Your Pet's Best Friend

Are Heartworms getting worse? A Seminar: Part 6 of 6

Doxycycline’s Role in the Treatment Process

This also relates back to our problems with heartworm treatment.

Doxycycline kills L3 and L4 larval stages of the heartworm, and it decreases embryogenesis (the production of microscopic baby heartworms -- microfilariae).  It has intrinsic anti-inflammatory effects.  It greatly inhibits Wohlbachia, which is a symbiotic rickettsial organism needed by Dirofilaria immitis (the canine heartworm) to survive. 

When you treat with Doxycycline at 10mg/kg/day for 30 days, it will clear microfilariae and it will shrink adult worms.  [Doses twice this high have been recommended, but some dogs do not tolerate the dose as well.]

We know that more inflammation is produced in the dog when worms die with Wohlbachia present, than in dogs with worms where the Wohlbachia have been suppressed with Doxycycline.

Clinically the effect is not very great in dogs that have few worms and no microfilariae. [Dogs who have been taking year-round preventive medicine, but develop a positive blood test]  In dogs that have not received preventive medicine, who have more worms present, the beneficial effect is more noticeable.

It would be advisable to use Doxycyline in dogs that one suspects to have a significant worm burden and who are not in need of immediate treatment.  It is combined with Ivermectin given weekly during the month of Doxycycline treatment, prior to giving Immiticide.  This should eliminate microfilariae, shrink the adult worms, and reduce the amount of inflammation associated with the death of the adult worms.

Conclusion

This is not a very satisfying conclusion to my seminar, but this reflects the fact that I don’t have a good answer to my problem.  I don’t know the cause of the apparent preventive medicine failures, nor why it is more difficult to eliminate adult worms and microfilariae than it used to be.  I'm starting to get used to it, but I've become used to dog-bites, too, and I don't like that either.

I don’t have a strategy to improve the situation, which is why I was eager to share experiences and information with the other veterinarians and the parasitologists.  I’m looking forward to seeing what the future holds here.

Are Heartworms getting worse? A Seminar: Part 5 of 6

Immiticide Treatment to Kill Adult Worms

In re failure to clear dogs of worms with the Immiticide treatment, there are several considerations that are important, particularly in dogs that have not been receiving preventive medicines.  I have written previously about problems with the treatment.

Immiticide does NOT kill immature adult worms, or “juvenile worms”.  These are small worms, less than one inch long, in the “tissue phase” or the pulmonary circulation (arteries in the lungs). These are worms 60 to 120 days post infection.  They are long past being susceptible to preventive medicines and the Immiticide doesn’t kill them either.  You would need to treat the dog at least four months after the mosquito season (peak July and August) to be sure these juveniles would be old enough to be killed by the medicine.  That would mean treating in January or February in dogs that have not been taking preventive medicine. [This is not as relevant to the dog that has been taking year-round preventive, but has developed a few heartworms in spite of that.]

In dogs who have not been taking year-round preventive, treating at the wrong time guarantees that juvenile heartworms will survive.  The dog WILL have adult heartworms within a few months, despite the treatment.

Effectiveness of different treatment regimens

When we talk about percentages of worms killed, we are talking about the number of worms that were experimentally implanted in test subjects.  We are not talking about the worms in a single dog.  In these tests, some dogs were totally cleared of worms and some were not.  In other words, if ten dogs were infected with ten worms each (100 worms), and ten worms survived, then we say 90% of worms were killed.  This is true whether the ten surviving worms were in one dog, two dogs, or divided equally between the ten dogs (and they weren’t).

Two stage Heartworm treatment:

A single dose of Immiticide kills male worms.  All females survive.  Statistically, infections are 50/50 male/female.  This is why you consider that you are killing “half the worms” with a single injection.

A treatment of two injections (24 hours apart) kills 90% of worms.  This has been the “standard” treatment.  This will totally clear some dogs (if they don’t have tough worms) and will leave a few worms present in others.  

Giving the two doses of Immiticide more than 24 hours apart decreases its effectiveness.  Giving the doses less than 24 hours apart increases the effectiveness, but also the toxicity of the drug.

Three injections (a single injection, followed four weeks later by the two injections 24 hours apart) kill 98% of worms.  In the past, this has been used primarily for dogs where larger worm burdens were suspected.  [The dog only had to deal with the breakup of half the dead worms at a time – less stress on his system.]  This will totally clear most dogs, but some dogs will still have worms present.

