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InFocus

Emerging issues in
heartworm disease
DVMs face emerging problems and issues with the development
of newer drugs, diagnostic methods and pet-owner awareness
By Byron L. Blagburn, Ph.D. now available for in clinic use.Possible dis-
CONTRIBUTING AUTHOR crepancies between traditional methods
anine and feline heart- such as microfilariae detection and antigen

C
worm diagnostic or antibody test results can lead to some
methodologies as well confusion regarding the actual infection sta-
as treatment and pre- tus of certain pets.In this article,I will briefly
vention strategies have discuss some of these issues.My purpose is
changed considerably to draw attention to these emerging issues
during the previous decade.We have expe- so that veterinarians can better deal with
rienced an unprecedented increase in num- problems that result from them.I also will
bers and kinds of available medications and discuss human heartworm infections.Lit-
diagnostic aids, and the capabilities of pet tle has been written about this uncommon,
owners to acquire information of both a but important, issue.
technical and lay nature. This can be both
beneficial and detrimental in our efforts to
establish and maintain effective strategies  Diagnostic challenges
for controlling heartworm infections. confronting veterinarians
Beneficial because pet owners have be- Widespread use of macrolide heartworms
come more aware of the potential dangers preventatives such as ivermectin, milbe-
of heartworm infections and because avail- mycin oxime, moxidectin and selamectin
able treatment and prevention products (see Table 1, p. 49) has had a profound ef-
have become more effective and con- fect on the numbers of heartworm-infected
Photo 1: Heavy venient to use.Detrimental because dogs seen by veterinarians. Reductions in
worm burdens are much misinformation can be com- the number cases of clinical canine heart-
seen less frequently municated through e-mail and Web worm infections are even more dramatic.
in heartworm
infected dogs sites dealing with heartworm.Addi- The excellent efficacies of the medications,
because of the tionally,the activities of newer aver- together with the convenience of monthly
widespread use mectins and milbemycins against or semi-annual administration has almost
of preventatives. microfilariae and larval heartworms, eliminated heartworm infection in some
and even demonstrated activity under areas — or so it seems (see Photo 1).
certain circumstances against adult stages With these enhanced efficacies come
of heartworms,add additional possibilities some additional problems. Failure to ad-
to veterinarians’choices in developing and minister these medications regularly or at
implementing control strategies.The same appropriate doses can result in heartworm
can be said for immuno-diagnostic assays infections. However, these infections gen-

