Diesel - We need help

[KaajalTiwary]

Hello there:

I posted about Diesel a few weeks ago. They couldn't determine if it was cancer or autoimmune. He developed an abcess that was surgically removed. So they also reduced his Prednisolone and decided to go back to the drawing board.

He is currently on 2.5 mg Prednisolone, Clavomox, Omniprezole and vit B 12 supplement. They are looking at another bone marrow biopsy and aspirate soon. Is it possible for anyone on this forum to tell me what we might be dealing with? Any insight you can offer will save my life.

Yesterday his CBC count read:
RBC 5.52 (5.65 - 8.87)
HCT 38.1% ( 37.3 - 61.7)
WBC 3.51 (5.05 - 16.76)
Neutrophil 0.85 (2.95 - 11.64)
Platelets 196 (148 - 484)

I am very worried about Diesel and no proper diagnosis for over 8 weeks since he fell really sick is devastating. We are working with the doctors at UC Davis since he got sick.

Please let me know if you have any additional questions for me. I'm desperate for help.

[Jo CIMDA]

Hello

He is now on a very low dose of prednisolone and his HCT is just within normal limits so why are they considering a bone marrow biopsy at this stage?

How is he in himself? Is he much better than he was?  Is he showing signs of acute or chronic disease?   

Jo

[KaajalTiwary]

Jo:

Thank YOU for your help and your amazingly prompt response.

Considering how his CBC count has been trending, they are still thinking it's either auto immune or some form of cancer. At this point they think a Bone Marrow Biopsy & Aspirate and Flow Cytometry will help them know if it's cancer and what form?

He is definitely is looking much better than he was, when he got really sick on the 17th of June but certainly not his old normal self. His appetite is good, no fever, peeing and pooping fine. He's more lethargic than normal.

UC Davis is concerned that he has a chronic disease just by looking at his CBC panel. His WBC and Neutrophils as of yesterday are extremely low and that is indicative of some chronic disease, is what they said.

From your experience, would you be able to tell me - what do you think Diesel is indicating (by his numbers). My research is making me reach a dead end. I am in a state of panic.

[BrookeR]

Hello,
I'm sorry to hear about diesel. Unfortunately I don't have any ideas of what may be going on.  I'm in a similar situation with my girl Pepper at the moment. My vet is concerned it may be cancer or some other chronic disease. But we can't pinpont what. She has been slightly anemic for a sometime now but has now lost a lot of weight.  She is a staffy and has lost her muscles and now is very drawn. She had a bout of pancreatitis and everything has been downhill from there. I stopped feeding her all treats after the bout of pancreatitis and she was eating a LOT of treats (sheeps ears & carob drops). I have now increased her normal food intake by 40%. But she hasn't gained any weight. Albeit her normal food is kangaroo mince and veggies, so it's not high in fat.

She has had a bad breath & we found ulcers in her mouth and then she had to have three rotten teeth removed. Her breath has improved from what it was but it still is a bit odourous. She still has ulcers in her mouth which we can not clear up. Since then she had an occasion where she got the vomits and became dehydrated and had to have an overnight hospital stay on a drip. We reintroduced salmon oil back into her diet (as we had dropped all supplements when she had the pancreatitis episode) and then after being back on it for maybe a month she got frequent diarrhoea with lots of mucous. We stopped the salmon oil again & the diarrhoea & mucous cleared. Her alt & alp levels are the lowest they have been in a long time. We dropped her back to 2.5mg pred once a day when she had the pancreatitis episode. She now weighs only 14kg & used to be between 16-18. This is the lowest pred dose that we have ever been able to achieve. We did a stool sample, urine test, & bloods a week a go. Her lipase was slightly increased , & again slightly anemic.