Two injections followed two months later by two more injections kills an even higher percentage of worms, but you cannot ever guarantee 100% kill.  This regimen is not in widespread use (but has been studied in the laboratory setting).

In the past, I have been treating dogs who are apparent "preventive failure cases" with two injections, 24 hours apart, based on the near certainty that they have very low worm burdens.  I am currently re-evaluating my position here, and considering going to treating all patients with the two-stage, 3-injection regimen.  While it should give me more "complete kill", it also extends the patient's exercise restriction by four weeks, and adds to the expense.  This is not a clear-cut decision for these dogs.

Are Heartworms getting worse? A Seminar: Part 4 of 6

Mosquito Considerations

In an October 2008 seminar, Dr. Tom Nelson made much of the increased numbers of tropical storms hitting the Gulf Basin in the past several years since Hurricane Katrina.  His thesis is that more storms equals more rain, equals more flooding, equals more mosquitoes. This was not much accepted as an explanation for the increased numbers of heartworm cases, as his audience was drawn from the banks of the Mississippi River and from reclaimed swampland.  These areas have always had enormous mosquito populations.

The mosquito population may be changing. The researchers at our seminar expressed great frustration over the fact that there is NO DATA readily available (possibly not even in existence) about the numbers of mosquitoes, the population density of mosquitoes, the species ratio of mosquitoes, or the percentage of mosquitoes carrying microfilariae.

The Asian Tiger mosquito, Aedes albopictus, has displaced Aedes aegypti in some locations.  It is a much more aggressive mosquito, and it bites in daytime as well as nighttime.  It can survive winters as far north as Toronto, Canada. It would be of interest to know whether the population of Aedes albopictus has burgeoned in our area, but I haven't been able to get any data from ag extension.

More mosquito bites equals more potential filaria infection.  The research guys made reference to the preventive medicine being “overwhelmed” by huge numbers of microfilariae.  Interestingly, they don’t recommend bigger doses of medication or more frequent dosing as effective strategies to deal with this ostensible “overwhelm”.

In 1978, I worked for a veterinarian in Pocahontas, Arkansas.  We were situated between the Black River bottom and the Current River bottom, with rice fields in the middle.  Horses in this low-lying flatland would run all night to escape the mosquitoes. [Researchers at LSU have documented horses there receiving 1,000 mosquito bites per hour.]  My employer moved from his home adjacent to the clinic into the foothills on the other side of town.  With daily heartworm preventive, he still could not keep all of his own dogs free of the parasite. 

As bad as our mosquitoes are here, they were dramatically worse in that environment.  We do have more rice-farming in our area now, and there are lots of folks who feel that the mosquitoes are worse than in years past, even in town. However, there are no hard numbers to work with.  Subjectively, I can't say myself that the mosquitoes are noticeably worse now than five years ago.

Are Heartworms getting worse? A Seminar: Part 3 of 6

Preventive Medicine Considerations

Heartworm preventive products have never been “100% effective”, but they have been pretty close.  It is interesting to note that in the drug approval process, testing is done in a (relatively) small number of Beagles in a laboratory setting, using only 100 microfilariae to infect the subjects.  This is a far cry from the outdoor Labrador Retriever getting infected with thousands of microfilariae each month.  In a way, I’m surprised that in years past we have seen almost 100% efficacy under field conditions.

As far as failure rates in one product versus another, it was the consensus of all present that there is no heartworm preventive that can be singled out as being worse or better than the rest.

Timing of the medicine dose does matter.  Does “once per month” equal every 30 days?  Maybe not.  Maybe a client gives the medicine on July 4 and August 20.  If you give the medications more than 30 days apart, risk of infection increases.  More than 45 days apart increases the risk even more.  Failing to give the medicine year-round in endemic areas dramatically increases risk of infection.  Client compliance is obviously a factor, but I doubt that we have experienced a sudden and dramatic change in the numbers of clients who “cheat” on their medication, versus years past.

Merial (the makers of Heartgard-30) has done a market research study showing that many dog-owners lack awareness of the severity of the disease and of the expense and complexity of treating it.  They don’t realize it is fatal, and believe it is easily and inexpensively treated “with a pill”.  Thus they lack incentive to bring their dogs in and start preventive medicine.  Here the company is looking at the “unchurched” for marketing purposes. 