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InFocus
worm tests on test attributes other than these excellent products and diagnostic
sensitivity and specificity.Examples of other aids to their full potential.
attributes include:
Photo 2: Infections 1) need to process single
with Dipetalonema vs. multiple simultaneous  Emerging issues in treating
reconditum (right)
result in detectable samples (batching); heartworn infections
circulating 2) ease of conduct of the For many years, the only adulticidal
microfilariae simi- test (i.e. number of steps, organoarsenical compound available to vet-
lar to those of D. reagents, etc.); erinarians was thiacetarsamide sodium.The
immitis (left) but a 3) ease of visualization of approval and marketing of melarsomine
negative heart-
erally involve fewer numbers of worm antigen test. results (brightness of line or dihydochloride led to the eventual disap-
worms — sometimes too few dot,or liquid color change); pearance of thiacetarsamide from the mar-
worms to detect. Fewer worms also mean 4) time required to conduct the test; ketplace.Melarsomine provides the veteri-
an increased possibility of single-sex infec- 5) cost per test. narian with a product with improved effi-
tions and failure of worms to produce de- Most of the immuno-ELISA and im- cacy,safety and ease of administration com-
tectable microfilariae. We also now know muno-chromatographic tests that are cur- pared to its predecessor. Melarsomine was
that the macrolide preventatives will,to vary- rently marketed would score well when introduced with a unique flexible dosing
ing degrees,reduce or eliminate circulating these criteria are applied to them.An un- regimen that was correlated to the clinical
microfilariae from infected dogs (see Photo derstanding of situations that today’s di- condition of the heartworm-infected dog.
2). Consequently, detection of microfilar- agnosis and prevention environments can Dogs that are asymptomatic or in the
iae no longer can be considered as reliable create is essential if veterinarians are to use Continued on next page 
a means of diagnosis as it once was.
Although point-of-care heartworm anti- Table 1:
gen tests have become increasingly sensi-
Selected heartworm preventatives
tive and rigorously specific,the lower worm approved for use in dogs or cats.
burdens likely to occur in infected dogs
Anthelmintic(s) Proprietary Regimen Target Pet Target
seen by veterinarians can even challenge
Name (Formulation) Animal Parasites†
the performance capabilities of these tests.
®
Other phenomena such as fluctuating anti- Diethylcarbamazine/ Filaribits Plus Daily Dog DI,TC,AC,TV
Oxibendazole (Pfizer) (Flavored tablet)
gen levels and potentially conflicting anti-
gen, antibody (for feline tests) and micro- Ivermectin HeartGard® Tablets Monthly Dog DI
(Merial) (Tablet)
filariae test results can create diagnostic
dilemmas for the veterinarian (see Table 2, HeartGard® Chewables Monthly Dog DI
(Merial) (Chewable)
p.51).Currently marketed antigen tests are
virtually 100 percent specific for heartworm. HeartGard® for Cats Monthly Cat DI,AT,AB
(Merial) Monthly (Chewable)
Specificity is a more important test attribute
than sensitivity, since most of the dogs in Ivermectin HeartGard® Plus Chewables Monthly Dog DI,TC,TL,
Pyrantel Pamoate (Merial) (Chewable) AC,AB,US
any region are negative.A test with limited
®
specificity would result in a significant num- Milbemycin Oxime Interceptor® Flavor Tabs Monthly Dog DI,TC,TL,AC,TV
(Novartis) (Flavored Tablet) Cat DI, Tca, AT
ber of false-positive dogs.These dogs would
TM
then be treated unnecessarily with an Sentinel § (Novartis) Monthly Dog DI,TC,TL,AC,TV
(Flavored Tablet)
organoarsenical compound.
Reduced sensitivity might fail to detect Moxidectin ProHeart® Monthly Dog DI
(Fort Dodge) (Tablet)
dogs with low worm burdens (false neg-
atives - a possible occurrence anyway; see ProHeart® 6 Every 6 months Dog DI,AC
Table 2). These dogs are less likely than (Fort Dodge) (Sustained release
dogs with high worm burdens to develop subcutaneous injectable
containing 10% moxidectin
severe heartworm disease. Research has microspheres)
shown that currently marketed tests do TM
Selamectin Revolution ¥ Monthly Dog DI,
differ somewhat in their sensitivities,par- (Pfizer) (Topical solution) Cat DI,Tca,AT
ticularly in dogs with low worm burdens. †TC=Toxocara canis, Tca=Toxocara cati, TL=Toxascaris leonina, AC=Ancylostoma caninum, AB=Ancylostoma braziliense, AT=Ancy-
However, for reasons explained above, it lostoma tubaeforme, US=Uncinaria stenocephala, TV=Trichuris vulpis, DI=Dirofilaria immitis.
is perhaps more important for veterinar- Note: Prevention, treatment or control claims vary; see labels for specific product claims.
§Also contains lufenuron for flea control; ¥Also effective against fleas and certain ticks and parasitic mites.
ians to base selection of point-of-care heart-

