Canine Guidelines
[ pdf version ]
Contents
Prepared and approved by the Executive Board of the American Heartworm Society
Officers: Dr. Sheldon B. Rubin, President; Dr. Charles Thomas Nelson, Past President; Dr. Doug Carithers, Vice President; Dr. Wallace Graham, Secretary-Treasurer; Dr. Lynn F. Buzhardt, Dr. Stephen Jones, Dr. Julie Levy, and Dr. Robert Stannard, Board Members; Dr. Carol Robertson-Plouch, Symposium Chair; Dr. Byron Blagburn, Symposium Co-Chair; and Dr. John W. McCall, Editor; and Dr. Jorge Guerrero, Co-Editor
Preamble
These recommendations are based on the latest information presented at the 2007 Triennial Symposium of the American Heartworm Society (AHS), new research and additional clinical experience. Guidelines for diagnosis, treatment and prevention of
heartworm infection in cats are contained in a separate document.
Highlights
Diagnostics: AHS recommends annual testing for canine heartworms.
Chemoprophylaxis: AHS recommends year-round administration of
chemoprophylactic drugs to prevent heartworm disease, increase compliance
and control pathogenic and/or zoonotic parasites.
Adulticide therapy: AHS recommends use of the “alternate (three-injection)
protocol” for treatment of heartworm disease in both symptomatic and
asymptomatic dogs.
EPIDEMIOLOGY
Heartworm infection in dogs has been diagnosed around the
globe, including all 50 of the United States of America (USA).
In the USA, its territories and protectorates, heartworm is
considered at least regionally endemic in each of the contiguous
48 states, Hawaii, Puerto Rico, U.S. Virgin Islands and Guam.
Heartworm transmission has not been documented in Alaska;
however there are regions in central Alaska that have mosquito
vectors and climate conditions to support the transmission
of heartworms for brief periods. Thus, the introduction of
microfilaremic dogs or wild canids could set up a nidus of
infection for autochthonous transmission of heartworm in this
State. Such re-location of microfilaremic dogs and expansion of
the territories of microfilaremic wild canids in other areas of the
USA continue to be important factors contributing to further
dissemination of the parasite, as the ubiquitous presence of one or
more species of vector competent mosquitoes makes transmission
possible wherever a reservoir of infection and favorable climatic
conditions co-exist.
Environmental changes created by humans, changes in
natural climatic conditions, and animal movement have increased
heartworm infection potential. Commercial and residential real
estate development of non-endemic and low incidence areas
has led to the spread and increased prevalence of heartworms
by altering drainage of undeveloped land and by providing
water sources in new urban home sites. In the western USA,
irrigation and planting of trees have expanded the habitat for
Aedes sierrensis (western knot hole mosquito), the primary
vector for transmission of heartworms in those states. Aedes
albopictus (Asian tiger mosquito), which was introduced into
the southeastern United States in 1987, has now spread north
approaching Canada and has extended past the Rocky Mountains
to the west coast. This urban-dwelling mosquito is able to
reproduce in small containers such as flower pots. In the northern
half of the United States, urban sprawl has led to the formation
of “heat islands”, as buildings and parking lots retain heat during
the day and subsequently radiate it during the night. This can
potentially create microenvironments that support development
of heartworm larvae in mosquito vectors during colder months,
thus lengthening the transmission season.
As these vectors expand their territory the number of
unprotected animals infected will continue to increase. A pivotal
prerequisite for heartworm transmission is a climate that provides
adequate temperature and humidity to support a viable mosquito
population, and sustains sufficient heat to allow maturation of
ingested microfilariae to infective, third-stage larvae (L3) within
this intermediate host. It has been shown under laboratory
conditions in three mosquito species that maturation of larvae
within mosquitoes ceases at temperatures below 57ºF (14ºC)
and similar activity is expected in other mosquitoes capable
of transmitting heartworms. Heartworm transmission does
decrease in winter months but micro-environments commonly
present in urban areas virtually ensure that the risk of heartworm
transmission never reaches zero. Some species of mosquitoes
overwinter as adults. While heartworm larval development in
mosquitoes may cease in cool temperatures, development quickly
resumes with subsequent warming.
The length of the heartworm transmission season in the
temperate latitudes is critically dependent on the accumulation
of sufficient heat to incubate larvae to the infective stage in the
mosquito. The peak months for heartworm transmission in the
Northern Hemisphere are usually July and August. Models predict
that heartworm transmission in the continental USA is limited
to six months or less above the 37th parallel, i.e., Virginia-North
Carolina State line. Furthermore, predictive risk maps have
been produced coupling these basic models with Geographic
Information Systems (GIS) based on a thermal regimen and
information about mosquito vectors. While these model-based
predictions are academically appealing, they do not yet consider
several potentially important factors, such as the influence of microclimate and the unique biological habits and adaptations of
the numerous mosquito vectors on larval development.
Once a reservoir of microfilaremic domestic and wild
canids is established beyond the reach of veterinary care, the
ubiquitous presence of one or more species of vector competent
mosquitoes makes transmission possible and eradication becomes
improbable.
BIOLOGY AND LIFE CYCLE
The domestic dog and some wild canids are the normal
definitive hosts for heartworms and thus serve as the main
reservoir of infection. However, even less suitable hosts such
as cats and ferrets occasionally have low-level, transient
microfilaremias and therefore may serve as a source of infection
for mosquitoes during these short periods of microfilaremia.
The life cycle of D. immitis is relatively long (usually
7-9 months) compared with most parasitic nematodes. The
susceptible mosquito becomes infected when taking a blood
meal needed for egg development from a microfilaremic host.
The microfilariae develop to the third stage in the mosquito’s
malpighian tubules and then migrate via the body cavity to
the head and mouthparts of the mosquito where they become
infective. The time required for the development of microfilariae
to the infective stage in the mosquito is temperature-dependent.
At 27° C and 80% relative humidity, development takes about
10-14 days.