I doubt that this data is as applicable in endemic areas like ours as it is where the parasite is less problematic.  Rarely (unlike 30 years ago) do I now find clients who have “never heard of heartworms.”  And in considering the treatment process, I personally encounter more people who believe that the disease is always fatal and untreatable (which is certainly not true).

Merial’s proposed solution to this lack of awareness  (found in their surveys among the “unchurched”) is to start a new ad campaign that diverges from the old “warm fuzzy” approach, to a new “scare hell out of them” approach. This ad appears to be the beginning.  It says: “Preventing heartworm disease is easy. Treating it, sadly, is anything but.” 

Again, this lack of awareness is not something that I am concerned with in my own patient population.  We work strenuously to educate our clients.  While there are certainly those with misconceptions, there are few who "never heard of it" these days.  It certainly doesn't explain the cases of apparent failure of year-round preventive medication.

Immune system participation is implicit (but not fully understood) in the degree of natural resistance to infection, performance of the preventive medication, and in the outcome of the treatment process.  This doubtless accounts for some variation in success in all these areas.  Dogs just aren’t all the same.

Unfortunately, no strategy was recommended to increase the effectiveness of preventive medication.  Clinical experience in our practice has shown no advantage to dosing more frequently or with higher doses (dramatically higher doses in some cases).

Are Heartworms getting worse? A Seminar: Part 2 of 6

Heartworm Testing Considerations

One explanation proposed for the increase in dogs diagnosed with heartworm is an increased sensitivity (or accuracy, if you will) in the tests that are being used.  In other words, if you have a better test, you'll find more dogs with low numbers of heartworms that you might have missed previously.

Thirty years ago, we primarily tested for microfilariae (microscopic baby heartworms) in the blood.  While I still perform the modified Knott's test (most sensitive for these) on many samples, we also perform antigen tests on all our samples. Many clinics perform only antigen tests.

Antigen tests presently being used test for protein from the female reproductive tract and have the capability of detecting an infection with one female worm… sometimes.  With fewer than four worms, many tests will miss 15% or more of infected dogs. “Exam Room” tests like the Heska Solostep CH or Idexx are definitely in this less sensitive category.  The upside is that you only need three drops of blood -- pretty helpful in tiny or uncooperative patients.  I use quite a few of these test kits.

The Dirochek Labkit by Synbiotics is the “gold standard” for sensitivity.  It's a lot more complicated and time-consuming to run.  We have been using this to batch test our (bigger)  blood samples weekly (with the same technician doing the tests) for over nine years at Kennett Veterinary Clinic.  Therefore, I do not believe this explanation can account for the increased number of heartworm infections we are diagnosing here.  In fact, many of our "surprise" heartworm infections (dogs who have allegedly never missed a dose) are detected on the Heska test.

We are also finding dogs that are positive for microfilariae while taking monthly preventive, something which never used to happen.  The meds would give you a false negative test if you only checked for microfilariae.

It's pretty hard for me to buy "Better Testing" as the explanation, at least in our clinic.

Are Heartworms getting worse? A Seminar: Part 1 of 6

The Problem

In the past three years, we have seen a significant increase in the number of dogs where heartworm preventive medication has not been 100% effective.  In addition, it has been more difficult to clear infected dogs of the worm burden with treatment. It has also been more difficult to clear microfilariae from dogs post treatment.  Some dogs who have been treated and cleared have heartworms again the next year, despite year-round preventive medicine. These reports come from the Mississippi valley, starting about 100 miles south of St.Louis, and getting worse as one goes south.

For my own part, it was as though in the year 2006 "the rules changed".  Many veterinarians and dog-owners have become convinced that a resistant population of heartworms has developed.  With no new drugs in the pipeline, this is a major concern.

The Experts

As late as October of 2008, educational meetings, publications and discussions tended to dismiss the problem as merely one of perception, rather than an actual change in the incidence of the disease.  

In April of 2009, I was privileged to be one of six veterinarians from private practices invited to a round-table discussion seminar.  Our input was sought in regard to our experience with heartworm disease, its prevention and treatment, and our problems with all of these.

Three leading parasitologists, all involved with heartworm research, opened the discussion by saying, “We know that something has changed, but we don’t know what it is.  There is a problem, but the underlying cause has not been determined.  We are here to gather and share information.” 

This was a refreshing change.  You know what they say: the first step is admitting you have a problem.