In Focus june 2002 49


InFocus
early symptomatic stages of heartworm animals,for which the flexible regimen was adult worms can induce a proliferative en-
disease are given a standard two-dose reg- designed. darteritis in the cardiopulmonary vessels
imen, with 24 hours intervening between Another inevitable in which they are found,
each dose.Dogs with late stage heartworm consequence of the im- and the longer they are left
disease (class III disease) can be given a sin-
proved product per- To date, 118 in those vessels, the more
gle dose of melarsomine and subsequently formance of melar- severe that reaction is likely
released to the owners care and vigilance
at home. The dog is returned one month
somine is increased
cost. In this case, it is cases of human to become.It is also notable
that the chronic effects of
later to receive the standard two-dose reg- undeniable that the ex- slow worm death have been
imen. The rational for the three-dose reg- cellent properties of pulmonary the subject of a very lim-
imen is that a partial kill of the adult worms
melarsomine are well ited amount of research.At
following the single treatment and the dog’s
subsequent recuperation prior to the full
worth the increase in
price. The cost of dirofilariasis this point it seems that the
best advice is to recom-
regimen a month later would impose less melarsomine therapy, mend the use of melar-
stress and potential for serious post-treat- particularly in large have been somine when adult infec-
ment thromboembolic disease.The safety dogs, has resulted in tions are detected.If the use
appeal of the flexible dosing regimen has
led many veterinarians to adopt this regi-
some hesitation by pet
owners in some mar- reported in the of the approved adulticide
is refused, then the use of
men as their only treatment protocol. Al- kets to pursue adultici- macrolide preventatives in
though this reasoning seems logical when dal therapy. This and United States. heartworm positive dogs,
devising therapeutic adulticidal protocols, other issues such as although investigative,could
veterinarians must also remember that the how to deal with heart- be justified.
flexible dosing regimen increases the pe- worm-infected geriatric patients, or pa-
riod of time that dogs must be confined tients suffering from other terminal con-
since worms are killed over two treatment ditions, has resulted in veterinarians con-  Feline heartworm infection:
periods. In addition, the pet owner must sidering other adulticidal options. Thoughts and strategies
bear the cost of an additional treatment The most popular of these options has Although heartworm infection in cats was
and must be responsible enough to return been the exploitation of the slow adultici- first reported in 1921, many pet owners
for all scheduled treatments.It is my opin- dal effects of the macrolide endecticide pre- and some veterinarians either remain un-
ion that melarsomine should be used as its ventatives (i.e. ivermection, milbemycin aware or do not believe that heartworms
label indicates - the standard two-dose pro- oxime, moxidectin and selamectin). Re- can cause serious and sometimes fatal dis-
tocol for all but the most seriously diseasedsearch has shown that most of the macrolide ease in cats. Most of us are with familiar
preventatives that are on the market pos- the potential consequences of heartworm
sess some exploitable slow adulticidal prop- infections in dogs,but we fail to recognize
erties.These adulticidal properties are best that heartworm in cats differs somewhat
characterized for ivermectin.For example, from dogs,and that this parasite induces a
if dogs harboring adult worms are given significantly different clinical response when
ivermectin using the dose band regimen present in cats.Although the prevalence of
(minimum target:dose 6 ug/kg) at monthly heartworm infection in cats has been stud-
intervals for 16 months,many of the heart- ied, unique features of feline infections
worms will die during the regimen. Many make the true prevalence of feline heart-
of the remaining worms appear structurally worm difficult if not impossible to assess.
abnormal and will likely die. A variety of techniques including radiog-
The stated attributes of this approach raphy/angiography, ultrasonography and
to killing adult worms is that worms are necropsy,as well as microfilariae,antibody
killed slowly which will result in less insult and antigen detection have been used to
to the lungs as the worms are elim- diagnose and determine prevalence of fe-
Photo 3: Few inated. Such a result does sound line heartworm infection. Not only does
heartworms are usually appealing,since dogs must be pro- use of these different tests make compari-
present in heartworm
infected cats. tected from future infection using son of the different studies difficult,it is im-
this same regimen anyway.It is also portant to remember that some of these
substantially less expensive than tests were developed for dogs or were ap-
removal of adult worms using melarsomine. plied to the study of feline prevalences based
However, it is important to note that the on guidelines for their use in dogs. Most

