Current Canine Guidelines for the. Prevention, Diagnosis, and Management of Heartworm (Dirofilaria immitis) Infection in Dogs

Transcription

1 Current Cnine Guidelines for the Prevention, Dignosis, nd Mngement of Hertworm (Dirofilri immitis) Infection in Dogs

2 Thnk You to Our Generous Sponsors: Printed with n Eduction Grnt from IDEXX Lbortories. Photomicrogrphs courtesy of Byer HelthCre Americn Hertworm Society PO Box 8266 Wilmington, DE E-mil: info@hertwormsociety.org

3 Current Cnine Guidelines for the Prevention, Dignosis, nd Mngement of Hertworm (Dirofilri immitis) Infection in Dogs (revised July 2014) Prepred by Dr. C. Thoms Nelson, Dr. John W. McCll, nd Dr. Doug Crithers (Editor), nd pproved by the Executive Bord of the Americn Hertworm Society (Officers: Dr. Stephen Jones, President; Dr. Wllce Grhm, Pst President; Dr. Cristino von Simson, Vice President; Dr. Robert Stnnrd, Secretry-Tresurer; Dr. Doug Crithers, Editor; Dr. Ptrici Pyne, Dr. Chris Rehm, Dr. Chrles Thoms Nelson, Dr. Mrth Smith-Blckmore, Dr. Elizbeth Clyde, nd Dr. Binc Zffrno, Bord Members; Dr. Mtthew Miller, Symposium Chir; Dr. Clrke Atkins, Symposium Co-Chir; Dr. John McCll, Co-Editor; Dr. Mike Loenser nd Dr. Tony Rumschlg, Ex Officio Members. Premble These recommendtions supersede previous editions nd re bsed on the ltest informtion presented t the 2013 Triennil Symposium of the Americn Hertworm Society (AHS), new reserch, nd dditionl clinicl experience. The recommendtions for the prevention, dignosis, nd mngement of hertworm infection in cts re contined in compnion feline document ( feline-guidelines.html). HIGHLIGHTS Dignostics: AHS recommends nnul ntigen nd microfilri testing. (Becuse the interprettion of dignostics hs become more complex, plese see the Microfilri nd Antigen Testing section for more complete informtion.) Chemoprophylxis: AHS recommends yerround dministrtion of chemoprophylctic drugs to prevent hertworm disese, control other pthogenic nd/or zoonotic prsites, nd enhnce complince, the ltter being prticulrly importnt in light of the documented presence of resistnt subpopultions. Adulticide therpy: AHS recommends use of doxycycline nd mcrocyclic lctone prior to the three-dose regimen of melrsomine (one injection of 2.5 mg/kg body weight followed t lest one month lter by two injections of the sme dose 24 hours prt) for tretment of hertworm disese in both symptomtic nd symptomtic dogs. Any method utilizing only mcrocyclic lctones s slow-kill dulticide is not recommended. EPIDEMIOLOGY Hertworm infection in dogs hs been dignosed round the globe, including ll 50 of the United Sttes. In the United Sttes, its territories, nd protectortes, hertworm is considered t lest regionlly endemic in ech of the contiguous 48 sttes, Hwii, Puerto Rico, U.S. Virgin Islnds, nd Gum. Hertworm trnsmission hs not been documented in Alsk; however, there re regions in centrl Alsk tht hve mosquito vectors nd climte conditions to support the trnsmission of hertworms for brief periods. Thus, the introduction of microfilremic dogs or wild cnids could set up nidus of infection for locl trnsmission of hertworm in this stte. Such reloction of microfilremic dogs nd expnsion of the territories of microfilremic wild cnids in other res of the United Sttes continue to be importnt fctors contributing to further dissemintion of the prsite, s the ubiquitous presence of one or more species of vector-competent mosquitoes mkes trnsmission possible wherever reservoir of infection nd fvorble climtic conditions co-exist. Chnge in ny of these fctors cn hve significnt effect on 2014 Cnine Hertworm Guidelines 1

4 Figure 1. Sketch of n urbn het islnd profile. From the trnsmission potentil in specific geogrphic loction. Environmentl chnges, both nturl climtic chnge nd those creted by humns, nd niml movement hve incresed hertworm infection potentil. Commercil nd residentil rel estte development of non-endemic res nd res of low incidence hs led to the resultnt spred nd incresed prevlence of hertworms by ltering dringe of undeveloped lnd nd by providing wter sources in new urbn homesites. In the western United Sttes, irrigtion nd plnting of trees hs expnded the hbitt for Aedes sierrensis (western knot hole mosquito), the primry vector for trnsmission of hertworms in those sttes. Aedes lbopictus (Asin tiger mosquito), which ws introduced into the Port of Houston in 1985, hs now spred northwrd, pproching Cnd, nd isolted popultions hve been identified in res in the western sttes. This urbn-dwelling mosquito is ble to reproduce in smll continers, such s flowerpots. Urbn sprwl hs led to the formtion of het islnds, s buildings nd prking lots retin het during the dy (Figure 1), creting microenvironments with potentil to support the development of hertworm lrve in mosquito vectors during colder months, thereby lengthening the trnsmission seson. As vectors expnd their territory, the number of nimls infected will continue to increse. A pivotl prerequisite for hertworm trnsmission is climte tht provides dequte temperture nd humidity to support vible mosquito popultion, nd lso sustin sufficient het to llow mturtion of ingested microfilrie into the infective, thirdstge lrve (L3) within this intermedite host. It hs been shown tht mturtion of lrve, within three mosquito species, ceses t tempertures below 57 F (14 C). Hertworm trnsmission does decrese in winter months, but the presence of microenvironments in urbn res suggests tht the risk of hertworm trnsmission never reches zero. Furthermore, some species of mosquitoes overwinter s dults. While hertworm lrvl development in these mosquitoes my cese in cool tempertures, development quickly resumes with subsequent wrming. The length of the hertworm trnsmission seson in the temperte ltitudes is criticlly dependent on the ccumultion of sufficient het to incubte lrve to the infective stge in the mosquito. The pek months for hertworm trnsmission in the Northern Hemisphere re typiclly July nd August. Models predict tht hertworm trnsmission in the continentl United Sttes is limited to 6 months or less bove the 37th prllel t pproximtely the Virgini North Crolin stte line. While modelbsed predictions of trnsmission using climtic dt re cdemiclly ppeling, they typiclly fil to consider severl potentilly importnt fctors, such s influence of microclimte, unique biologicl hbits nd dpttions of the mosquito vectors, vritions in time of lrvl development, mosquito life expectncy, nd temperture fluctutions. Predictive risk mps ssume tht mosquito vectors live for only one month; however, severl significnt mosquito vectors live nd breed for 2 Americn Hertworm Society