She is the same as you say diesel is. Her appetite is good, no fever, peeing and pooping fine now. She's more lethargic than normal. She also has a bubbly stomach. No letting off of gas, just if you are near her in a quiet room you can hear soft bubbles in her belly.
There is a number of conditions that we are tossing up including cancer in the digestive tract/ pancreas , epi, ibd to name a few, plus other nasty muscle wasting auto immune disorders. My vet is also worried about her bone marrow (like you have said) & that since we have dropped the pred back we may have allowed other immune disorders that we have previously had kept in the back of our minds, to have now been allowed to progress. Particularly in hindsight of her muscle wastage.
We are going back for more bloods in a week and then deciding what to do from there.
My vet wants to do an ultrasound but I really can't afford it. We have spent more than a new car on her since she got impa and my partner is putting his foot down. Anything we find on an ultrasound i imagine is going to be not an easy fix and I would rather not know if it's something horrible like cancer. As she is too old to have treatment and I will not put her through that.
Also Pepper doesn't seem to give very accurate results in tests. We have ran so many in the past & never get reliable results. 

Have you had any other similar systems to us?
I really hope you get some answers soon. I too have been doing so much reading & research to try work out what is going on with her. But she is so hard to read. She never seems to follow the 'normal' with her symptoms that she displays for any of her health problems. So it is so hard to pin point anything. I was pushing for the diagnosis prior to her last bloods of EPI but then my vet said she should have regular loose fatty stools same for ibd. Which she doesn't have?. I wish they could talk and tell us what's going on.

Best of luck!

[Jo CIMDA]

Hi

Sorry I couldn't get back to you sooner. Brooke has given an interesting account of Pepper's problem, which you may be able to relate to.

It is not always easy to differentiate between some cancers and autoimmune diseases and this is why the vets have to treat speculatively sometimes.  Personally, unless Diesel is very unwell and needs further treatment, I would wait until the preds are out of the system (at least a couple of weeks) before doing a bone marrow biopsy because the effect of steroids is likely to mask the results. Also, a bone marrow biopsy is done mainly to rule out cancer as opposed to diagnosing an AI disease. A diagnosis of immune mediated or autoimmune bone marrow disease is often arrived at (assumed)  by eliminating other conditions.   

Long term glucocorticoid (pred) administration can cause a drop in some of the white blood cells.  See this link for more information: 
https://endocrinevet.blogspot.com/2012/04/how-glucocorticoids-affect-complete.html

When do you go back to UC Davis?

Jo

[Jo CIMDA]

My vet wants to do an ultrasound but I really can't afford it. We have spent more than a new car on her since she got impa and my partner is putting his foot down. Anything we find on an ultrasound i imagine is going to be not an easy fix and I would rather not know if it's something horrible like cancer. As she is too old to have treatment and I will not put her through that.
Also Pepper doesn't seem to give very accurate results in tests. We have ran so many in the past & never get reliable results. 


Hi Brooke

Thank you for your detailed reply for Diesel.  I am very glad you have written the above because it illustrates that some tests are done because they 'can be' and they don't necessarily enlighten or give a definitive diagnosis. 

I am not saying this is the case with Diesel but many years ago someone called me on the telephone and she was crying.  Her dog had been on high doses of steroids for a prolonged period of time and the vet college specialist was weaning her down.  This girl's liver enzymes were high and the vet wanted to do a liver biopsy.  This lady had spent thousands on her dog  (they could afford it) but she didn't want her to go through an invasive procedure if it was unnecessary, so she called me.  Considering the high doses of preds this dog has been on one would have expected her liver enzymes to be very high, but they were reducing the tablets and therefore the levels would start to reduce, so I suggested that this lady told the vet that she couldn't afford to do the liver biopsy and the response from the vet was, that's OK bring her back in two months to have her blood checked.  So this was not a necessary procedure and when they took the dog back in two months, as predicted, the liver enzymes had significantly reduced. 

Saying you can't afford it (whether it be true or not) is sometimes a good way of finding out if the procedure is necessary or not and also it might provoke  'plan B' which could be much less invasive. 

Hoping Pepper is still enjoying her life regardless of her problems. 

Jo

[BrookeR]

Thanks Jo. Back before Christmas when Pep got the diagnosis of plasmacytoma that had metasized there was possible suggestions going around from pathologists saying to amputate her toe, do chemo, X-rays, & ultrasounds. I'm so glad that I chose not to venture down those paths and went with my gut. Miraculously it disappeared! Although it's constantly in my mind that cancer may reappear again somewhere else. But I'm glad I didn't put her through any of that unnecessarily.

Pep has had so many possible diagnosis's over the years and so many tests have been suggested. Usually we wait a bit longer and things normally change anyway and the tests weren't needed.