Infective, third-stage larvae (L3) are deposited in a droplet of
hemolymph (mosquito blood) on the host while the mosquito
is taking a blood meal. Immediately after the blood meal, these
sexually differentiated L3 enter the animal’s body via the puncture
wound in the skin made by the mosquito’s mouthparts. Three
days after experimental subcutaneous injection of the L3 in the
inguinal region of the dog, most of the larvae are found in the
subcutaneous tissues near their entry site. By day 21, most of the
larvae have migrated to the abdominal tissues of the dog, and
by day 41, they may be recovered from either the abdominal or
thoracic tissues. Apparently L3 and L4 travel between muscle
fibers during migration, whereas juveniles (immature adults)
penetrate muscle and eventually veins, transporting them toward
the heart and lungs. The molt from L3 to L4 begins as early as day
3 and ends as late as day 9-12. L4 molt to the final stage at day
50-70. Worms reach the pulmonary vasculature as early as day
70 and all have arrived by day 90-120. The first worms entering
the pulmonary vasculature on day 70-85 are 1-1.5 inches in
length. Thereafter the female worms will increase in length by
almost tenfold. They become sexually mature about day 120 post
infection. Dogs develop patent infections (i.e., have microfilariae
circulating in their blood) as early as 6 months but usually by 7-9
months post-infection.
When juvenile heartworms first reach the lungs, the blood
pressure forces them into the small pulmonary arteries. As they
grow and increase in size, they progressively occupy larger and
larger arteries until they become fully mature. The eventual
location of the mature adult worms appears to depend mainly
on the size of the dog and the worm burden. A medium-sized
dog (e.g., Beagle) with a low worm burden (i.e., 10) usually has
worms mainly in the lobar arteries and main pulmonary artery.
As the worm burden increases, worms are also located in the right
ventricle. Dogs with more than 40 worms are more likely to have
caval syndrome, where most of the worms migrate into the right
ventricle, right atrium and the caudal vena cava, thus interfering
with valvular function and/or blood flow.
A clear understanding of heartworm transmission,
development, prepatent period, and the susceptibility of the
different life stages to the parasite to available pharmaceutical
drugs is critical. This knowledge base is necessary to effectively
select the most appropriate adulticide treatment option and
treatment time, and to develop realistic expectations for the
veterinarian and client for the outcome of therapy.
PRIMARY DIAGNOSTIC SCREENING
Test Timing for Optimal Results
Currently available heartworm antigen tests detect protein
secreted mainly by adult female Dirofilaria immitis and the most
useful microfilaria tests concentrate microfilariae and allow for
more accuracy in identifying the filarial species. The earliest that
heartworm antigen and microfilariae can be detected is about
five and six months post-infection, respectively. Antigenemia may
precede, but sometimes lags the appearance of microfilariae by
a few weeks. Antigen may never be detected or only sporadically
detected in dogs with very low worm burdens. Also antigenemia
may be suppressed until about nine months post infection
in heartworm positive dogs placed on macrocyclic lactone
chemoprophylaxis. To determine when testing might become
useful, a predetection period should be added to the approximate
date on which infection may have been possible. A reasonable
interval is seven months. Thus, there is no need or justification
for testing a dog for antigen or microfilariae prior to about seven
months of age.
Microfilaria vs. Antigen Testing
Whether screening a population of asymptomatic dogs or
seeking verification of a suspected heartworm infection, antigen
testing is the most sensitive diagnostic method. Microfilaria testing is complementary and may be done in tandem with
antigen testing to specifically determine whether this life-cycle
stage is also present in dogs that are antigenemic. Even in areas
where the prevalence of heartworm infection is high, many
(~20%) heartworm-infected dogs may not be microfilaremic,
and this figure is even higher for dogs on a macrocyclic lactone
prevention program. The current generation of heartworm
antigen tests identify most “occult” (adult worms present but
no circulating microfilariae) infections consisting of at least one
mature female worm and are nearly 100% specific. Because less
than 1% of infections are patent but not antigenemic, testing only
for microfilariae is not recommended.
Antigen Tests
ELISA and immunochromatographic test systems are
available for detecting circulating heartworm antigen. Each
testing format has proved to be clinically useful. Differences in
sensitivity exist but are minor. False negative results also can
occur rarely with any one test, so unexpected negative results
should be followed by retesting with a different test. Specificity
is consistently very high with all the antigen tests, and this
is an important attribute. Selection of a test kit should not
be based solely on claims of comparative sensitivity, but also
should consider practice preference for “batching” multiple
(but separate) samples or individual, “in-room” sample testing,
technician capabilities, technical support, critical timing for
reading results, clarity of end result and unit cost.
The amount of antigen in circulation bears a direct, but
imprecise, relationship to the number of mature female
heartworms. A graded test reaction can be recognized by
ELISA test systems but quantitative results are not displayed by
immunochromatographic tests. The utility of the ELISA tests
for assessing the degree of parasitism is limited by confounding
complications such as the transient increase in antigenemia
associated with recent worm death or low antigen levels from
infections with young adult female worms and/or only a few
adult females. Therefore, quantitative analysis of antigen results
is highly speculative and requires correlation with other relevant
information. For example, radiographic evidence of advanced
pulmonary arterial disease typical of chronic heartworm disease
coupled with a low or absent antigenemia is consistent with the
aftermath of a previous infection that has been cleared, either
naturally or by treatment.
To obtain reliable and reproducible results, antigen tests
must be performed in strict compliance with the manufacturer’s
instructions. This has been simplified for several tests that use
devices that minimize the number of steps and partially automate
the procedure. False positive results can occur but usually are
due to technical error, such as inadequate washing steps or delay
in reading the test. If the validity of a weakly positive result is
in doubt, verification may be achieved by repeating the test and
if still ambiguous, independent confirmation by some other
means, such as a different antigen test format. Concentration
tests for microfilariae, thoracic radiography to detect signs of
heartworm disease or ultrasonographic visualization of worms
may also validate weakly positive antigen test results. In addition,
upon request, most test manufacturers will analyze ambiguous
samples in their own laboratories. In cases of minimal exposure,
it is recommended to confirm all positive antigen tests in
asymptomatic dogs prior to any adulticide therapy.
