may not have to be quite as high as before. A combination drug may need to be added at this stage. The weaning process will then have to start all over again. Returning to an immunosuppressive dose will mean that he has to go back on a gastroprotectant.
Side Effects of the Drugs – Iatrogenic Cushing's Syndrome
Iatrogenic Cushing's syndrome is a side effect of high dose steroids and is caused by too much corticosteroid in the body. To a lesser extent, the immediate side effects observed when the dog initially goes on steroids eg., drinking, eating and urinating excessively is a mild example of Cushing's syndrome.  Personally I like to see dogs responding to high doses of prednisolone in this way, as it means that they are responding to the drugs as they should.
Usually, Cushing's syndrome only becomes a real problem when exceptionally high doses, or prolonged high doses of steroids are administered, maybe due to a relapse, or in some cases where the vet is inexperienced in reducing steroid doses and keeps the dog on a high dose for longer than necessary; or when the dog is not responding to treatment and higher doses are necessary to control the disease.  This is where the cytotoxic drug Azathioprine, and other more recently used, immunosuppressive drugs are very useful. 
All drugs carry side effects and Azathioprine is no exception, but it does not carry the same side effects as prednisolone, therefore by using this drug in combination with prednisolone it reduces the risk of iatrogenic Cushing's syndrome.  As Azathioprine takes at least 10 days to take effect, starting the 'combination' therapy at the beginning of treatment may enable the prednisolone to be lowered within the 10-28 day band and still maintain a good level of immunosuppression. If your dog is not responding to treatment then your vet may consider changing his treatment to other immunosuppressive drugs.
How Can I Tell if My Dog Develops Iatrogenic Cushing's Syndrome?
Iatrogenic means 'drug induced'.  Clinical signs of Iatrogenic Cushing's syndrome are the same as primary Cushing's syndrome but can present with acute clinical signs. It reflects the level of corticosteroid in the body.
The most notable side effects are, heavy panting, some hair loss, and an increase in drinking and urinating, excessive pigmentation.  This is something everyone seems to be aware of and accepts as normal when a dog is on high dose steroids. Very often the dog will be weaned down to a low dose before any major problems arise. 
Acute Cushing's syndrome due to overdosing of corticoid steroids can be very serious.  Blood results will reflect this, especially the liver enzymes which may be extremely high. Red blood cells and blood platelets may also be high and blood clotting may be a risk.
So when should you alert your vet to suspected, unacceptable level of corticosteroid?  The owner should take note when other clinical signs occur, such as: Depression, anorexia, muscle wasting and extreme weakness, continuous panting, lethargy - unwillingness to exercise, skin lesions and thinning of the skin, excessive hair loss, pot-bellied appearance and sagging back, behavioural changes (aggression).
If your dog is showing these signs it will probably mean that the dose of steroids needs to be lowered. It is important that it is not confused with a relapse of the dog's condition or an infection. The dilemma is that steroids must not be withdrawn too quickly otherwise the dog may go into an adrenal insufficiency crisis.  If the clinical signs of iatrogenic Cushing's syndrome is intolerable, it is hoped that the high dose of steroids that he has been on will have already done their job and that his autoimmune disease will be stable. As long as the steroids are lowered in a controlled manner and in time, all the symptoms of Cushing's will subside and your dog will return to normal, but extreme signs must not be ignored.

Reducing the Tablets
When significant improvement in the dog's condition is seen, usually between 10-28 days, the initial steroid dose is usually reduced by 25%. The dose is generally given for another 10 - 28 days and depending on the dog's progress and clinical signs the dose is significantly reduced once more for a further 10-28 days; and again in another 10-28 days. Anecdotal evidence has shown that if at this stage the dose is lowered more slowly, or reduced to an every other day dose over a period of months rather than weeks, relapse are less likely to occur.  It is always tempting to get your dog off steroids as soon as possible, but when treating autoimmune disease, as long as the dog is on a low, every other day dose then taking the last stage slowly seems to work best, depending, of course, on the severity of the disease and allowing for the difference in individual response - no two dogs reactions are exactly the same.  With some autoimmune diseases such as SLE, the dog is likely to be on steroids for the rest of his life. Usually an every other day dose can be achieved, but you risk a relapse if you take the dose too low. Below is the best example of a reducing immunosuppressive protocol I have come across. It is an excellent guide and can be adjusted to the individual.