5 much longer periods, including Aedes lbopictus (3 months), Aedes sticticus (3 months), Aedes trivitttus (2 months), Aedes vexns (2 months), nd Aedes cndensis (severl months). There re lso documented cses of hibernting Anopheles qudrimcultus surviving for 4 to 5 months, so the predictive risk mps likely reflect shorter trnsmission seson thn ctully exists. Survey studies of trpped mosquitoes rndomly collected t vrious loctions hve demonstrted hertworm infection rtes in mosquitoes rnging from 2% to 19.4% in known endemic res. When mosquito smpling ws restricted to kennel structures where known positive dogs were being housed, the infection rtes of the mosquitoes in these restricted smplings resulted in rtes of 30% djcent to nd 74% inside the fcilities. Bsed upon these dt, it is importnt to protect pets from mosquito exposure. This my be ccomplished by environmentl control mesures, including tretment of stnding wter sources with insect growth regultors (IGRs) combined with mosquito dulticidl mesures (sprys, CO 2 trps, etc.). In ddition to mosquito control, keeping pets inside during pek mosquito hours nd/or the use of mosquito repellnts on pets my lso reduce the risk of infection. Once reservoir of microfilremic domestic nd wild cnids is estblished beyond the rech of veterinry cre, the ubiquitous presence of one or more species of vector-competent mosquitoes mkes trnsmission possible nd erdiction becomes improbble. BIOLOGY AND LIFE CYCLE The domestic dog nd some wild cnids re the norml definitive hosts for hertworms nd thus serve s the min reservoir of infection. Even less suitble hosts, such s cts nd ferrets, occsionlly hve low-level, trnsient microfilremi nd therefore, theoreticlly, my serve s limited source of infection for mosquitoes during these short periods of microfilremi. The life cycle of Dirofilri immitis is reltively long (usully 7 to 9 months) compred with most prsitic nemtodes (Figure 2). The susceptible mosquito becomes infected when tking blood mel from microfilremic host. Microfilrie cnnot develop into dult hertworms without first developing into lrvl stge 1 (L1) in the mlpighin tubules of the mosquito, then molting into lrvl stge 2 (L2), nd finlly molting into n infective third-stge lrv (L3). The third-stge lrve then migrte vi the body cvity to the hed nd mouthprts of the mosquito, where they become infective. The time required for the development of microfilrie to the infective stge in the mosquito is temperture dependent. At 27 C nd 80% reltive humidity, development tkes bout 10 to 14 dys; with cooler tempertures mturtion tkes longer. When the mosquito tkes blood mel, the infective lrve rupture the end of the mosquito s lbrum nd emerge within droplet of hemolymph (mosquito blood) on the skin of the host. Immeditely fter the blood mel, these sexully differentited lrve enter the niml s body vi the puncture wound mde by the mosquito s mouthprts. Apprently L3 nd L4 trvel between muscle fibers during migrtion, wheres juveniles (immture dults) penetrte muscle nd eventully veins, trnsporting them towrd the hert nd lungs. The molt from L3 to L4 begins s erly s dy 3 nd ends s lte s dys 9 to 12. L4 molt to the finl stge t dys 50 to 70. Immture dult (fifth stge) worms rech the pulmonry vsculture s erly s dy 67 nd ll hve rrived by dys 90 to 120. The first worms entering the pulmonry vsculture on dys 67 to 85 re 1 to 1.5 inches in length. Therefter, dult worms increse in length, with femles incresing by lmost tenfold, becoming sexully mture bout dy 120 post infection. Dogs develop ptent infections (i.e., hve circulting microfilrie) s erly s 6 months but usully by 7 to 9 months fter infection. When juvenile hertworms first rech the lungs, the flow of blood forces them into the smll pulmonry rteries. As the worms grow nd increse in size, they progressively occupy lrger nd lrger rteries until they become fully mture. The eventul loction of the mture dult worms ppers to depend minly on the size of the dog nd the worm burden. A medium-sized dog (e.g., Begle) with low worm burden (i.e., 5) usully hs worms minly in the lobr rteries nd min pulmonry rtery. As the worm burden increses, worms lso cn be locted in the right ventricle. Dogs with more thn 40 worms re more likely to hve cvl syndrome, where the worms mneuver into the right ventricle, right trium, nd the ven cve, thus interfering with vlvulr function nd/or blood flow nd producing hemolysis, liver nd kidney dysfunction, nd hert filure. A cler understnding of hertworm trnsmission, development, preptent period, nd the 2014 Cnine Hertworm Guidelines 3

6 B A S Hertworm-infected Dog 6 7 months post infection Developing Adult / 4 5 months o o l Adults live 5 7 yers / microfilrie cn live 1 2 yers d s u d t r e m P Mture Adult producing microfilrie (pre-lrvl stge) l L 4 t / L T i S 4 5 s s 6 t u e 5 r d v h P h y g s l s s e e e S t g e L3 / 3 4 dys Mosquitio Phse Mosquito ingests microfilrie L1 ^ L2 ^ L dys Infective lrve cquire new host Mosquitio Phse L r Adults live 2 3 yers / microfilrie rrely circulte v Mture Adult producing microfilrie L3 / 3 4 dys l T i s s S u e L 4 t P h / B g ~ 2 l s e e m o A o o n d d u s s t h l t t e r e m t g P h s e 7 8 months post infection Developing Adult / 4 6 months Figure 2. The hertworm life cycle. susceptibility of the different life stges of the prsite to vilble phrmceuticl drugs is criticl. This knowledge bse is necessry to effectively select the most pproprite dulticidl tretment option nd tretment time, nd to develop relistic expecttions for the veterinrin nd client for the outcome of therpy. HEARTWORM PREVENTION The prescription of hertworm chemoprophylctic mediction requires uthoriztion by licensed veterinrin hving vlid reltionship with the client nd ptient. To estblish this reltionship, hertworm prevention should be discussed with the client. If records of pst tretment nd testing do not exist, it is necessry to test the ptient before dispensing or prescribing chemoprophylxis. Options for effective chemoprophylxis include severl drugs dministered monthly either orlly or topiclly, or prenterlly t 6-month intervls. Hertworm infection is preventble despite the dog s inherently high susceptibility. Becuse ll dogs living in hertworm-endemic res re t risk, chemoprophylxis is high priority. Puppies should be strted on chemoprophylxis s erly s possible, no lter thn 8 weeks of ge. Puppies strted on hertworm preventive fter 8 weeks of ge, or housed unprotected outdoors in hevily endemic res, should be tested 6 months fter the initil dose nd nnully therefter. Before inititing preventive regimen in older dogs (7 months of ge or older), ntigen nd microfilri testing should be performed (see PRIMARY DIAGNOSTIC SCREENING). This prctice voids delys in detecting subclinicl infections nd the potentil confusion concerning effectiveness of the prevention progrm if preexisting infection becomes evident fter beginning chemoprophylxis (e.g., chemoprophylxis initited during the preptent period). 4 Americn Hertworm Society