False-negative test results occur most commonly when
infections are light, female worms are still immature, only male
worms are present and/or the test kit instructions have not been
followed. Antigen test results should be interpreted carefully,
taking other relevant clinical information into consideration.
However, in general, it is better to trust rather than reject positive
antigen test results.
Microfilaria Tests
Most microfilaremic dogs can be detected by microscopically
examining fresh blood for microfilariae or cell movement created
by the motility of the microfilariae. A stationary rather than a
migratory pattern of movement is indicative of a Dirofilaria
species, nearly always D. immitis in the USA.
Movement beneath the buffy coat in a microhematocrit tube
also may be visible microscopically. However, these are insensitive
methods for examining blood in which low numbers (50-100/
ml) of microfilariae are present. Therefore, at least 1.0 ml of blood
should be examined using a concentration technique (modified
Knott test or filtration test) to determine the absence or presence
of microfilariae. The modified Knott test is the preferred method
for observing morphology and measuring body dimensions
to differentiate D. immitis from non-pathogenic filarial species
such as Acanthocheilonema (formerly Dipetalonema) reconditum.
Although screening may be based entirely on antigen testing,
antigen-positive dogs should also be tested for microfilariae,
because a microfilaremia validates the serologic results, identifies
the patient as a reservoir of infection and alerts the veterinarian
to potential severe reaction if administering a microfilaricide to a
dog with a high microfilarial count.
HEARTWORM CHEMOPROPHYLAXIS
Canine heartworm infection is preventable, despite the
inherently high susceptibility of dogs. Since dogs living in
heartworm endemic areas are at risk, chemoprophylaxis is a
high priority. Puppies should be started on chemoprophylaxis as early as possible, preferably no later than eight weeks of
age. Evidence strongly suggests that by reducing the reservoir
population through increasing the number of dogs receiving
chemoprophylaxis, a disproportionately large decrease in
the prevalence of infection among unprotected dogs may
occur relative to the percentage of additional dogs receiving
chemoprophylaxis. This collateral protection spreads the umbrella
of chemoprophylaxis most effectively in communities where
heartworm prevalence and dog population density are both
relatively low.
Even though continuous, year-round, transmission may
not occur throughout the country, year-round use of broadspectrum
chemoprophylaxis products with endoparasitic and/or
ectoparasitic activity during this extended period should enhance
compliance and assists in preventing pathogenic and/or zoonotic
parasitic infections.
Options for effective chemoprophylaxis include several drugs
administered either in oral, topical or parenteral formulations at
a monthly or six-month interval. Before starting a prophylactic
regime, all mature dogs that may have been infected for seven
months or longer should be antigen-tested, and in appropriate
instances, also tested for microfilariae (see PRIMARY DIAGNOSTIC
SCREENING). It is strategically important to determine heartworm
status before starting chemoprophylaxis for the first time in a
dog seven months of age or older. This will avoid unnecessary
delay in detecting sub-clinical infections and potential confusion
concerning effectiveness of the prevention program should
a pre-existing infection become evident after beginning
chemoprophylaxis (e.g. chemoprophylaxis initiated during the
pre-patent period).
Heartworm chemoprophylaxis requires authorization by
a licensed veterinarian having a valid relationship with the
client and patient. To establish this relationship, heartworm
prevention should be discussed with the client and if records of
past treatment and testing do not exist, it is advisable to test the
patient before dispensing or prescribing chemoprophylaxis.
Macrocyclic lactones
The most commonly used heartworm chemoprophylactics
are the macrocyclic lactones (ivermectin, milbemycin oxime,
moxidectin and selamectin). These drugs have excellent
therapeutic/toxic ratios and possess anthelmintic activity against
microfilariae, third- and fourth- stage larvae, and in some
instances of continuous use, young adult heartworms. The
filaricidal effect of oral and topical formulations on precardiac
larvae can be achieved by brief pulsing at low doses, which makes
these drugs virtually 100% effective when given following label
instructions and among the safest used in veterinary medicine.
All oral and topically administered macrocyclic lactone
chemoprophylactic products are labeled for a monthly dosing
interval. Thereafter, efficacy against late fourth-stage larvae
declines and is unpredictable. Juvenile worms, which can be
found as early as 52 days post infection, are even less susceptible
to chemoprophylaxis. As worms age, they require progressively
longer-term administration to achieve a high level of protection.
The extended post-infection efficacy of the macrocyclic lactones
is a partial safeguard in the event of inadvertent delay or omission
of regularly scheduled doses but does not justify lengthening the
recommended one month interval of administration for the oral
and topical formulations.
The extent of efficacy against late fourth-stage larvae and
juvenile worms has important implications for chemoprophylaxis
in dogs that have either missed doses during the transmission
season, or are already into the transmission season before
chemoprophylaxis is started and may already be infected. Short
lapses in administration may not result in mature infection,
particularly in areas where challenges are low and seasons when
transmission potential is lowest. However, lapses in medication
during the transmission period that exceed 4 weeks will increase a
dog’s risk of infection; therefore, continued monthly prophylaxis
throughout the year even in cooler climates has merit and may
provide substantial protection. In fact, dogs of some compliant
owners still become infected.
Some Collies and other p-glycoprotein deficient dogs are
unusually sensitive to a variety of commonly used veterinary
drugs. The macrocyclic lactones, the only chemical class of drugs
currently used for heartworm prevention, are included in this
list. This sensitivity was first seen with high doses of ivermectin
(in excess of 16 times the minimum effective prophylactic
dose) but toxicosis has been reported with overdosing of other
macrocyclic lactones as well. Often, these instances have occurred
when concentrated livestock preparations of these drugs have
been ingested. Dose miscalculation with extra-label use makes
livestock formulations hazardous for dogs. The standard
chemoprophylactic doses of medications specifically approved for
dogs have been shown to be safe in all breeds.