Epidemiology Considerations

Everyone now concedes that something has been different in the past three years.  There was a sudden “uptick” to a higher level of problem (observed in my practice in 2006 and continuing over 2007 and 2008), rather than a slowly growing problem.  In other words, we went from “Plateau A” to “Plateau F” without going through B,C,D,&E.  The change seemed abrupt, rather than gradual.  This speaks against the development of a resistant population of heartworms.  There are other epidemiological objections to this, as well. 

The parasite has a very long life cycle: six months minimum.  It requires a vector, the mosquito.  Reservoirs are widespread and act as carriers for years, and more than half of the reservoir hosts are never treated.  Coyotes are a big reservoir of the disease, but their rate of infection has not been studied anywhere except in California.  There are, of course, also many, many dogs in communities and the countryside that do not receive preventive medicine, and act as reservoirs of the disease.

This makes the development of a resistant population of worms by “Darwinian” selection almost impossible.

On the other hand, as yet no other reasonable explanation has been put forward.  An increase in the numbers of mosquitoes might explain it, but there is no data to support or refute this.  There just is no helpful mosquito data. Our subjective experience locally is that the mosquitoes are terrible, but they have been so for many years.

More Heartworm Questions

After my last post, one reader asked me if I would post the questions and answers.  I replied (pretty much without thinking) that they are posted as comments on the original post.  So how would you know where to look, gentle reader?   I'm going to start posting the ones that have more general interest. I'm taking more time to write some of them than I do to write a regular blog entry.  This one, for instance, popped up as a comment on "Problems with Heartworm Treatment".

The Question:
I have enjoyed reading your thoughtful responses to so many questions. Here is mine asked with much respect.
What are your thoughts on the "slow kill" method? A rescue I foster for recommends Doxy for a month (although I found a study that suggests 2 weeks is better) then Ivermectin every 2 weeks for up to a year until a negative result [blood test free of heartworms] is met. The reasons are primarily to make the treatment less harsh and of course financial [less dollars].

My second question is what Heartworm treatment is recommended for a lethal white [gene] Aussie with heartworms. I believe they are in the Collie family and cannot have ivermectin.

My Answer:

The doxycycline is intended to kill a microorganism called Wohlbachia that infests the heartworm itself.  Many researchers believe that a great deal of the reaction we see to the breakup of the dead worms is related to the presence of this organism.  The doxycyline pre-treatment is not a universally adopted practice, but is inexpensive and does no harm (unless the delay allows more heart and artery disease to develop in dogs who have clinical signs of disease, versus just a "positive blood test").

Even when the Wohlbachia is gone, you still have chunks of dead worm to deal with, and they WILL cause inflammation in the pulmonary arteries. The inflammation causes swelling of the blood vessel, which restricts its inner opening.  This makes circulation in the lung tissue poor, and increases the pressure on the compromised artery, and increases the back-pressure the hear must pump against.

This brings us to your question about using long-term ivermectin to kill the worms, and whether this is somehow "less harsh".  Dead worms are dead worms, no matter what kills them.  When they die and drift downstream, it doesn't matter what drug killed them or how long it took. They will still lodge and plug things up and cause inflammation.

With the dramatic increase in the number of dogs who get small numbers of heartworms despite taking monthly ivermectin (Heartgard 30, etc.) I have serious doubts that taking ivermectin every two weeks is going to kill the heartworms.  Previous studies documenting this noted that it took as long as two years for the worms to die with this treatment (with no treatment at all, the worms would die of old age in about four years).  These studies were made before we began to see the apparent failure of the drug to prevent heartworms 100% (in the past 3 years).  Since they are getting new worms while taking the ivermectin, it's hard for me to have confidence in the drug getting rid of the old ones.

Even if we accept that giving ivermectin twice monthly would eventually kill the heartworms (and I am not confident of this), we have to ask if this is really a good thing.  When we give the standard treatment of the Immiticide injections, we know that the worms will die within the next few days.  Thus we are alert for signs of complications. We also are now giving the dogs prednisone after their treatment in order to minimize the inflammation experienced when the dead worms move. 

The bottom line is that we know when the worms will be dying and moving, so we can be on the alert and detect complications rapidly, and deal with them. We know that the dog's activity should be restricted while the dead worms are clogging up the works, and we can do this for the next five or six weeks.

If the worms were going to die at some unspecified time in the indefinite future, how in the dickens are you going to be on constant "red alert" for the next two years?  Are you going to crate the dog for two years?  Give him prednisone for two years?  I submit that you will not be doing any of these things.  Therefore, when the worms DO die, you are more likely to experience complications.