7 Evidence strongly suggests tht by reducing the reservoir popultion through incresing the number of dogs receiving chemoprophylxis, disproportiontely lrge decrese in the prevlence of infection mong unprotected dogs my occur. This collterl protection spreds the umbrell of chemoprophylxis most effectively in communities where hertworm prevlence nd dog popultion density re both reltively low. Even though continuous, yer-round trnsmission my not occur throughout the country, the dministrtion of brod-spectrum chemoprophylctic products with endoprsitic nd/or ectoprsitic ctivity for 12 months ech yer likely enhnces complince nd my ssist in preventing pthogenic nd/or zoonotic prsitic infections. Mcrocyclic Lctones The hertworm preventives currently mrketed (ivermectin, milbemycin oxime, moxidectin, nd selmectin) belong to the mcrocyclic lctone clss of drugs. These drugs ffect microfilrie, thirdnd fourth-stge lrve, nd in some instnces of continuous use, dult hertworms. Becuse their filricidl effect on precrdic lrve cn be chieved by brief pulsing t very low doses, they hve excellent therpeutic/toxic rtios. Mcrocyclic lctones, when given ccording to lbel instructions, re highly effective nd re mong the sfest medictions used in veterinry medicine. All orlly nd topiclly dministered mcrocyclic lctone chemoprophylctic products re lbeled for 30-dy dosing intervl. Beyond this intervl efficcy ginst lte fourth-stge lrve declines nd is unpredictble. Juvenile worms, which cn be found s erly s 52 dys post infection, re even less susceptible to chemoprophylxis. As worms ge, they require progressively longer-term dministrtion to chieve high level of protection. The extended post-infection efficcy of mcrocyclic lctones is prtil sfegurd in the event of indvertent dely or omission of regulrly scheduled doses but does not justify lengthening the recommended one-month intervl of dministrtion for the orl nd topicl formultions. The extent of efficcy ginst lte fourth-stge lrve nd juvenile worms hs importnt implictions for chemoprophylxis in dogs tht hve either missed doses during the trnsmission seson, or re lredy into the trnsmission seson before chemoprophylxis is strted nd my lredy be infected. Continuous, yer-round dministrtion of hertworm preventive is criticl in most, if not ll, res of the United Sttes. Some Collies nd other P glycoprotein deficient dogs re unusully sensitive to vriety of commonly used veterinry drugs, including some ntidepressnts, ntimicrobil gents, Some Drugs nd Other Substnces Tht Inhibit P-Glycoproteins Antidepressnts Fluoxetine St. John s Wort Proxetine Antimicrobil Agents Erythromycin Itrconzole Ketoconzole Opioids Methdone Pentzocine Crdic Drugs Verpmil Amiodrone Quinidine Nicrdipine Immunosuppressnts Cyclosporine Tcrolimus Miscellneous Bromocriptine Chlorpromzine Tmoxifen Grpefruit juice (Source: edu/depts-vcpl/drugs.spx) opioids, immunosuppressnts, nd crdic drugs (see sidebr). The mcrocyclic lctones re lso included in this list with toxicities being reported with overdosing or in combintion with other P-glycoprotein inhibiting drugs. These intoxictions hve occurred most often when concentrted livestock preprtions of mcrocyclic lctones re either ccidentlly ingested or overdosed becuse of 2014 Cnine Hertworm Guidelines 5