Oral administration: Ivermectin, milbemycin oxime and
moxidectin are available for monthly oral administration. Some
of these formulations are flavored and chewable to increase
patient acceptance and facilitate administration. Dose units
are packaged for dogs within prescribed weight ranges. To be
maximally effective, heartworm prophylaxis should be given
year-round, but if seasonal treatment is chosen, administration
should begin within one month of the anticipated start of
transmission and the last dose should be given until one month
after transmission ceases.
Topical administration: Moxidectin and selamectin are
available as a topically applied liquid. The parameters for
treatment with topical products are the same as for monthly oral
chemoprophylaxis.
Parenteral administration: A single dose of the slow-release (SR)
formulation of subcutaneously injected moxidectin-impregnated,
lipid microspheres provides continuous protection in excess of
six months. Moxidectin SR should be administered within one
month of exposure to infective mosquitoes. Treatment every
six months is recommended for maximal protection, but in
areas where the risk of infection is limited to five to six months,
a properly timed injection of moxidectin SR should provide a
comfortable margin of protection. This injectable formulation is
not approved in the USA for use in dogs younger than six months
of age.
Moxidectin SR was voluntarily removed from the U.S.
market in September 2004 for issues related to safety; however,
the product was not withdrawn from the market in other
countries. With the return of this product to the U.S. market
in June of 2008, the U.S. Food and Drug Administration put
certain restrictions in place. These restrictions are described in
a Risk Minimization Plan (RiskMAP) based on programs used
for human drugs. The RiskMAP is an educational program for
veterinarians that covers the risks and benefits of the drug and
provides information about the product to pet owners. The
effort includes comprehensive veterinarian training, pet owner
education and consent forms, and specific requirements for the
purchase and administration of the product.
Reports of Lack of Efficacy
Lack of efficacy (LOE) of a heartworm preventive product
is defined by the Center for Veterinary Medicine of the Food
and Drug Administration (FDA) in the USA as a dog testing
heartworm positive while consistently receiving heartworm
prevention. There are many possible reasons for reports of LOE,
including failure to administer sufficient preventive, failure to
administer the preventive at the appropriate time interval, failure
of a dog to retain a dose and failure of absorption of active
ingredient. There is also biological variation in how hosts within
the same species metabolize a drug as well as how parasites
respond to a drug. Thus, the exact cause of a reported LOE of a
product is extremely difficult to determine.
Most LOE claims can be explained by compliance issues,
either between the clinic and the client or the client and the
pet. It is possible for an animal to become infected by missing
or receiving a delayed administration of just one dose of a
heartworm preventive product. The likelihood of this occurring
is increased in endemic areas where infection challenges are
exceptionally high when compared with other sections of the
USA. Highly endemic areas typically have warm temperatures
most of the year, an abundance of standing water and substantial
mosquito populations. Many of these areas also have large
populations of wild canids, with most of the animals infected
with heartworms providing a large reservoir of infection.
In addition, manufacturers have improved the sensitivity of
heartworm antigen tests during the past decade and more animals
with low female worm burdens are now being detected.
The increase in the number of LOE reports to the FDA during
the past several years has lead to concerns of possible heartworm
resistance to the current heartworm preventives. First, it is
important to understand that parasites do not become resistant
to drugs, but rather, product use under specific conditions
inadvertently selects worms with resistance genes. These
populations of surviving worms are called resistant strains. Some
conditions are known to favor the selection of resistant strains,
as occurs with trichostrongylid nematodes of small ruminants
and with horn flies. Limited refugia (i.e., worms with wild-type
genes), a direct life cycle, treatment of entire groups of confined
individuals, and the presence of heavy parasites burdens reduce
the refugia and support the concentration of selected, resistant
genes. Thus, the shorter the life cycle of the parasite, the more
rapidly the resistant-gene-selection process proceeds.
If we examine heartworm infection using the same selection
factors, we see a converse scenario. Factors such as a long life
cycle, relatively light worm burden, an indirect life cycle with
mosquitoes as vectors, a large refugia of infected but untreated
pets and wild canids that roam freely throughout their territories,
treatment of dogs singly rather than in large groups, and pets
that travel widely with their owners do not favor the selection
of resistant strains. The epidemiology, treatment patterns and
abundance of refugia of parasites such as heartworms ensures
the wide distribution of large populations of heartworms that are
not under strong selection pressure, and their wild-type genes
serve to dilute any resistance genes that exist in geographically
different worm populations. These conditions greatly decrease
the likelihood of widespread emergence of resistant heartworm
strains and any resistant strain would likely remain localized.
Professional and client education are perhaps the most
important factors to consider in addressing the reports of
apparent lack of efficacy of preventive products. The complex
biology of the parasite, the effect of changing environmental
conditions that affect vector populations, the dynamics of host
(wild and domestic) populations, and even the dynamics of
human interactions with their pets are also relevant. In the face of the many variable factors, it is critical that veterinary
practices ensure that clients understand the risk of heartworm
infection in their area and provide their pets with appropriate
heartworm prevention, i.e., consistent year-round administration
of preventives.
TESTING CONSIDERATIONS:
ANNUAL TESTING AND RETESTING
Annual testing is an integral part of ensuring that prophylaxis
is achieved and that more timely treatment can be provided to
dogs that test positive in order to minimize pathology.
Testing Considerations Following
Noncompliance and When Changing Products
In instances of noncompliance or changing the brand or
type of heartworm preventive, it is important to first ensure
that the dog is free of heartworm infection. The dog should be
tested prior to starting or changing products. A positive test at
this time indicates earlier infection. Typically, most practitioners
retest at six months to coincide with refilling prescriptions and
performing semiannual exams. A positive antigen test at this
time is most likely due to an infection acquired before starting or
resuming preventive therapy; however, in rare instances, existing
infection may be missed (i.e., false negative test due mainly to
young- or low-worm-burden infection). Therefore, subsequent
antigen testing should be performed on the one-year anniversary
date of the initial test and annually thereafter.