Since complications are related to how many dead worms are breaking up and hitting the smaller pulmonary arteries, it would make sense that the dog would do better if the worms died one at a time over a long period of time.  There is NO evidence to say that this is what happens with the ivermectin (if indeed, anything is happening with the ivermectin).  Even if you could prove that "in six months, the worms began to die one at a time, regular as clockwork, one-tenth of the worms per month for ten months" (and this is absurd), would you crate the dog for ten months, starting six months from now?

The sad fact of the business is that the Immiticide treatment is the only thing that we know is effective.  We can reduce the risk  by giving a half-treatment, and then waiting a month to give the full treatment.  This also makes it more likely that ALL of the worms will be killed.  (Unfortunately, there is no such thing as 100%, "always" or "never" when we're talking about this).

This (Immiticide treatment) would be the appropriate treatment for the Aussie.  While they cannot tolerate high doses of ivermectin, they tolerate the preventive dose in Heartgard 30.  You could certainly use Interceptor as your preventive instead, but it's not going to be effective in ridding the dog of adult heartworms.

It is certainly cheaper to give Ivermectin twice monthly for years than to do the Immiticide treatment.  On the other hand, giving nothing is even cheaper.  Doesn't work, but it's cheap.

Sorry that I don't have a quick fix for you.

Thanks for reading and writing,
Everett Mobley, D.V.M.

Ticks in winter?!?!

"Dr. Mobley!" cried Shannon, "There's something on this dog's head." 

 "Oh, it's probably just some trash." 

 "No, it's a tick." 

"Shannon, it's January. It was nine degrees yesterday."

Son of a gun, though, it was a tick, and alive, and attached, and partially engorged, at that.  This pup is an outside dog, and he does live in the hills of PIggott, Arkansas, but January?  Nine degrees?

 The only thing I can think of is that this is a byproduct of global warming.  I don't have any proof, but neither did Al Gore, and he got the Nobel prize (when his personal carbon footprint is bigger than Godzilla).

"Maw, where did we put that Frontline?"

DON'T Stop the treatment too soon.

Last night was the third night out of six that I didn't get to bed until after midnight.  Man, I didn't do that when I was in college.  I've got lots of things to post, just not enough time to sit around at the computer.

Hey, remember this kid from a previous post?  Too much cortisone in treating the allergy let her demodectic mange mites go crazy, with secondary skin infections.  She came back in today because her skin has been "breaking out a little" in the last two weeks.  The good news is that she looks pretty great now, compared to our last visit.  In fact, the owner says that she was looking great after two weeks of treatment. So, since she looked so great, they stopped treating after two weeks.  Sure, sure, I told them we would have to treat until she looked good, and the mites were gone on skin scrapings, and for two more weeks after that .  But, hey, she looked great!

Actually, she still looks pretty great, especially compared to our last visit.  On the other hand, she has a few little sore places, and they are full of active demodex mites.  They shouldn't have stopped the meds, but they did.  Now they are starting back on again.  Maybe I can convince them to stay the course this time.  At least she's not so bad this time, just a few zits really.  Of course, all that mongo cortisone dose is finally worn off now, so we have a little clearer picture of the dog's actual condition.

If you've got a drawer full of medicine you didn't finish out, why is that?  Who did you save it for?

Comfortis + High-dose Ivermectin = Adverse Drug Reaction

I've been thinking about getting started with Comfortis.  We're looking for more information.  I don't think that Comfortis users should panic, but if your dog needed to take extremely high doses of ivermectin (as in being treated for demodectic mange, not as in Heartgard-30), extreme caution is indicated.  Here's a news release:

FDA warns of adverse Comfortis, ivermectin interactions Rockville, Md. — Dogs receiving the drug Comfortis (spinosad) concurrently with high, extra-label doses of ivermectin are having adverse reactions in some cases, the Food and Drug Administration's Center for Veterinary Medicine (CVM) announced today.  The regulatory agency warns that it's received adverse reaction reports that are consistent with ivermectin toxicity. CVM advises veterinarians to not prescribe the two drugs concurrently for canine patients. The safety warning also comes from Elanco Animal Health, which manufactures Comfortis, a monthly oral, chewable tablet used for the prevention and treatment of flea infestations on dogs. The company is addressing the issue, CVM officials say. Visit http://elms.xh1.lilly.com/10788_03_tech_Bulletin.pdf for more information.

Date Published: June 24, 2008