8 humn error in dosge clcultion. This prctice is n off-lbel use of the drugs nd is discourged. The stndrd chemoprophylctic dosges of ll mcrocyclic lctones hve been shown to be sfe in ll breeds. Orl dministrtion: Ivermectin nd milbemycin oxime re vilble for monthly orl dministrtion. Some formultions re flvored nd chewble to increse ptient cceptnce nd fcilitte dministrtion. Dose units re pckged for dogs within prescribed weight rnges. To be mximlly effective, hertworm prophylxis should be given yer-round, but if sesonl tretment is chosen, dministrtion should begin t lest one month prior to the nticipted strt of hertworm trnsmission nd, depending on the product used, my need to be continued for up to 6 months fter trnsmission typiclly ceses (see section on Lck of Efficcy). Topicl dministrtion: Moxidectin nd selmectin re vilble s topiclly pplied liquid formultions. The prmeters for tretment with topicl products re the sme s for monthly orl chemoprophylxis. Prenterl dministrtion: A single dose of the slowrelese (SR) formultion of subcutneously injected moxidectin-impregnted lipid microspheres provides continuous protection for 6 months, with the potentil to enhnce complince. Tretment every 6 months is recommended for mximl protection. Reports of Lck of Efficcy Lck of efficcy (LOE) of hertworm preventive product is considered by the Center for Veterinry Medicine (CVM) of the U.S. Food nd Drug Administrtion (FDA) s dog testing hertworm positive regrdless of ppropriteness of dosge or dministrtion consistency. There re mny possible resons for reports of LOE, including filure to dminister sufficient preventive, filure to dminister the preventive when it should be given, filure of dog to retin dose, nd filure of bsorption of the ctive ingredient. There is lso biologicl vrition between hosts in drug metbolism nd immune response, nd in prsite susceptibility to the drug. Thus, the exct cuse of reported LOE cn be difficult or impossible to determine. Fortuntely most LOE clims re explined by complince filure, either between the clinic nd the client or the client nd the pet, rther thn product filure. It is possible for n niml to become infected becuse of skipped or delyed dministrtion of just one preventive dose, prticulrly in highly endemic res. Such res typiclly hve wrm tempertures most of the yer, n bundnce of stnding wter, nd substntil mosquito popultions. These endemic res lso hve lrge popultions of infected dogs nd wild cnids providing reservoir of infection. Another considertion for LOE reports my include improved sensitivity of hertworm ntigen tests over time possibly resulting in detection of more nimls with low femle worm burdens. When considering the possibility of resistnce, it is generlly ccepted tht genetic polymorphism hs lwys existed in popultions of hertworms nd resistnce-contributing lleles on gene, or multiple genes exist tht could led to decrese or loss of susceptibility to mcrocyclic lctones. Wht is not known is the frequency of these resistnce-contributing lleles, the number of genes involved, nd whether these lleles re dominnt or recessive in expressing the resistnt phenotype. The phenomenon of developing resistnce in popultion is much more complex thn merely the presence of resistnt lleles in individuls. Other fctors to consider re the distinct biology of the prsite, the extent of refugi (untreted popultion of hosts), the reltive fitness of the wild-type (susceptible) nd resistnt genotypes in the bsence nd presence of mcrocyclic lctones, the number of nimls treted, nd the drug dosge used. Product use under specific off-lbel conditions hs been shown to geneticlly select for worms with reltive resistnce. These surviving worms over genertions cn become resistnt subpopultion. In vitro ssys hve identified microfilrie tht re less susceptible to high doses of ll the mcrocyclic lctones. These microfilrie exhibit n llele on the P-glycoprotein gene tht differs from the generl popultion. Subsequent in vitro lrvl migrtion inhibition ssys (LMIA) utilizing L3 derived from these sme isoltes of microfilrie hve demonstrted no significnt difference in susceptibility of these propgted isoltes s compred with known susceptible isoltes. This suggests tht either the LMIA is mesuring phenotype tht is not ssocited with resistnce, the isoltes tested from these prophylxis filures re not resistnt, or other unknown fctors re involved. Severl published studies exmined the susceptibility of the MP3 isolte (lso referred to 6 Americn Hertworm Society

9 s the MP3 strin 1 ) originlly collected in northest Georgi to vrious hertworm preventives. One study compred the efficcy of single orl dose of ivermectin nd milbemycin t stndrd prophylctic doses following n experimentl infection with 50 MP3 L3 in groups of 14 purpose-bred lbortory dogs. A single dult worm ws recovered in both the ivermectin- nd milbemycin-treted groups out of possible 700 L3. A second study compred the efficcy of single orl dose of ivermectin or milbemycin or topicl dose of moxidectin or selmectin, gin t stndrd prophylctic doses, following n experimentl infection with 100 L3 in groups of 8 dogs. In this second study, 7 of 8 dogs hd 23 to 24 worms out of possible 800 L3 recovered from the ivermectin, milbemycin, nd selmectin groups. No worms were recovered from the moxidectin group. A third study utilizing the MP3 isolte tested three monthly doses of milbemycin fter experimentl infection with 40 L3 in 10 dogs. No worms were recovered in ny of these 10 dogs. Looking t these three studies collectively, it is evident the MP3 isolte hd decresed susceptibility to single monthly doses of ivermectin, milbemycin, nd selmectin but ws susceptible to three consecutive monthly doses of milbemycin nd single dose of topicl moxidectin. Of greter interest ws the 20-fold increse in number of worms recovered when the number of L3 injected ws doubled. This would led one to hypothesize tht chllenge rtes could be involved in LOE nd the problems seen in the Mississippi River Vlley (MRV) re multifctoril. Geneticlly, the MP3 isolte does not exhibit the sme llele on the P-glycoprotein gene tht ws noted in the field isoltes from the MRV, whose microfilrie hd decresed susceptibility to mcrocyclic lctones, suggesting multiple genes my be involved. Severl in vivo studies were reported in which microfilrie collected from hertworm-infected dogs mny of which were on preventive, hd received microfilricidl doses of mcrocyclic lctones nd therefore were preselected for mcrocyclic lctone resistnce were fed to mosquitoes. The L3 were then collected nd subsequently injected into lbortory dogs, which were then plced on vrious preventives. These studies identified the presence of resistnt subpopultions of hertworms in these dogs. Every compound currently mrketed in every form of dministrtion (orl, topicl, nd prenterl) ws less thn perfect in t lest one study. It seems tht lthough this resistnce ffects ll mcrocyclic lctones, differences in ctive ingredients, doses, nd product formultion mong the vilble preventives cn result in vrying rtes of filures. Another possible fctor in LOE is the host prsite reltionship. The exct mode of ction of the mcrocyclic lctones t preventive doses is not fully known. A study involving Brugi mlyi, filril nemtode cusing lymphtic filrisis in humns, indictes tht ivermectin disrupts the bility of the prsite to secrete n immunomodulting protein from the secretory vesicle, exposing microfilrie to the host immune response. This finding suggests tht mcrocyclic lctones might work in conjunction with the host immune system to eliminte the microfilrie of Brugi. A seprte study, utilizing Dirofilri immitis microfilrie, demonstrted ttchment of leukocytes to microfilrie in whole blood in the presence of ivermectin. No such ttchment of white blood cells to microfilrie in untreted whole blood ws noted. Additionlly, the investigtors found no ttchment of cells to microfilrie, in the presence of ivermectin, when no serum ws present. In seprte studies, these sme cellulr ttchment tendencies hve been observed with D immitis lrve. These dt collectively led us to believe ivermectin, nd likely the other ML products, ct by ffecting the D immitis microfilrie nd lrve s bility to inhibit immune recognition, exposing them to immunologic clernce. Reserch is ongoing to determine the reson for LOE locted predominntly in the MRV. Every new study dds to our knowledge bse nd increses our understnding but lso produces new questions. The complex biology of the prsite, the effect of chnging environmentl conditions tht ffect vector popultions, the dynmics of host (wild nd domestic) popultions, nd even the dynmics of humn interctions with pets re lso relevnt. In the fce of the mny vrible fctors, it is criticl tht 1 The term strin is being used to describe popultions of worms being mintined in lbortories. More ppropritely, these popultions should be described s propgted isoltes. These popultions consist of numerous mle nd femle worms, ech with unique genetic mkeup, undergoing sexul reproduction leding to production of offspring with their own unique genetic design. Strins more ppropritely describe the result of sexully derived popultions, such s bcteri Cnine Hertworm Guidelines 7

