Heartworm Disease

Report
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
Heartworm Disease
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 Disease
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
Heartworm Disease
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
Heartworm Disease
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 Disease
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
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
Lack of Efficacy (LEO) of HW Prevention
• Most are explained by compliance failure
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–
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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 Disease
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
Heartworm Disease
Heartworm Resistance
• 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
Heartworm Disease
Heartworm 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
Heartworm Disease
Heartworm Resistance
LMIA (Larval Migration Inhibition Assays)
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
Heartworm Disease
Heartworm Resistance
LMIA (Larval Migration Inhibition Assays)
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%
Heartworm Disease
“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”
Heartworm Disease
“Slow Kill” Heartworm Treatment
• 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.
Heartworm Disease
“Slow Kill” Heartworm Treatment
• 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
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
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 (104Fo) 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
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
Modified Knott Test
• Acanthocheilonema reconditum
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Formerly Dipetalonema reconditum
Blunt head
Smaller – 250-290 um
Curved tail
• Dirofilaria immitis
– Tapered head
– Larger – 300-325 um
– Straight tail
Heartworm Disease
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
Heartworm Disease
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
Heartworm Disease
Moderate Heartworm Disease
Heartworm Disease
Moderate Heartworm Disease
Heartworm Disease
Severe Heartworm Disease
Heartworm Disease
Severe Heartworm Disease
Heartworm Disease
Assessing Severity of Disease
Summary of Clinical Signs of Heartworm Disease
Mild (Class 1)
Asymptomatic or cough
Moderate (Class 2)
Cough, exercise intolerance, abnormal lung sounds
Severe (Class 3)
Cough, exercise intolerance, dyspnea, abnormal
heart and lung sounds, hepatomegaly, syncope,
ascites, death
Caval Syndrome
(Class 3)
Sudden onset of severe lethargy and weakness,
anemia, hemoglobinemia and hemoglobinuria
Heartworm Disease
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
Heartworm Disease
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
Heartworm 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
Heartworm Disease
Pulmonary Thromboembolism
• An inevitable consequence of adulticide therapy
• May be serious if disease is severe
• Symptoms:
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•
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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
Heartworm Disease
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
Heartworm Disease
Wolbachia spp.
• Obligate intracellular gram negative rickettsiae
• Surface antigens (WSP) produce a host IgG response
– Can in turn result in immune complex disease
• Doxycycline
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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
Heartworm Disease
Melarsomine Only
Pretreated Doxy & HWPrev
Heartworm Disease
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
Heartworm Disease
• 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
Heartworm Disease
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)

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