If a practitioner wants to more precisely determine if a dog
is infected when starting, resuming, or changing any preventive
therapy, testing can be performed at this time and again four
months later. When one considers that an antigen test may be
positive as early as five months after infection and most dogs
are positive by nine months after infection, a positive antigen
test before dosing is started (or resumed) and/or four months
later clearly indicates that the dog was infected prior to initiating
(or resuming) dosing or changing products. However, it is
important to note that a negative antigen test at four months is
highly supportive but does not ensure that a dog was negative for
heartworms at the time of starting, resuming or changing any
preventive therapy. To minimize the potential for a false-negative
test at four months, a second antigen test can be performed one to
five months later. A positive antigen test at this later time cannot
be unequivocally attributed to earlier or later infection; however,
the earlier in this five-month period the test is positive, the more
likely infection was acquired prior to initiating (or resuming)
dosing or changing products.
Testing of Dogs on Macrocyclic Lactone
Preventives
Consistent macrocyclic lactone (ivermectin, milbemycin
oxime, moxidectin or selamectin) chemoprophylaxis will
eventually clear microfilariae from the blood of most dogs with
patent infections. This is achieved by the drugs’ ability to exert a
direct or indirect microfilaricidal effect, depending on the specific
product used, and retard repopulation by gradually suppressing
embryogenesis. Consistent dosing will usually eliminate
microfilariae within six to 12 months of oral dosing with monthly
macrocyclic lactones or one month following moxidectin SR
injection. In the event a pre-existing prepatent infection matures
after starting macrocyclic lactone chemoprophylaxis, microfilariae
are unlikely to be found, or appear only transiently in small
numbers. Since macrocyclic lactone chemoprophylaxis may
negate microfilaria testing and microfilariae do not contribute
to heartworm antigenemia, antigen testing is the most reliable
method of retesting.
OTHER DIAGNOSTIC AIDS
Additional testing methods are useful for confirming the
diagnosis and staging the severity of heartworm disease.
Radiography
Radiography provides the most objective method of assessing
the severity of cardiopulmonary disease secondary to heartworm
infection. Typical (nearly pathognomonic) signs of heartworm
vascular disease are enlarged, tortuous, and often truncated
peripheral intralobar and interlobar branches of the pulmonary
arteries, particularly in the diaphragmatic (caudal) lobes. These
findings are accompanied by variable degrees of pulmonary
parenchymal disease. The earliest and most subtle pulmonary
arterial changes are most commonly found in the dorsal caudal
wedge of the diaphragmatic lung lobes. As the severity of
infection and chronicity of disease progress, the pulmonary
arterial signs are seen in successively larger branches. In the worst
cases, eventually the right heart enlarges.
Echocardiography
The body wall of adult heartworms is highly echogenic
and produces distinctive, short parallel-sided images with the
appearance of “equal signs” where the imaging plane cuts across
loops of the parasite. Echocardiography can provide definitive
evidence of heartworm infection, as well as allow for assessment
of cardiac anatomic and functional consequences of the disease.
However, it is not an efficient method of making this
diagnosis, particularly in lightly infected dogs, since the worms
often are limited to the peripheral branches of the pulmonary arteries beyond the echographic field of view. When heartworms
are numerous, they are more likely to be present in the main
pulmonary artery, right and proximal left interlobar branches or
within the right side of the heart where they can be imaged easily.
In dogs with hemoglobinuria, visualization of heartworms in the
orifice of the tricuspid valve provides conclusive confirmation of
caval syndrome.
PREADULTICIDE EVALUATION
The extent of the preadulticide evaluation will vary depending
on the clinical status of the patient and the likelihood of coexisting
diseases that may affect treatment outcome. Clinical
laboratory data should be collected selectively to complement
information obtained from a thorough history, physical
examination, antigen test and usually thoracic radiography.
The most important variables influencing the probability of
post-adulticide thromboembolic complications and the outcome
of treatment are the extent of concurrent pulmonary vascular
disease, the severity of infection and the activity level of the
dog. Assessment of cardiopulmonary status is indispensable
for evaluating a patient’s prognosis. Post-adulticide pulmonary
thromboembolic complications are most likely to occur in heavily
infected dogs already exhibiting clinical and radiographic signs
of severe pulmonary arterial vascular obstruction, especially if
congestive heart failure is present.
Although a very crude method of assessing the severity of
infection, the strength of ELISA-based antigen test reactions
may provide an indication of whether an infection is light or
heavy (see Antigen Tests). Since radiographic signs of advanced
pulmonary vascular disease may persist long after an infection
has run its course, some of the most severely diseased dogs may
have disproportionately low levels of circulating antigen by the
time they are tested. Also some inactive dogs can have large
worm burdens and be clinically asymptomatic with minimal
radiographic changes.
PRINCIPLES OF TREATMENT
Successfully treating heartworm disease in asymptomatic
patients or those exhibiting signs of mild disease usually is
straightforward, but occasionally can be demanding. Those
with moderate or severe heartworm disease or patients with
concurrent disease are especially challenging (See SUMMARY OF CLINICAL SIGNS OF CANINE HEARTWORM DISEASE).
The goals of any heartworm treatment are to improve the
clinical condition of the animal and to eliminate all life stages
of the heartworms (microfilariae, larval stages, juveniles and
adults) with minimal post-treatment complications. Dogs
exhibiting significant clinical signs of heartworm disease should
be stabilized before administering an adulticide. This may require
administration of glucocorticosteroids, diuretics, vasodilators,
positive inotropic agents and fluid therapy.