10 ll members of the veterinry prctice ensure tht clients understnd the implictions of hertworm infection nd the risk of hertworm infection in their re, nd tht they re providing their pets with pproprite yer-round hertworm prevention. The mcrocyclic lctones continue to be the best nd only option for preventing hertworm infections nd efforts need to be intensified in incresing the number of dogs receiving chemoprophylxis. Reminder systems need to be implemented to ssist pet owners in purchsing nd dministering products in timely mnner. It is now generlly ccepted tht isolted instnces of resistnt hertworms hve been identified. The extent, the degree of spred, nd the resons for resistnce re not understood nd re controversil. All gree tht owner complince is the biggest fctor in the filure of preventives. There is generl greement tht resistnce to hevy experimentl infections is worrisome, nd tht the products now vilble re highly effective nd should continue to be used s the mnufcturers suggest. PRIMARY DIAGNOSTIC SCREENING Annul testing is n integrl prt of ensuring tht prophylxis is chieved nd mintined. Should n infection be dignosed, more timely tretment cn be provided to minimize pthology nd the potentil selection of resistnt subpopultions. Test Timing for Optiml Results Currently vilble hertworm ntigen tests detect protein secreted minly by dult femle Dirofilri immitis, nd the most useful microfilri tests concentrte microfilrie (modified Knott or filtrtion test) nd llow for greter sensitivity. The erliest tht hertworm ntigen nd microfilrie cn be detected is bout 5 nd 6 months post infection, respectively. Antigenemi usully precedes but sometimes lgs the ppernce of microfilrie by few weeks. Antigen my never be detected or my only be spordiclly detected in dogs with very low femle worm burdens. In ddition, ntigenemi my be suppressed until bout 9 months post infection in infected dogs receiving mcrocyclic lctone chemoprophylxis. To determine when testing might become useful, pre-detection period should be dded to the pproximte dte on which infection my hve been possible. A resonble intervl is 7 months. Thus, there is no need or justifiction for testing dog for ntigen nd microfilrie prior to 7 months of ge. Microfilri nd Antigen Testing Whether screening popultion of symptomtic dogs or seeking verifiction of suspected hertworm infection, ntigen testing is the most sensitive dignostic method. It is now recommended, however, tht microfilri testing be done in tndem with ntigen testing. This is especilly importnt if there is high degree of suspicion or if the hertworm prevention history is unknown (e.g., dogs dopted from shelters). It hs come to light tht in some dogs infected with hertworms, ntigen ntibody complexes my led to flse-negtive ntigen test results. These dogs will be ntigen negtive nd microfilrie positive; study conducted on shelter dogs in the southestern United Sttes reported this occurred t rte of 7.1%. It is importnt tht these dogs re identified nd treted to decrese the potentil for selection of resistnt subpopultions of hertworms. There will be instnces where n infected dog is both ntigen nd microfilrie negtive. Antigen Tests Enzyme-linked immunosorbent ssy (ELISA) nd immunochromtogrphic test systems re vilble for detecting circulting hertworm ntigen. Ech testing formt hs proven to be cliniclly useful. The current genertion of hertworm ntigen tests identifies most occult (dult worms present but no circulting microfilrie) infections consisting of t lest one mture femle worm nd re nerly 100% specific. Differences in sensitivity exist especilly in cses with low worm burdens nd/or low ntigenemi. Currently there re no verified tests cpble of detecting infections consisting of only dult mle worms. To obtin relible nd reproducible results, ntigen tests must be performed in strict complince with the mnufcturer s instructions. Accurcy of ll hertworm tests under field conditions is influenced by dherence to the instructions nd storge nd hndling of the test kit nd smple. This hs been simplified for severl tests tht use devices tht minimize the number of steps nd prtilly utomte the procedure. Flse-negtive nd flse-positive results cn occur. If test result is unexpected, the test should be repeted. If the result is still mbiguous, independent confirmtion by reference lbortory is recommended to confirm the result. Concentrtion tests for microfilrie, thorcic rdiogrphy to detect signs of hertworm disese, or ultrsonogrphic visuliztion of worms my lso 8 Americn Hertworm Society

11 vlidte wekly positive ntigen test results. In cses of miniml exposure, it is recommended to confirm ll positive ntigen tests in symptomtic dogs prior to ny dulticide therpy. The color intensity of positive ntigen test result cnnot relibly be used to determine the level of worm burden. The mount of ntigen in circultion bers direct, but imprecise, reltionship to the number of mture femle hertworms. A grded test rection cn be recognized by ELISA test systems, but quntittive results re not displyed by immunochromtogrphic tests. The utility of the ELISA tests for ssessing the degree of prsitism is limited by confounding complictions such s the trnsient increse in ntigenemi ssocited with recent worm deth or low ntigen levels from infections with young dult femle worms nd/or only few dult femles. Therefore, quntittive nlysis of ntigen results is highly specultive nd requires correltion with other relevnt informtion. For exmple, rdiogrphic evidence of dvnced pulmonry rteril disese typicl of chronic hertworm disese coupled with low or bsent ntigenemi is consistent with the ftermth of previous infection tht hs been clered, either nturlly or by tretment. Flse-negtive test results occur most commonly when infections re light, femle worms re still immture, only mle worms re present, nd/or the test kit instructions hve not been followed. There re lso documented cses of ntigen ntibody complexes interfering with ntigen testing, resulting in flse-negtive tests. Lbortory studies hve shown tht heting serum will brek down these complexes, relese ntigen, nd result in more ccurte test results. The routine heting of blood smples IS NOT RECOMMENDED t this time s this is contrry to the lbel instructions for these tests. It lso could interfere with the results of combintion tests tht include n ntibody test for detection of other infectious gents. Due to this possible interference, nd the other considertions mentioned, hertworm test results should only be recorded s positive or no ntigen detected (NAD) nd should not be written s negtive. Antigen test results should be interpreted crefully, tking other relevnt clinicl informtion into considertion. In generl, however, it is better to trust rther thn reject positive ntigen test results. Microfilri Tests In res where the prevlence of hertworm infection is high, mny (~20%) hertworminfected dogs my not be microfilremic, nd this figure is even higher for dogs on mcrocyclic lctone prevention progrm. Considering this, most microfilremic dogs cn be detected by microscopiclly exmining drop of fresh blood under cover slip for microfilrie or cell movement cused by the motile microfilrie. A sttionry rther thn migrtory pttern of movement is indictive of Dirofilri species, nerly lwys D immitis in the United Sttes. Movement beneth the buffy cot in microhemtocrit tube lso my be visible. These re insensitive testing methods when low numbers (50 100/mL) of microfilrie re present; however, such ptients re t lower risk for severe rection fter the dministrtion of microfilricide nd re less likely to pose thret s reservoir of infection. For more ccurte results concentrtion technique (modified Knott test or filtrtion test) should be used to determine the bsence or presence of microfilrie. The modified Knott test remins the preferred method for observing morphology nd mesuring body dimensions to differentite D immitis from non-pthogenic filril species, such s Acnthocheilonem (formerly Dipetlonem) reconditum. The modified Knott test is performed by mixing 1.0 ml of EDTA blood with 9.0 ml of 2% formlin in centrifuge tube. The tube is inverted severl times to mix the blood with the formlin solution, lysing the red blood cells. The tube is then plced in centrifuge, spun t 1100 to 1500 rpm for 5 to 8 minutes, nd the liquid is poured off leving the sediment. A drop of methylene blue is dded to the sediment nd then the stined sediment is plced on glss slide nd cover slip pplied. The slide is exmined under low power (100X) for the presence of microfilrie. To observe the chrcteristics of the microfilrie, the slide cn be exmined under highdry (400X). The microfilrie of Dirofilri immitis re 295 to 325 microns (µm) long nd hve tpered heds. The microfilrie of Acnthocheilonem reconditum re 250 to 288 µm long with blunt heds nd curved tils (Figure 3). All dogs should be tested for microfilrie. Microfilremi vlidtes serologic results, is dignostic should dog hve ntigen ntibody complexes (no ntigen detected on ntigen tests), 2014 Cnine Hertworm Guidelines 9