Yes Pep is still happy in her self and seems fine other than being a bit more lethargic than normal (but she is 11 now) and she looks frail due to the muscle wastage. It has taken her some time to come to terms with having no treats. But I have now made her slow baked sweet potato chips that she enjoys.

I have been reading about supplementing digestive enzymes for senior dogs & other dogs with compromisesd immune systems. The idea seems to follow more of a holistic approach as it's been discussed in natural books & journals. I mentioned it to my vet but without the diagnoses of EPI she doesn't believe there is any proven evidence to back the use of them.
So I am going to wait until our follow up bloods and weigh in on Friday and see what that brings.

I'll be interested to hear how diesel goes.

[KaajalTiwary]

Hello Jo:

Thank you again for your time on Diesel's case. We are currently at UC Davis. Diesel has his follow up appointment today.

RBC 4.8 (below normal range)
Hematocrit 31.7 (below normal range)
WBC 3760 (very low)
Neutrophils 745 (very low)
Platelets 386000 (normal)

They want to do the bone marrow aspirate and biopsy in the next 2 to 3 days so they can get a clear understanding of 'what next'. I asked what they'd do differently from the last time. They are looking to do Flow Cytometry and also send the sample to Colorado State University for a second opinion.

About Prednisolone: She said since Diesel has been on 2.5 mg for the last 10 days and we are seeing low CBC counts, she's certain it won't mask anything. Your thoughts?

Thank you again for all the time you are investing in Diesel's case. I am very grateful.

[Jo CIMDA]

Hello

The low level of pred will not be having any therapeutic effect. 

Diesel's HCT had dropped so I can understand why UC Davis is concerned and the need to find out why.

I presume Diesel was initially put on a correct immunosuppressive dose of prednisolone and this has over time been reduced to his current dose.   I can only suggest questions for you to ask the vets but with limited information these might not be appropriate, so I apologise.  I  presume that his bone marrow has been functioning to reach an HCT of 38.1%.  As there has been a drop in HCT, does Diesel still have non- regenerative  haemolytic anaemia or is his bone marrow producing red blood cells (regenerative anaemia) but the red cells are being destroyed within the circulation of the blood or by the spleen, liver or gastric ulcer  etc...? 

Another really long shot but it might be worth mentioning to your vet,  is Addison's disease (adrenal insufficiency).  Sometimes a dog prior to being diagnosed with Addison's disease will become anaemic and diagnosed with AIHA, and the white blood cells will be opposite to what one would expect in a poorly dog and that is: low neutrophils, increased numbers of lymphocytes and eosinophils (known as a reverse stress leucogram).  UC Davis has done a lot of work on Addison's disease so they will be aware of this. 

You may have no choice but to go ahead with the bone marrow biopsy but just check what answers the vet hopes to get from the results and how will they go forward from there.

All the best.

Jo

[KaajalTiwary]

Hi Jo:

Need your input. Thank you for all your insight on Diesel's case so far. I think I need a lot of help.

I got an email from Diesel's doctor 30 minutes ago. Here's what she said:

1. FLOW cytometry - as you probably remember, we sent out FLOW cytometry on both Diesel's blood and from the aspirate of the bone marrow. This is a test that looks for specific markers on the outside of the cells and tries to give us a "break down" of the cells seen in a specific sample. The blood sample did not show any abnormal cells - there was no evidence of cancerous lymphocytes or any other abnormalities in the blood sample. The bone marrow sample also did not show any specific evidence of cancer (lymphoma or leukemia) in the FLOW sample. There was a decreased number of neutrophils (as would be expected given his low number of neutrophils in the blood that we have been monitoring).

Bone marrow biopsy - this sample unfortunately did not give us a lot of additional information after further analysis, but also did not show any overt evidence of lymphoma or other cancers.

Given that Diesel previously had a population of T-cell lymphocytes in his 1st bone marrow sample, the lab at CSU added on a test to the bone marrow aspirate sample called PARR. This is a test that looks at whether the cells are coming from one population (monoclonal), or many populations (polyclonal). As you probably remember, cancers tend to be monoclonal. This test is still pending from the lab, however, the results likely will not change what our recommendations for Diesel are at this time.