A thorough understanding of the host–parasite relationship
is necessary to effectively manage heartworm cases. As expected,
the number of worms has an effect on the severity of disease,
but of equal, if not greater, importance is the activity level of the
dog. Controlled studies have shown that dogs infected by surgical
transplantation with 50 heartworms and exercise-restricted took
longer to develop clinical disease and developed less pulmonary
vascular resistance than dogs with 14 heartworms that were
allowed moderate activity. This was also evident in naturally
infected dogs where there was no correlation between the number
of heartworms and pulmonary vascular resistance and is an
indication that the host-parasite interaction plays a significant
role in the severity of disease. A subsequent study reported similar
findings in dogs being treated with melarsomine.
Whereas live heartworms can cause endarteritis and muscular
hypertrophy of arteriole walls especially in the caudal pulmonary
arteries, dying and dead heartworms cause a significant portion
of pathology seen in clinical disease. As worms die from either
natural causes or as a result of administration of adulticidal
drugs, they decompose and small worm fragments lodge in
the distal pulmonary arteriole and capillary beds in the caudal
lung lobes blocking blood flow. These worm fragments along
with the elicited inflammation and platelet aggregation result
in thromboembolisms. During periods of increased activity
or exercise, the increased blood flow to these blocked vessels can cause capillary delamination, rupture and subsequent
fibrosis. This leads to increased pulmonary vascular resistance
and potential right-sided heart failure. This illustrates a direct
correlation between the activity level of the dog and the severity
of disease.
ADULTICIDE THERAPY
Melarsomine Dihydrochloride
Melarsomine, administered via deep intramuscular injection
into the belly of the epaxial lumbar muscles, is the only adulticidal
drug approved by the FDA for heartworm treatment. Mild
swelling and some soreness at the injection site may be present
for a few days, but this can be minimized by ensuring that
the injection is deposited deeply with a needle of appropriate
length and gauge for the size of dog and body condition. Strictly
adhering to the manufacturer’s instructions for administration
is imperative. Exercise restriction during the recovery period is
essential for minimizing cardiopulmonary complications (see
Pulmonary Thromboembolism).
Melarsomine has not been shown to have any activity against
worms less than 4 months old. The two-injection protocol (i.e.,
two injections of 2.5 mg/kg body weight 24 hours apart) listed
on the product insert for treating class 1 & 2 heartworm disease
kills only about 90% of the adult worms. The three-dose alternate
protocol (one injection of 2.5 mg/kg b. wt. followed at least one
month later by two injections of the same dose 24 hours apart)
listed for treating class 3 heartworm disease kills 98% of the
worms. These overall efficacy values reflect the percentage of
worms killed in groups of dogs and not the percentage of dogs
cleared of worms, which are considerably lower than these
overall efficacy values.
Staging of the disease and use of the two-injection protocol
has failed to adequately ensure treatment success. Therefore,
regardless of the stage of the disease, the three-injection
alternative protocol is the treatment of choice of the American
Heartworm Society and several university teaching hospitals,
due to the increased safety and efficacy benefits and decreased
possibility that further treatment with melarsomine would be
necessary. Furthermore, by initially killing fewer worms and
completing the treatment in two stages, the cumulative impact of
worm emboli on severely diseased pulmonary arteries and lungs
is reduced.
ADJUNCT THERAPY
Macrocyclic Lactones
It is highly probable that a heartworm-positive dog has
heartworms ranging in age from less than one month to as much
as seven years old. Melarsomine’s lack of efficacy against stages
less than four months old presents a problem in achieving the
goal of eliminating all of the worms. The figure below illustrates
the susceptible and non-susceptible ages of heartworms to
macrocyclic lactones and melarsomine based upon the age of the
worm in days (See figure TIMELINE).
This gap can be eliminated by administering a macrocyclic
lactone preventive for two to three months prior to administering
melarsomine. This will eliminate the migrating larvae less than two months old and allow those worms between two and four
months of age to reach an age at which they are susceptible to
melarsomine.
While controversial due to the theoretical risk of selecting
heartworm populations that are resistant to macrocyclic lactones,
it is beneficial to administer a macrocyclic lactone for up to three
months prior to administration of melarsomine, when the clinical
presentation does not demand immediate intervention. The logic
for this approach is to kill susceptible heartworm larvae and thus
prevent re-infection of the dog, while allowing less susceptible
juvenile worms, the opportunity to develop into more susceptible
adult worms. This tactic increases the chance for removal of the
existing heartworm infection when the adulticide injections are
given later. Additional benefits of this protocol are the effects
of macrocyclic lactones in greatly reducing, if not eliminating
circulating microfilariae, stunting immature D. immitis and
reducing female worm mass by compromising the reproductive
system. Administration for two to three months should result in
reduced antigenic mass, which in turn may reduce the severity of
pulmonary thromboembolism.
Exercise restriction should be enforced from the time of
heartworm diagnosis through the period of treatment and
recovery, with the most extreme degree of exercise restriction
recommended for the first four weeks following melarsomine
administration. Macrocyclic lactones administered as
microfilaricides may cause a rapid decrease in the numbers of
microfilariae and should be used with caution in dogs with
high microfilarial counts. Pretreatment with antihistamines and
glucocorticosteroids will minimize potential reactions.
Doxycycline
Many filarial nematodes, including D. immitis, harbor
obligate, intracellular, gram-negative bacteria belonging to the
genus Wolbachia (Rickettsiales). In infections with other filarial
parasites, treatment with tetracyclines during the first month of
infection was lethal to some Wolbachia-harboring filariae, but
not to a filariae that did not harbor Wolbachia, and treatment of
Wolbachia-harboring filariae suppressed microfilaremia. Similar
prophylaxis studies with D. immitis have not been reported,
but in one study, tetracycline treatment of heartworm-positive
dogs resulted in infertility in the female worms. These bacteria
also have been implicated in the pathogenesis of filarial diseases,
possibly through their endotoxins. Recent studies have shown
that a major surface protein of Wolbachia (WSP) induces a
specific IgG response in hosts infected by D. immitis. It is also
hypothesized that Wolbachia contribute to pulmonary and renal
inflammation through its surface protein WSP independently
from its endotoxin component. Doxycycline is now being
evaluated in humans for possible use in the treatment of several
filarial diseases and has been the subject of several studies in heartworm treatment. Studies have shown that heartworm
positive dogs pretreated with ivermectin and doxycycline prior to
receiving melarsomine injections had less pulmonary pathology
associated with the death of the heartworms.