12 Figure 3. Acnthocheilonem reconditum (top) nd Dirofilri immitis (below). Photogrph courtesy of Byron Blgburn, PhD. identifies the ptient s reservoir of infection, nd lerts the veterinrin to high microfilrie burden, which my precipitte severe rection following dministrtion of microfilricide. Testing Considertions Following Noncomplince nd When Chnging Products In instnces of noncomplince or chnging the brnd or type of hertworm preventive, it is importnt to determine the hertworm sttus of the dog. The dog should be ntigen nd microfilri tested prior to strting or chnging products. A positive test indictes preexisting infection. The dog should lwys be retested 6 months lter (Figure 4). A positive test t this time would most likely be due to n infection cquired before strting or resuming preventive therpy; however, in rre instnces, n existing infection might be missed (i.e., flsenegtive test due minly to young or low worm burden infection). Antigen nd microfilri testing should be performed on the one-yer nniversry dte of the initil test nd nnully therefter. OTHER DIAGNOSTIC AIDS Additionl testing methods re useful for confirming the dignosis nd stging the severity of hertworm disese. Rdiogrphy Assessment of crdiopulmonry sttus my be useful for evluting ptient s prognosis. Rdiogrphy provides the most objective method of ssessing the severity of hertworm crdiopulmonry disese secondry to hertworm infection. Typicl (nerly pthognomonic) signs of hertworm vsculr disese re enlrged, tortuous, nd often truncted peripherl intrlobr nd interlobr brnches of the pulmonry rteries, prticulrly in the diphrgmtic (cudl) lobes (Figure 5). These findings re ccompnied by vrible degrees of pulmonry prenchyml disese. The erliest nd most subtle pulmonry rteril chnges re most commonly found in the dorsl cudl wedge of the diphrgmtic lung lobes. As the severity of infection nd chronicity of disese progress, the pulmonry rteril signs re seen in successively lrger brnches (Figure 6). In the worst cses, the right hert eventully enlrges. Echocrdiogrphy The body wll of dult hertworms is highly echogenic nd produces distinctive, short prllelsided imges with the ppernce of equl signs where the imging plne cuts cross loops of the prsite. Echocrdiogrphy cn provide definitive evidence of hertworm infection, s well s llow for ssessment of crdic ntomic nd functionl consequences of the disese (Figure 7). It is not n efficient method of mking this dignosis, however, prticulrly in lightly infected dogs, becuse the worms often re limited to the peripherl brnches of the pulmonry rteries beyond the echocrdiogrphic field of view. When hertworms re numerous, they re more likely to be present in the min pulmonry rtery, right nd proximl left interlobr brnches, or within the right side of the hert where they cn be imged esily. In dogs with hemoglobinuri, visuliztion of hertworms in the orifice of the tricuspid vlve provides conclusive confirmtion of cvl syndrome. PRE-ADULTICIDE EVALUATION The extent of dignostic testing necessry in the pre-dulticide evlution vries depending on the clinicl sttus of ech ptient. Selected clinicl nd lbortory tests should only be performed to complement informtion obtined from thorough Figure 4. The testing protocol following known noncomplince includes three tests in the first yer, with nnul testing therefter. 10 Americn Hertworm Society

13 Figure 5. Moderte hertworm disese. Rdiogrphic imges courtesy of C. Thoms Nelson, DVM. Figure 6. Severe hertworm disese. Rdiogrphic imges courtesy of C. Thoms Nelson, DVM. history, physicl exmintion, nd ntigen nd microfilri tests. It is importnt to note tht some key fctors influencing the probbility of postdulticide thromboembolic compliction nd outcome of tretment re not esily mesured with stndrd dignostic procedures, including 1) the ctivity level of the dog, 2) the extent of concurrent pulmonry vsculr disese, nd 3) the severity of infection (high versus low worm burdens). nd cn be helpful in evluting the potentil for post-dulticide tretment complictions. Thromboembolic disese is commonly seen in infected dogs exhibiting rdiogrphic signs of severe pulmonry rteril obstruction, especilly in those nimls presenting with clinicl signs. Regrdless of rdiogrphic findings, hertworms must be eliminted, lthough not necessrily immeditely, in ll ptients tht cn tolerte the deth of worms. High ctivity levels of the dog re one of the most significnt fctors contributing to post-dulticidl complictions. Prior to tretment, the owner s bility nd willingness to properly confine treted dogs should be thoroughly investigted. Restricting ctivity is impertive s exercise, excitement, nd overheting re hrbingers of complictions. The greter the number of hertworms killed during n dulticide tretment, the more significnt the potentil for obstructive nd inflmmtory pthology. Unfortuntely, no test (or combintion of tests) is vilble to ccurtely determine the number of hertworms present. Whether crrying low or high worm burdens, infected dogs cn be cliniclly symptomtic nd hve miniml rdiogrphic chnges. So, even with extensive dignostics, predicting post-dulticide complictions Thorcic rdiogrphs cn ssist in providing n ssessment of the niml s crdiopulmonry sttus 2014 Cnine Hertworm Guidelines 11