All of this being said, we do not have any overt evidence of cancer (lymphoma or leukemia) in Diesel's samples. After discussing his case with Dr. Pressel and Dr. Burton, we agreed that these results are most consistent with an immune-mediated destruction of his neutrophils. Additionally, his response when he was on higher doses of prednisone (doses that are high enough to lower the immune system) showed us that his neutrophil count was able to increase, which Dr. Pressel pointed out is very typical of dogs who have immune-mediated destruction of the neutrophils. As such, we feel that it would be in Diesel's best interest to begin treatment for immmune-mediated disease that is leading to destruction of his neutrophils.

As you can imagine, the first step of this would be to increase his prednisone dose ---  we know that Diesel has had a difficult time with higher doses of steroids in the past, so it is something that we would increase for a short period of time and then try to taper quickly (over the course of 2-4 weeks) to a manageable level. We would also recommend adding in an additional immunosuppressive drug, called Cyclosporine. The hope would be that by using both of these medications together, they would 1) suppress the immune system so that it would not destroy his neutrophils and 2) that we could ultimately use lower doses of both medications by using them together and try to reduce side effects of these medications.

All of that being said, we cannot 100% say that Diesel does not have a small component of an underlying lymphoma or leukemia. If cancer is there to some degree, it is difficult to find, difficult to quantify, and (ultimately) may or may not have anything to do with the destruction of the neutrophils. As such, Dr. Burton, Dr. Pressel and I agree that it would be most reasonable to treat the disease that we are able to monitor with bloodwork and establish if our treatments are being effective. If we were to treat this nebulous "possible cancer" it would be very difficult to know how to make adjustments to therapy because we cannot readily sample anything to find these cancerous cells. For example, when dogs have lymphoma in the lymph nodes that we can feel, we can measure those lymph nodes and sample them to determine if dogs are responding to treatment. In Diesel's case, really the only thing that we can measure on him reliably is the neutrophil count. As such, it makes the most sense to treat that as the main problem, especially because this additional testing has, so far, not revealed any evidence of underlying cancer.

All of this leads us to our next recommendations for Diesel.

We recommend scheduling a recheck examination with Dr. Pressel at your earliest convenience. She is VERY familiar with immune-mediated diseases and would absolutely be the best person to recommend treatment and to monitor his response. She did let us know that she would recommend that Diesel's steroid be increased to 40mg once per day. This would not be a level that he would remain at for a long period of time, but is the dose she would start in order to try and get his neutrophil count back up quickly. From there, she would guide you on tapering the dose down to a lowest effective dose, as well as adding in the other medication (cyclosporine) that would be recommended. Dr. Pressel is comfortable with Diesel starting this higher dose of steroid even before his next recheck with her.  We would also recommend that his antibiotics be continued for the time being.

I know there will be concerns about increasing Diesel's steroid dose again, and if he could develop another abscess or other side effects, which we completely understand. We want Diesel to feel good no matter what treatment he is getting and we certainly do not want to put him in another position where that could happen again. Unfortunately, we also feel that if we do not treat Diesel with immunosuppressive medications, that he is eventually going to develop an infection despite being on the antibiotics. As such, we feel that the benefit from starting treatment outweighs the risks.

Lastly, I wanted to tell you a little bit about the other medication that Dr. Pressel is going to recommend starting. As stated above, it is a medication called Cyclosporine. It has been used as an immunosuppressive in both humans and animals and also has anti-inflammatory properties. It is an oral tablet that is given at home, usually once per day (although Dr. Pressel will make the final recommendation about his dose). Side effects of this medication are possible, and include GI upset (vomiting, diarrhea, decreased appetite) although these generally improve over time. There have been small studies where small populations of people or dogs who receive this drug go on to develop lymphoma. There has been no specific link to say that cyclosporine causes cancer, however it is something that is on the label as a possible side effect. That being said, there are many dogs who develop lymphoma who have never been on cyclosporine, and there are plenty of dogs who receive cyclosporine who never go on to develop lymphoma. As such, it would still be a recommendation for Diesel in this case. Dr. Pressel would likely have more information about this medication for you, but I wanted you to have a little background about it.

[Jo CIMDA]

Hi

Basically, the bone marrow biopsy has all but ruled out cancer and therefore an assumptive diagnosis of immune mediated neutropenia has been made - which is a reasonable assumption and predictable.