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InFocus
heartworm experts agree that results of pub- feline asthma. Consequently, feline heart- cats make available antigen tests less sensi-
lished studies indicate that exposure to heart- worm disease must be differentiated from tive(see Photo 3,p.50).A positive antibody
worm infected mosquitoes in cats is sur- asthma. A small percentage of cats exhibit test might result from one of several situa-
prisingly high, and that the risk of feline acute respiratory distress and may die sud- tions including current adult infection,re-
heartworm infection remains a concern in denly.This peracute presentation also mim- cently cleared adult infections, ectopic in-
many regions of the country. ics signs of feline asthma or cardiomyo- fections,exposed cats on a heartworm pre-
Most cats infected with heartworm are pathy (dyspnea).Many of these cats are clin- ventative or simply exposure to heartworm
asymptomatic.However,it is impossible to ically normal prior to the acute heartworm- from infected mosquitoes. These results
predict when and under what conditions induced event. cannot be used independent of other tests
asymptomatic cats will develop clinical heart- Diagnosis of feline heartworm infection or data to confirm adult infections of the
worm disease.Cats with clinical heartworm is based on history,clinical signs and ancil- heart or lungs.Because infected cats do not
disease present with respiratory signs such lary diagnostic aids already mentioned.Both commonly demonstrate circulating mi-
as coughing and/or dyspnea, or intermit- antigen and antibody tests are available and crofilariae,standard microfilariae detection
tent vomiting which according to the pet approved for use in cats.While detection of assays also cannot be used reliably to con-
owner is not associated with eating. Some adult heartworm antigen in cats is confir- firm infections. Studies also indicate that
cats also have signs of weight loss and or di- mation of infection, it is important to re- clinical signs do not correlate with positive
arrhea without respiratory signs. Respira- member the lower worm burdens and in- serological test results,further substantiat-
tory signs are similar to those observed with creased likelihood of all-male infections in Continued on next page 

Table 2: Possible causes or explanations for observed heartworm test


results in dogs and cats.
Antigen Antibody Microfilariae Possible Cause/
Test* Test*` Test Explanation
Canine
Positive NA** Negative  Failure to use a microfilaria concentration test could result in false negative if
numbers of circulating microfilaria are low.
 Maturing adult female worms are detectable with antigen test prior to production of
microfilaria (uncommon).
 Dog may have been treated with a microfilaricide, but not with an adulticide.
 Dog may be receiving or may have received heartworm preventatives that eliminated
microfilaria but not adult worms.
 Dog may be true natural occult [single-sex (female-only) infection; immune-mediated
clearance of microfilaria].
Negative NA Positive  Microfilaria are those of another species such as Dipetalonema reconditum or Dirofilaria
spp. other than D. immitis (usually few in number).
 Microfilaria were accquired from the dam via the placenta (usually few in number and
usually seen in young dogs).
 Adults were removed or have died, but microfilaria persist.
 Contamination of test materials with microfilariae from a previous positive sample.
Variable§ NA Negative or positive  Fluctuating antigen level usually due to few female worms or age of worms (detection
may vary from test to test). Presence or absence of circulating microfilaria could depend
on age of female worms, numbers of circulating microfilaria and method of detection
and type and frequency of use of preventatives, and host immune responses
Feline
Negative Positive Negative  Most common result. Usually due to exposure but failure of larvae to reach maturity.
 Could be due to low adult worm burden. Cats are usually transiently microfilaremic (due
to immune mechanisms) or harbor too few microfilaria to detect. Some tests conducted
by reference laboratories may be capable of clarifying infection status.
 Could be due to elimination of migrating larvae by preventative. However, larvae survived
long enough to induce antibody response.
 Could be due to presence of heartworms at aberrant (ectopic) sites.
Positive Negative Negative  Uncommon for antibody test to be negative. Rarely, cats do not produce antibody, even
when detectable adult worms are present .
Negative Positive Positive  Uncommon. Too few adult female worms to detect. Cat was examined during brief
microfilaremic phase.
*Results of point-of-care tests. Some tests conducted by reference laboratories may provide more definitive results.
**Not applicable: antibody tests not used routinely in dogs.
§Positive at one time; negative at another or positive with one test and negative with another test. This situation also might be encountered when dogs or cats are
tested by two different veterinarians.

