Heartworm Disease

Basic Echocardiography

Additional Information

Wendy Blount, DVM

Nacogdoches TX

Heartworm Disease

AHS Guidelines

• Yearly occult heartworm and microfilaria check

• Year round monthly heartworm prevention

– Emphasized with the emergence of resistant populations

• Year round monthly dewormer

• Doxycycline and macrocyclic lactone prior to 3-dose regimen of melarsomine

– One injection at 2.5 mg/kg

– Two injections 2.5 mg/kg 24-hours apart, at least 1 month later

• Any “slow kill” method using macrocyclic lactones is not recommended


Reservoir

• Domestic dogs and wild canids

• Cats and ferrets are sometimes microfilaremic for a very short time

• Common misconception of clients

– My dog is at risk being housed near a microfilaria positive dog

• My answer:

– It doesn’t matter. Heartworms are endemic in the area.

– Most if not all mosquitoes in the area are already carrying heartworm larvae


Heartworm Life Cycle

• The entire life cycle is 7-9 months

– It can take that long after exposure for occult heartworm and microfilaria tests to become positive

• Immature adult (L5) worms reach the pulmonary vasculature as early as day 67 as late as day 120

– 2-4 months post infection

– Blood flow forces them into the small pulmonary arteries

– As they grow, larger arteries and the heart are occupied

• Microfilaria are produced as early as 6 months to as late as 9 months

– Adults seen in the heart with high worm burdens and in small dogs


Caval Syndrome

• Usually more than 40 worms are present

• Adult worms fill the RV, RA, jugular veins and cross the tricuspid valve

– They interfere with circulation causing RHF

– They destroy RBC causing hemolytic anemia

– Kidney and liver failure might ensue

• History

– Sudden onset of weakness, pallor, dyspnea, lethargy

– May be signs of right heart failure – swollen abdomen, swelling of the legs

– Dark urine


Caval Syndrome

• Physical Exam

– Positive hepatojugular reflux

– Hepatomegaly and splenomegaly (severe passive congestion)

– Tricuspid Murmur

• Diagnosis – find heartworms in the jugular veins, as well as right heart

• Prognosis – often fatal within days to weeks if heartworms not extracted

– Description of the procedure in the AHS guidelines


Heartworm prevention

• p. 4, “If records of past treatment and testing do not exist, it is necessary to test the patient before dispensing or prescribing chemoprophylaxis.”

– If the dog is older than 7 months old

– If they have their adult canine teeth fully in, we test them

• HWPrev should be started no later than 8 weeks of age

• Puppies started on HWPrev after 8 weeks of age or housed outdoors should be tested 6 months after the first dose and annually thereafter


Macrocyclic Lactones

• Ivermectin (Heartgard, Iverhart, Trihart, etc.)

• Selamectin (Revolution)

• Milbemycin (Interceptor, Sentinel, Trifexis)

• Moxidectin (ProHeart, Advantage Multi)

• They kill all L3 and L4

• With some instances of sustained use, there is some effect against L5 and adults

• As the larvae get older, they become more resistant

• HWPrev must be given every 30 days


P-glycoprotein deficiency

• aka MDR1 deletion

• aka ABC deletion

• p-glycoprotein pumps drugs out of the CNS

• Dogs deficient in this protein are predisposed to toxicities when these drugs are administered

• All commercial heartworm prevention products are safe for p-glycoprotein deficient dogs

• Life threatening toxicity can occur at much higher doses

– Usually off label use of food animal products


P-glycoprotein deficiency

Antidepressants

Fluoxetine

St. John’s Wort

Paroxetine

Antimicrobial Agents

Erythromycin

Itraconazole

Ketoconazole

Opioids

Methadone

Pentazocine

Cardiac Drugs

Verapamil

Amiodarone

Quinidine

Nicardipine

Immunosuppressants

Cyclosporine, Tacromilus

Vinca alkaloids, doxorubicin

Miscellaneous

Bromocriptine

Chlorpromazine

Tamoxifen

Grapefruit juice


Lack of Efficacy (LEO) of HW Prevention

• Most are explained by compliance failure

– Failure to administer

– Failure to administer every 30 days

– Failure of dog to retain the dose

– Failure of absorption (Revolution in dogs)

• Variation in host drug metabolism and immune response

• Parasitic resistance

• Heartworm tests have become increasingly sensitive over time


Heartworm Resistance

• We know genetic polymorphism has always existed

– resistance-contributing alleles

• What is not known

– the frequency of resistance-contributing alleles

– the number of genes involved

– Whether alleles are dominant or recessive



• The phenomenon of developing resistance in a population is much more complex than merely the presence of resistant alleles in individuals

– Biology of the parasite

– Extent of untreated reservoir population

– Fitness of susceptible and resistant genotypes in absence and presence of treatment

– Drug dose used

• “Slow Kill” heartworm prevention genetically selects for worms with relative resistance



LMIA (Larval Migration Inhibition Assays)

Testing using “MP3 isolate”

• In vitro tests have identified microfilariae that are less susceptible to high doses of macrocyclic lactones