If doxycycline is incorporated into a heartworm treatment
protocol it should be given before administration of melarsomine
so the Wolbachia organisms and their metabolites are reduced
or absent when the worms die and fragment. Doxycycline
administered at 10mg/kg BID for four weeks has been shown to
eliminate over 90% of the Wolbachia organisms and the levels
remain low for three to four months.
ALTERNATIVE THERAPIES
Long-term Macrocyclic Lactone Administration
Continuous monthly administration of prophylactic doses of
ivermectin, moxidectin and selamectin is effective in reducing the
life span of juvenile and adult heartworms. The older the worms
when first exposed to macrocyclic lactones, the slower they are
to die. So, the adulticidal effect of macrocyclic lactones generally
requires more than a year of continuous monthly administrations
and may take more than two years before adult heartworms are
eliminated completely. In the meantime, the infection persists
and continues to cause disease. Therefore, long-term continuous
administration of macrocyclic lactones generally is not a
substitute for conventional arsenical adulticide treatment.
If arsenical therapy is declined, a lengthy course of
prophylactic doses of aforementioned macrocyclic lactones
will gradually reduce the number of adult heartworms. Should
long-term macrocyclic lactone administration be considered for
heartworm-positive dogs, exercise should be greatly restricted and
the dog should be examined by a veterinarian at least once every
four to six months until confirmed to be free of heartworms.
The results of a recent study in which monthly ivermectin
was administered to client-owned heartworm infected dogs for
two years indicated that this method of killing adult heartworms
should not be used in dogs with signs of heartworm disease or
very active dogs. As worsening of radiographic signs may be
observed, periodic radiographic evaluations may be useful in
monitoring the treatment. Another concern in using macrocyclic
lactones long-term in heartworm positive dogs as standalone
therapy is selection of resistant strains of heartworms.
Ivermectin/Doxycycline
In cases where arsenicals are contraindicated and the animal’s
overall condition makes standard adulticidal therapy impractical,
the use of a monthly ivermectin-based heartworm preventive
along with doxycycline could be considered. It has been reported
that ivermectin and doxycycline administered periodically over
36 weeks resulted in a 78% reduction in adult worm numbers.
Moreover, microfilariae from dogs treated with doxycycline that
were ingested by mosquitoes developed into third-stage larvae
that appeared to be normal in appearance and motility, but these
larvae were not able to develop into adult worms, thus negating
the risk of selecting for resistant strains. The administration of
doxycycline at 10 mg/kg BID for a 4 week period every three to
four months should eliminate most Wolbachia organisms and not
allow them to repopulate.
Herbal Therapies
No “natural” or herbal therapies that have been shown to be
safe and effective treatment for heartworm disease.
Pulmonary Thromboembolism
Pulmonary thromboembolism is an inevitable consequence
of successful adulticide therapy and may be severe if infection
is heavy and pulmonary arterial disease is extensive. If signs of
embolism (low grade fever, cough, hemoptysis, exacerbation of
right heart failure) develop, they are usually evident within 7 to
10 days, but occasionally as late as four weeks after completion
of adulticide administration. Mild embolism in relatively healthy
areas of lung may be clinically inapparent. A pivotal factor in
reducing the risk of thromboembolic complications is exercise
restriction during the critical month following the first injection
and then again after the second/third injections.
Steroids
Administration of diminishing anti-inflammatory doses of
glucocorticosteroids helps control clinical signs of pulmonary
thromboembolism. Whereas studies showed a decrease in efficacy
of the arsenical thiacetarsamide when glucocorticosteroids
were administered, no such problem has been reported with
melarsomine. In highly endemic areas where animals are likely
to have significant worm burdens, the use of prednisone is
advocated by many clinicians. It is routinely dosed at 0.5mg/kg
BID for the first week and 0.5mg/kg SID for the second week,
followed by 0.5mg/kg every other day for 1 to 2 weeks.
NSAIDS/Aspirin
The empirical use of aspirin for its antithrombotic effect or to
reduce pulmonary arteritis is not recommended for heartworminfected
dogs. Convincing evidence of clinical benefit is lacking,
and there is some research suggesting that aspirin may be
contraindicated.
SURGICAL EXTRACTION OF ADULT
HEARTWORMS
Caval Syndrome (Dirofilarial Hemoglobinuria)
Caval syndrome develops acutely in some heavily infected
dogs when adult heartworms partially obstruct blood flow
through the tricuspid valve and also interfere with valve
closure. Severe passive congestion of the liver, a coarse systolic
murmur of tricuspid regurgitation and jugular pulsations are
characteristic features of the syndrome. The diagnosis is based
on a sudden onset of severe lethargy and weakness accompanied
by hemoglobinemia and hemoglobinuria. Caval syndrome can
be confirmed conclusively by echocardiographic visualization of
heartworms within the tricuspid orifice and posterior vena cava.
The clinical course usually ends fatally within two days, if surgical
extraction of the worms is not pursued promptly.
Surgical removal of worms from the right atrium and orifice
of the tricuspid valve can be accomplished using light sedation
(may not be necessary), local anesthesia and either a rigid or
flexible alligator forceps or an intravascular retrieval snare
introduced preferentially via the right external jugular vein.
With fluoroscopic guidance, if available, the instrument should
be passed until worms can no longer be retrieved. Immediately
following a successful operation, the murmur should soften or
disappear, and within 12 - 24 hours hemoglobinuria should
disappear. Fluid therapy may be necessary in critically ill,
hypovolemic dogs to restore hemodynamic and renal function.
Within a few weeks following recovery from surgery, adulticide
chemotherapy is recommended to eliminate any remaining
worms, particularly if many are still visible echocardiographically.