In Focus june 2002 51


InFocus
ing the difficulty of diagnosis.Consequently,  Human heartworm infections: although all races and both sexes appear
diagnosis of feline heartworm infection An emerging zoonosis? susceptible.
remains a challenge that requires multiple Many veterinarians and pet owners are not Although uncommon, human pul-
approaches including collection of ade- aware that humans can be infected with monary dirofilariasis appears to be an emerg-
quate historical information and/or im- Dirofilariaspp.Humans,however,are aber- ing zoonosis. Increased awareness by the
munological testing,imaging and perhaps rant hosts and do not usually harbor adult medical community and advances in early
additional hematological tests. worms or circulating microfilariae. These diagnosis have resulted in increased detec-
The decision to recommend prevention worms usually die either in the subcuta- tion rates. Although impossible to elimi-
to clients whose cats might be exposed to neous tissues or pulmonary vessels before nate entirely,increased emphasis on canine
heartworms is a controversial one.It is im- they mature to adult worms.At these sites, heartworm prevention could reduce the
portant to make three points about feline the dead or dying worms usually evoke a prevalence of heartworm infected mos-
heartworm infections to clients that are in- demonstrable granulomatous response. quitoes in heartworm endemic areas.This
decisive about feline heartworm prophy- Most human infections with D. immitis aspect of prevention rests with the veteri-
laxis.First,clients should be told that feline manifest as pulmonary nodules.Other sites narian and pet owner. DVM
heartworm infections are difficult to diag- of infection with D. immitis or D. immitis-
nose. The points made in this discussion like worms include the eye,testicle,subcu- Dr. Blagburn holds the appointment
can be used to support this statement.Sec- taneous tissues,urinary bladder,porta caval of Distinguished University Professor
ond, feline heartworm disease is not easily shunt and peritoneal cavity. Human pul- at the Auburn University College of
or safely treated,nor are there approved or monary infection results when infective lar- Veterinary Medicine. He received his
safe medications for removal of adult heart- vae introduced by mosquitoes cannot com- doctorate in parasitology from the
worms from cats.Third,and perhaps most plete their maturation in the cardiopul- University of Illinois College of Veterinary Medicine.
important,clients should be informed that monary vasculature. The heartworm lar- A significant portion of Dr. Blagburn’s research effort
there are safe,effective and approved heart- vae die and subsequently pass to the lungs is dedicated to collaborative development of new
worm preventative medications available where the release of antigens and inflam- pharmaceuticals directed against parasites and para-
for cats (see Table 1,p.49).In addition,these matory mediators lead to endarteritis,pul- sitic diseases. He is currently an associate editor for
medications also are effec- monary infarction and nodule formation. the Journal of Parasitology. He currently serves on the
Photo 4: Cross tive against other impor- Nodules usually are 1-3 cm in diam- editorial board of Veterinary Therapeutics and is the
section of heart-
tant internal and external eter, well-circumscribed, spherical, gray- author of more than 190 publications.
worms in a
pulmonary vessel. parasites.It is essential that ish-yellow and contain a necrotic core. If
Human pulmonary veterinarians inform and worms are present, they can be identified
dirofilariasis can instruct pet owners about by their cross-sectional morphology (see
be confirmed by
observing similarly
Photo 4). Identification usually requires
submission of the specimen to an expert
Suggested reading
sectioned imma-
ture worms in soli- laboratory.  Shah MK: Human Pulmonary Dirofilaria-
tary lung nodules. Most cases are asymptomatic, thus the sis. 1999, Southern Medical Journal
condition is likely under reported. Gener- vol 92, pp. 276-279.
ally, it is misdiagnosed as carcinoma or
metastatic disease. Surgical resection has  Recent Advances in Heartworm Disease:
been the treatment of choice.As we would Symposium ‘01. American Heartworm
expect, the frequency and distribution of Society, Batavia, IL, 2002, In Press.
human pulmonary dirofilariasis is associ-
ated directly with the prevalence and dis-  Rew R and J Vercruysse (eds). Macrocylic
tribution of canine heartworm infections. Lactones in Antiparasitic Therapy. Ox-
The greatest numbers of human cases occur ford University Press, NY, (ISBN
in the Atlantic, Gulf Coast and Mississippi 0851996175), 2002, In Press.
valley regions — areas where prevalences
of canine heartworm infections are high-  Knight, DH. Review and Update of Ameri-
est.To date,118 cases of human pulmonary can Heartworm Society Recommen-
risks of exposure to heartworm-infected dirofilariasis have been reported in the United dations for Diagnosis, Treatment, and
mosquitoes and about the availability of ap- States.Thirty-seven of these cases have been Prevention of Heartworms in Dogs and
proved preventive medications.In that way, reported since 1990.Infected persons ranged Cats. Proceeding of the North Ameri-
pet owners can make informed decisions in age from 28-79 with most reported pa- can Veterinary Conference 2002, Small
concerning the most appropriate course of tients in the fifth or sixth decade of life.The Animal - Parasitology, pp.613-619.
action for them and their pet. majority of infections occur in white males,

52 june 2002 www.dvmnewsmagazine.com