14 hertworm disese (Tble 1) or in ptients with concurrent disese often re chllenging. The gols of ny hertworm tretment re to improve the clinicl condition of the niml nd to eliminte ll life stges of the hertworms (microfilrie, lrvl stges, juveniles, nd dults) with miniml post-tretment complictions. Dogs exhibiting significnt clinicl signs of hertworm disese should be stbilized before dministering n dulticide. This my require dministrtion of glucocorticosteroids, diuretics, vsodiltors, positive inotropic gents, nd fluid therpy. Figure 7. Echocrdiogrm imge courtesy of Mtthew Miller, DVM. is difficult. One must lwys ssume post-tretment complictions re likely, nd every infected pet must be mnged s though substntil hertworm mss is present or potently violent individul immune rection to the ded nd dying worms could occur. Historiclly, due to finncil limittions of some pet owners nd niml shelters, lrge numbers of dulticide tretments hve been successfully performed without the benefit of extensive dignostics. While dignostics cn be n importnt prt of defining n individul s hertworm disese sttus, ech pln must be developed considering both the niml nd individul pet owner. No set protocol hs been estblished for pre-tretment workup nd resonble judgment should lwys be used to weigh the necessity, benefit, nd extent of ech dignostic procedure performed. Adult hertworms re grve risk to our cnine ptients. The longer they remin in n niml, the greter the dmge to the crdiopulmonry system nd the greter the risk of illness nd deth. It is probble tht treting in the bsence of dignostics, while not idel, is better thn refusing to perform needed tretment. PRINCIPLES OF TREATMENT Treting hertworm infections in symptomtic ptients or those exhibiting signs of mild disese usully is not problemtic if exercise is curtiled. Infections ssocited with moderte or severe A thorough understnding of the host prsite reltionship is necessry to effectively mnge ll cses. As expected, the number of worms hs n effect on the severity of disese; but of equl, if not greter, importnce is the ctivity level of the dog. Controlled studies hve shown tht dogs infected by surgicl trnsplnttion with 50 hertworms nd exercise-restricted took longer to develop clinicl disese nd developed less pulmonry vsculr disese thn dogs with 14 hertworms nd llowed moderte ctivity. This ws lso evident in study in nturlly infected dogs where there ws no correltion between the number of hertworms nd pulmonry vsculr resistnce nd is n indiction tht the host prsite interction plys significnt role in the severity of disese. A subsequent study reported similr findings in dogs being treted with melrsomine. Wheres live hertworms cn cuse endrteritis nd musculr hypertrophy of rteriolr wlls, primrily of the cudl pulmonry rteries, dying nd ded hertworms cuse significnt portion of pthology seen in clinicl disese. As worms die from either nturl cuses or s result of dministrtion of dulticidl therpy, they decompose; nd worm frgments lodge in the distl pulmonry rterioles nd cpillry beds in the cudl lung lobes, blocking blood flow. These worm frgments long with the elicited inflmmtion nd pltelet ggregtion result in thromboembolisms. During periods of incresed ctivity or exercise, the incresed blood flow to these blocked vessels cn cuse cpillry delmintion, rupture, nd subsequent fibrosis. This leds to incresed pulmonry vsculr resistnce nd potentilly, right-sided hert filure nd illustrtes direct correltion between the ctivity level of the dog nd the severity of disese. 12 Americn Hertworm Society

15 Tble 1. Summry of Clinicl Signs of Cnine Hertworm Disese Mild Moderte Severe Cvl Syndrome Asymptomtic or cough Cough, exercise intolernce, bnorml lung sounds Cough, exercise intolernce, dyspne, bnorml hert nd lung sounds, enlrged liver (heptomegly), syncope (temporry loss of consciousness from reduced blood flow to the brin), scites (fluid ccumultion in the bdominl cvity), deth Sudden onset of severe lethrgy nd wekness ccompnied by hemoglobinemi nd hemoglobinuri ADULTICIDE THERAPY Melrsomine Dihydrochloride Melrsomine, dministered vi deep intrmusculr injection into the belly of the epxil lumbr muscles (between L3 nd L5), is the only dulticidl drug pproved by the FDA. Mild swelling nd some soreness t the injection site my be present for few dys, but this cn be minimized by ensuring tht the injection is deposited into the belly of the epxil musculture with needle newly chnged fter the drug is drwn into the syringe nd of pproprite length nd guge for the size of dog nd body condition. Strictly dhering to the mnufcturer s instructions for dministrtion is impertive. Exercise restriction during the recovery period is ESSENTIAL for minimizing crdiopulmonry complictions (see Pulmonry Thromboembolism). Melrsomine hd not been shown to hve ctivity ginst worms less thn 4 months old; recent unpublished dt, however, suggest tht melrsomine my hve more efficcy ginst juvenile worms thn previously believed. The two-injection protocol with melrsomine (i.e., two injections of 2.5 mg/kg body weight 24 hours prt) listed on the product insert for treting clss 1 nd 2 hertworm disese kills only bout 90% of the dult worms. The three-dose lternte protocol (one injection of 2.5 mg/kg body weight followed t lest one month lter by two injections of the sme dose 24 hours prt) listed for treting clss 3 hertworm disese kills 98% of the worms. These overll efficcy vlues reflect the percentge of worms killed in groups of dogs nd not the percentge of dogs clered of worms, which re considerbly lower thn these overll efficcy vlues. The three-dose protocol hs the dded dvntge of decresed compliction rtes nd incresed sfety s number of the dult worms re killed with the first melrsomine injection nd most, if not ll, of the remining worms re killed with the second nd third injections. Stging of the disese nd use of the two-dose protocol hs filed to dequtely ensure tretment success. Therefore, regrdless of the severity of the disese (with the exception of cvl syndrome), the three-dose protocol is recommended by the Americn Hertworm Society due to the incresed sfety nd efficcy. Pulmonry Thromboembolism Pulmonry thromboembolism is n inevitble consequence of successful dulticide therpy nd my be severe if infection is hevy nd pulmonry rteril disese is extensive. If signs of embolism (low grde fever, cough, hemoptysis, excerbtion of right hert filure) develop, they re usully evident within 7 to 10 dys, but occsionlly s lte s 4 weeks fter completion of dulticide dministrtion. Mild embolism in reltively helthy res of lung my be cliniclly unpprent. A pivotl fctor in reducing the risk of thromboembolic complictions is STRICT exercise restriction. ADJUNCT THERAPY Steroids Administrtion of diminishing nti-inflmmtory doses of glucocorticosteroids helps control clinicl signs of pulmonry thromboembolism. Wheres studies showed decrese in efficcy of the rsenicl thicetrsmide when glucocorticosteroids were dministered concurrently, study showed no decrese in the efficcy of melrsomine when used in conjunction with prednisone. In highly endemic res where nimls re more likely to hve significnt worm burdens, glucocorticosteroids such s prednisone my be used. Prednisone is routinely 2014 Cnine Hertworm Guidelines 13