Pulmonary Arterial Infections
The main pulmonary artery and lobar branches can be
accessed with flexible alligator forceps, aided by fluoroscopic
guidance. Intraoperative mortality with this technique is very
low. Overall survival and rate of recovery of dogs at high risk
of pulmonary thromboembolism is improved significantly
by physically removing as many worms as possible before
beginning adulticide therapy. When the facilities are available,
worm extraction is the procedure of choice for the most heavily
infected and high risk dogs. However, before electing this method
of treatment, echocardiographic visualization of the right heart
and pulmonary arteries should be performed to determine that a
sufficient number of worms are in accessible locations.
CONFIRMATION OF ADULTICIDE EFFICACY
Clinical improvement is possible without completely
eliminating the adult heartworms. Worms that do survive
adulticide treatment are invariably the antigen-producing
females. Most microfilaremic dogs with post-adulticide, female
unisex infections become occult within six to nine months,
with or without microfilaricide treatment, and particularly if
they are on a macrocyclic lactone preventative during and after
adulticidal therapy. Consequently, clinical improvement and
successful clearance of microfilariae from the blood do not verify
a complete adulticide effect. Recurrence of microfilaremia six
months later may be due to incomplete clearance of adult worms,
maturation of immature worms if a preventive was not given
during adulticide therapy or a new infection due to a lapse in
chemoprophylaxis.
Heartworm antigen testing is the most reliable method of
confirming the efficacy of adulticidal therapy. If all of the adult
female worms have been killed, heartworm antigen should
become undetectable by six months post-treatment. However,
this single test result does not verify that the dog is negative
for heartworms, as larval and/or juvenile heartworms may be
present in the dog and an insufficient amount of antigen is
being produced by these young worms to elicit a positive test
result. This is especially critical if a macrocyclic lactone was not
administered prior to or initiated concurrently with adulticidal
therapy. If a heartworm-positive dog is immediately treated
with adulticide and a macrocyclic lactone is not given until three
to four weeks after the last dose of adulticide, the dog should
have a negative antigen test seven months after the initial dose
of macrocyclic lactone before being considered cleared of adult
worms.
Since adult worms may continue to die for more than a
month following adulticide administration, dogs that are still
antigenemic at any time less than six months post-treatment
should be allowed more time to clear antigen before retreatment
is considered. The health risk of a few residual heartworms
should be assessed on an individual case basis, since complete
elimination does not assure further clinical improvement. Factors
to consider before electing retreatment are the general health of
the patient, age in relation to life expectancy, and the performance
expectations for the dog. Before committing to retreatment there
should be a strong expectation that additional benefit will be
achieved.
ELIMINATION OF MICROFILARIAE
No drugs are approved currently as microfilaricides by the
U.S. FDA. However, under the Animal Medicinal Drug Use
Clarification Act of 1994, licensed veterinarians are permitted
extra-label use of certain drugs having an established clinical
application, if a valid veterinarian-client-patient relationship
exists. The dispensing veterinarian is personally responsible
for ensuring administration of the proper dose and providing
appropriate aftercare when products are used in an extra-label
application. The use of monthly administered heartworm
chemoprophylactics as microfilaricides is governed by this
regulation.
Prior to the introduction of the macrocyclic lactones,
elimination of circulating microfilariae was the second step in
the stage-specific sequential treatment (adult, microfilariae,
and precardiac larvae) of heartworm infection. Microfilaricidal
treatment was usually done about three weeks after adulticidal
therapy, with the understanding that several weekly treatments
were often required to completely eliminate circulating
microfilariae. The macrocyclic lactones are the safest and
most effective drugs for eliminating microfilariae to date. All
are effective at the prescribed prophylactic doses. It is both
unnecessary and dangerous to use livestock preparations of these
drugs to achieve higher doses for the purpose of achieving more
rapid results. Today, the broad life-cycle filaricidal activity of
the macrocyclic lactones has generally reduced microfilaricide
treatment to a by-product of chemoprophylaxis. Administration
of a macrocyclic lactone should begin as soon as the dog is
diagnosed with a heartworm infection.
Of the products formulated for dogs, milbemycin oxime is
the most potent microfilaricide at its label dose and produces the
most rapid rate of clearance. If prompt termination of a dog’s
reservoir potential following adulticide treatment is considered
important, this can be achieved most rapidly with milbemycin
oxime. Monthly administered macrocyclic lactones allow
the flexibility of shortening the customary intervals between
14
treatments (perhaps to two weeks) in order to accelerate removal
of microfilariae. Regardless of the method used for clearing
microfilariae, the rapid death of large numbers of microfilariae
during the early elimination phase, 4-8 hours following the first
dose, can cause systemic side effects such as lethargy, inappetence,
salivation, retching, defecation, pale mucous membranes and
tachycardia. If reactions occur, most are transient and the signs
usually are too innocuous to be appreciated. Occasionally,
however, a dog with microfilaremia as low as 5000 mf/ml develops
acute circulatory collapse. Prompt treatment with parenteral
fluids and one or two shock therapy doses of glucocorticosteroids
is usually an effective antidote. Close observation of higher risk
dogs is advised for the first 8-12 hours following administration
of microfilaricidal drugs at doses that produce a rapid reduction
in circulating microfilariae. This precaution becomes unnecessary
for subsequent doses, since the pool of microfilariae will have
been depleted below the critical level.
When elimination of microfilariae is accomplished in the
course of heartworm chemoprophylaxis, a microfilaria test
should be performed in adulticide-treated dogs at the time the
antigen test is conducted six months post-treatment. Controlling
the spread of heartworms entails decreasing the microfilaremic
reservoirs of infection in the dog population and the benefits of
doing so have been cited (see HEARTWORM CHEMOPROPHYLAXIS).
These guidelines are based on the latest information on heartworm disease and the available treatments. In keeping with the objective of
the Society to encourage adoption of standardized procedures for the diagnosis, treatment and prevention of heartworm disease, they will
continue to be updated as new knowledge becomes available.
These guidelines have been peer reviewed by independent experts.