I don't know if 40mg pred a day is the correct dose or not. How much does Diesel weigh?  If the dose of prednisolone is not high enough, or the duration not long enough,  immunosuppression won't be achieved and if the dose is too high the side effects can be a major problem.  Smaller dogs cope much better with high doses of pred than larger dogs. 

Most dogs can just about cope with a good immunosuppressive protocol, and it is a balance between having the dose high enough to suppress the immune system and monitoring the side effects of the drugs.  Dogs are being treated like this every day and in general it works very well and remission can be achieved.   The best protocol I have come across is by Prof Michael J Day.  It is widely used and it is the most successful protocol I know, but it has to be tailored to the individual.  See below:


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.

Example: Reduction Protocol for prednisolone:
Clinical Immunology of the Dog & Cat , 2nd Edition,  by Michael J Day
Professor Michael DayBSc, BVMS(Hons), PhD, DSc, DiplECVP, FASM, FRCPath, FRCVS 

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/q 12hrs (q = every)
Dose                           Duration (based on clinical effect)
1.0mg/kg/q 12h                          10-28 days
0.75mg/kg/q 12h                       10-28 days
0.5mg/kg/q 12h                         10-28 days
0.25mg/kg/q 12h                        10-28 days
0.25mg/kg/q 24h                        10-28 days
0.25-0.5mg/kg EOD                    at least 21 days
0.25-0.5 mg/kg every third day      at least 21 days

Every reduction is made after consideration to improvement of clinical signs, blood results and side effects of the drugs.

Important note:

Prednisolone:  "Doses above 2.2mg/kg/day do not give more immunosuppression but do cause more side effects. Many internists believe that prednisolone doses should not exceed 80mg per day, regardless of the dog's weight."  Plumb's Veterinary Drug Handbook Eight Edition.




If Diesel were mine I would want a blood test done to check the current level of neutrophils and red blood cells (HCT) and also check liver values etc.  If the results indicate that treatment should be started then this should be at 1mg/kg/12hrs prednisolone.  The dose of 2mg/kg once  a day pred can be given but it is easier on the body, in particular the stomach if the dose is divided into two. Over a period of 24 hours you are giving the same dose whether it is split or not. If his results are normal or near normal, I personally wouldn't treat at this stage and I would monitor.

The main stay of treatment is prednisolone.  The reason for wanting to introduce another immunosuppressive drug is reasonable and is common practice, but it isn't essential.    Diesel's Dr has given the reasons why they want to use a 'combination' therapy.  There are several immunosuppressive drugs that can be used in 'combination' therapy.  Cyclosporine has been used for many years now as a combination drug, other drugs commonly used in veterinary medicine are azathioprine, mycophenolate, leflunomide etc......... 

The use of these additional drugs is sometimes necessary if prednisolone alone can't achieve remission or if the dog can't cope with the high doses of preds, or if, perhaps because of a relapse,  preds have been used for a prolonged period of time. 

This is an excellent resource:  http://veterinarymedicine.dvm360.com/immunosuppressive-drugs-beyond-glucocorticoids

Info re: cyclosporine: http://veterinarymedicine.dvm360.com/busy-clinicians-review-cyclosporine?id=&sk=&date=&pageID=2
  https://onlinelibrary.wiley.com/doi/full/10.1111/jvim.12265

As your vet says, there are cases where cyclosporine has caused lymphoma in humans but I don't know if this is relevant in dogs.  This may simply be  because our life span is much longer.

It might be prudent to start Diesel on a broad spectrum antibiotic when immunosuppressive treatment is started in an attempt to avoid infections and abscesses etc.     

I hope the above helps.  If you have further questions I will try to answer them so you have some peace of mind about how to go forward. 

Jo

[KaajalTiwary]

Hello Jo:

I am unable to upload some test results. It says the file size is too large. Is there a way to speak with you? I desperately need some guidance. I am very sorry for making this request. I don't know what else I can do.

[Jo CIMDA]

Hi

I am sorry for the delay in replying.  My computer has been down for a few days.  It is back up and running now so if you want to contact me, you can email me on:   cimda@aslog.co.uk.

Jo