• These microfilariae have a p-glycoprotein allele that is different from the general population

• However, in vitro tests utilizing L3 from these propagated isolates show no difference in susceptibility

– 25 (1.6%) adult worms matured from 1500 L3 in dogs treated with ivermectin and milbemycin (no comparison to wild types)

– None were recovered from dogs treated with moxidectin




Testing using “MP3 isolate”

• MP3 isolate had decreased susceptibility to single monthly doses of ivermectin, milbemycin, and selamectin

• MP3 isolate susceptible to three consecutive monthly doses of milbemycin

• MP3 isolate susceptible to a single dose of topical moxidectin

• 20-fold increase in number of worms recovered when the number of L3 injected was doubled




Testing using “MRV isolate”

• MRV = Mississippi River Variant

• Every compound currently marketed in every form of administration (oral, topical, and parenteral) was less than perfect in at least one study

• differences in active ingredients, doses, and product formulation among the available preventives can result in varying rates of failures

Efficacy of HWPrev in FDA approval studies was not

100%


“Slow Kill” Heartworm Treatment

• We are bound by veterinary ethics to consider public health implications of our treatments

• We are bound ethically and legally to also consider the best interest of our patients and owner requests

• macrocyclic lactones continue to be the best and only option for preventing heartworm infection (95%+ effective)

– It’s generally accepted that small pockets of microfilaria relatively resistant to macrocyclic lactones do exist

– The extent, the degree of spread, and the reasons for resistance are not understood and are controversial

– compliance is the biggest factor in prevention “failure”



• Macrocyclic lactones alone weaken but do not kill adult heartworms

– Adult heartworms live as long as 7 years

• ML plus doxycycline can kill some adult heartworms

• “Slow Kill” using HWPrev along is not recommended by

AHS.



• However:

– “In cases where arsenical therapy is not possible or is contraindicated, the use of a monthly heartworm preventive along with doxycycline at 10 mg/kg BID for a 4-week period might be considered. “

– Occult heartworm test every 6 months is recommended

– If still heartworm positive after 12 months, repeat 4 weeks doxycycline

– Strictly limit exercise during the entire treatment period


Yearly Testing

• Most common cause of false negative occult test is low female heartworm burden

• Most common cause for discordant test results is low female heartworm burden

• there is no need or justification for testing a dog for antigen and microfilariae prior to 7 months of age or a dog that has missed preventive for less than 7 months

• Testing for microfilaria is important to choosing the preventative

– Milbemycin carries increased risk of fatal reaction in microfilaremic dogs


Yearly Testing

• less than 1% of infections are patent but not antigenemic

– testing for microfilariae alone is not recommended

– 20% of infected dogs not on prevention are microfilaria negative

• The current generation of heartworm antigen tests identify most adult worm infections consisting of at least one mature female worm and are nearly 100% specific

– Almost never see a false positive

• Microfilaria test

– At least 1 ml of whole blood

– Concentrated by Modified Knott or filtration


Unexpected test results

• Minimize blocking immune complexes which can cause false negative

– Repeat the test using plasma

– Heat sample test tube in warm water bath (104F o ) for 10 minutes

• Send sample to a reference lab

• Gather corroborating information

– Concentration microfilaria test (Knott’s)

– Thoracic radiographs

– Echocardiogram

• In case of minimal exposure, test results should be confirmed prior to melarsomine treatment


Idexx SNAP “Strong Positive”

• Interpret results “with a grain of salt”

• transient increase in antigenemia associated with recent worm death

• low antigen levels from infections with young adult female worms and/or only a few adult females

• Interference of blocking antibodies

• Use chest radiographs to corroborate


Modified Knott Test

• Mix 1cc blood with 9cc 2% formalin in a centrifuge tube

• Invert several times

– Mixes and lyses the RBC

• Centrifuge 5 minutes

• Pour off supernatant

• Add a drop of methylene blue and mix

• Examine a drop of sediment with coverslip under 100x



• Mix 1cc blood with 9cc 2% formalin in a centrifuge tube

• Invert several times

– Mixes and lyses the RBC

• Centrifuge 5 minutes

• Pour off supernatant

• Add a drop of methylene blue and mix

• Examine a drop of sediment with coverslip under 100x



• Acanthocheilonema reconditum

– Formerly Dipetalonema reconditum

– Blunt head

– Smaller – 250-290 um

– Curved tail

• Dirofilaria immitis

– Tapered head

– Larger – 300-325 um

– Straight tail


Heartworm Prevention Guarantees

• Do and occult heartworm test and microfilaria test when starting a new product

• Retest 6 months later

• Internet Pharmacies

– If product bought on the Internet is determined to be counterfeit, the guarantee is void

– If product is genuine, the guarantee is valid

– Most Internet pharmacies have their own guarantee which is as good as the manufacturer’s


Assessing Severity of Disease

• Radiography provides the most objective method of assessing the severity of heartworm disease

– Nearly pathognomonic radiographic signs:

• Enlarged, tortuous, truncated pulmonary arteries

• especially caudal lobar aa

– Pneumonitis

– Signs of especially severe disease

• Right heart enlargement

• Echocardiography ( video )

– Seen in MPA, RPA and LPA in severe infections

– Seen in the right heart as well in caval syndrome


Moderate Heartworm Disease


Moderate Heartworm Disease


Severe Heartworm Disease


Severe Heartworm Disease


Assessing Severity of Disease

Summary of Clinical Signs of Heartworm Disease

Mild (Class 1) Asymptomatic or cough

Moderate (Class 2)

Severe (Class 3)

Caval Syndrome

(Class 3)

Cough, exercise intolerance, abnormal lung sounds

Cough, exercise intolerance, dyspnea, abnormal heart and lung sounds, hepatomegaly, syncope, ascites, death

Sudden onset of severe lethargy and weakness, anemia, hemoglobinemia and hemoglobinuria


Pre-Adulticide Work-Up

• History, Physical Exam

– Owner’s ability to prevent exercise and overheating is paramount to preventing PTE

• Occult heartworm test, microfilaria test

• Chest radiographs

– Severity of radiographic signs correlates with risk of PTE

• Echocardiogram

– If heartworms are seen, you know worm burden is high

– Worm burden positively correlates with risk of PTE

• Pre-Treatment bloodwork is not mentioned in AHS

Guidelines


Preparation for Adulticide Treatment

• In addition to doxycycline and HWPrev 2-3 months prior

• Treat pneumonitis if present

– Prednisone

• Treat right heart failure if present

– Diuretics

– ACE inhibitor

– Pimobendan if no obstructive disease


Melarsomine Administration

• Minimize post injection muscle soreness

– Inject deep IM epaxial muscles L3-L5

– Use 22 gauge needle put on the syringe after the drug is drawn up

(5/8” to 1-1/2” in length)

– Apply pressure for 30 seconds after injecting

• Administer prednisone on the day of injection

• Two dose protocol kills 90% of adult worms

– Recommended on label for Class 1 and 2 heartworm disease

• Three dose protocol kills 98% of adult worms

– Recommended on label for Class 3 heartworm disease


Pulmonary Thromboembolism

• An inevitable consequence of adulticide therapy

• May be serious if disease is severe

• Symptoms:

– Fever

– Cough

– Hemoptysis

– Exacerbation of right heart failure

• Greatest risk is 7-10 days post adulticide injection

• Can occur as long as 4 weeks post injection

• Can occur in any dogs with heartworms at any time

• Treatment – CORTICOSTEROIDS , oxygen therapy


Adjunct Therapy

• Corticosteroids

– No decrease in efficacy of melarsomine as was seen with Caparsalate

– 0.5 mg/kg PO BID x 7 days, then 0.5 mg/kg PO SID x 7 days, then 0.5 mg/kg PO QOD x 7 doses

• NSAIDs/Aspirin

– aspirin for antithrombotic effect is not recommended

– Convincing evidence of clinical benefit is lacking and there is research suggesting that it may be contraindicated


Wolbachia spp.

• Obligate intracellular gram negative rickettsiae

• Surface antigens (WSP) produce a host IgG response

– Can in turn result in immune complex disease

• Doxycycline

– reduces Wolbachia numbers in all stages

– Doxycycline is lethal to L3s and L4s and reduces microfilaremia

– Reduces lung pathology in dogs treated with melarsomine

– Doxycycline treated L3 introduced into mosquitos did not mature into adults in infected dogs

– 10 mg/kg PO BID x 4 weeks

• 95% eliminated for at least 12 months


Melarsomine Only Pretreated Doxy & HWPrev


Adjunct Therapy

• Macrocyclic Lactones

– It takes 2-4 months for L3s to develop into L5s

– Melarsomine is not as effective for L5s as mature adult worms

– Pre-treating with macrocyclic lactones for 3 months prior to beginning the 3 injection protocol of melarsomine ensures that no L5s are present at the last melarsomine injection

• Also reduces or eliminates microfilariae


• Microfilaria test AND occult heartworm test should be performed 6-9 months post treatment

• Microfilaricide administered only if found

Positive Occult Test 6 months after Melarsomine

• Sometimes additional time is needed for all antigens to be cleared form the body

• Retest in 3-6 months prior to considering administration of additional melarsomine


Elective Surgery in HW+ dogs

• no increase in perioperative complications in heartwormpositive dogs with no to mild clinical signs of heartworm disease

• No surgery for 6 months post adulticide

• Well HW+ dogs that need to be spayed or neutered should have surgery prior to heartworm treatment

• Treatment with doxycycline and HWPrev prior to surgery is warranted, if possible

( AHS Heartworm Treatment Protocol )

Heartworm Disease

Basic Echocardiography

Additional Information

• Corticosteroids

• NSAIDs/Aspirin

• Macrocyclic Lactones

Elective Surgery in HW+ dogs

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Heartworm Disease

Basic Echocardiography

Additional Information

• Corticosteroids

• NSAIDs/Aspirin

• Macrocyclic Lactones

Elective Surgery in HW+ dogs

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