16 Melrsomine only Ivermectin / Doxycycline / Melrsomine Melrsomine only Ivermectin / Doxycycline / Melrsomine Figure 8. Pulmonry pthology ssocited with the deth of hertworms in experimentlly infected hertworm-positive dogs pretreted with ivermectin nd doxycycline prior to receiving melrsomine injections. Photogrphs courtesy of John McCll, PhD nd Lur Krmer, DVM, PhD. dosed t 0.5 mg/kg twice dy (BID) for the first week nd 0.5 mg/kg once dily (SID) for the second week, followed by 0.5 mg/kg every other dy (EOD) for 1 to 2 weeks. NSAIDs/Aspirin The empiricl use of spirin for its ntithrombotic effect or to reduce pulmonry rteritis is not recommended for hertworm-infected dogs. Convincing evidence of clinicl benefit is lcking nd there is some reserch suggesting tht spirin my be contrindicted. Doxycycline Mny filril nemtodes, including Dirofilri immitis, hrbor obligte, intrcellulr, grm-negtive, endo-symbiotic bcteri belonging to the genus Wolbchi (Rickettsiles). Doxycycline reduces Wolbchi numbers in ll stges of hertworms. Doxycycline dministrtion during the first or second month following experimentl hertworm infection ws lethl to third- nd fourth-stge hertworm 14 lrve. In ddition, in dogs with dult infections, doxycycline grdully suppressed microfilremi. Microfilrie ingested by mosquitoes on dogs treted with doxycycline developed into third-stge lrve tht ppered to be norml in ppernce nd motility, but these lrve were not ble to develop into dult worms, thus reducing the risk of selecting for resistnt subpopultions. Wolbchi hve lso been implicted s component in the pthogenesis of filril diseses, possibly through their metbolites. Recent studies hve shown tht mjor surfce protein of Wolbchi (WSP) induces specific IgG response in hosts infected by D immitis. It is hypothesized tht Wolbchi my contribute to pulmonry nd renl inflmmtion through its surfce protein WSP. Studies hve shown tht experimentlly infected hertworm-positive dogs pretreted with ivermectin nd doxycycline prior to receiving melrsomine injections hd less pulmonry pthology ssocited with the deth of the hertworms (Figure 8). Americn Hertworm Society

17 Figure 9. Timeline of D immitis development, showing periods of susceptibility to mcrocyclic lctones nd melrsomine. The dotted line represents the tretment gp, when D immitis is not considered to be susceptible to either tretment. From Meril Limited, Duluth, GA All rights reserved. When incorported into hertworm tretment protocol, doxycycline should be given before dministrtion of melrsomine so the Wolbchi orgnisms nd their metbolites re reduced or bsent when the worms die nd frgment. Doxycycline is dministered t 10 mg/kg BID for 4 weeks. Doxycycline hs been shown to eliminte over 95% of the Wolbchi orgnisms in the filril nemtode Wuchereri bncrofti, resulting in microfilremi for 12 months. These dt suggest the bsence of Wolbchi, or t lest very low numbers, s the orgnism is necessry for embryogenesis. In D immitis (dults nd microfilrie) dt suggest Wolbchi numbers remin low for t lest 12 months following doxycycline dministrtion. Minocycline hs been shown to be highly effective in eliminting Wolbchi orgnisms from the filril nemtode Onchocerc gutturos. No published studies hve been conducted in D immitis but vilble phrmcologicl dt nd necdotl reports suggest this is vible lterntive if doxycycline is not vilble. The dosing regimen is the sme s doxycycline. Mcrocyclic Lctones It is highly probble tht hertworm-positive dog hrbors hertworms tht cn rnge from less thn 1 month to s much s 7 yers of ge. The incomplete efficcy of melrsomine ginst young dult worms could present problem in chieving the gol of eliminting ll of the worms. The susceptibility gp between the mcrocyclic lctones nd melrsomine is demonstrted in Figure 9. The susceptibility gp cn be minimized by dministering mcrocyclic lctone preventive for 2 months prior to dministering melrsomine. This will reduce new infections, eliminte existing susceptible lrve, nd llow older worms (2 nd 4 months of ge) to mture to point where they would be more susceptible to melrsomine. Reduction of the susceptibility gp cn lso be potentited with concurrent use of doxycycline for 30 dys, s this will essentilly eliminte ll developing lrve during the first 60 dys of infection. Mcrocyclic lctones dministered s microfilricides my cuse rpid decrese in the numbers of microfilrie nd should be used with cution in dogs with high microfilril counts. Pretretment with ntihistmines nd glucocorticosteroids will minimize potentil rections. Topicl moxidectin is now FDA-pproved for use in hertworm-positive dogs to eliminte microfilrie. No dverse rections due to high microfilril counts were observed in the lbortory or field studies conducted for pprovl of this lbel clim. Mcrocyclic Lctones/Doxycycline Select mcrocyclic lctones coupled with doxycycline individully suppress embryogenesis nd weken dult hertworms. As mentioned previously doxycycline reduces Wolbchi levels in ll stges of hertworms. Studies hve shown tht dministrtion of doxycycline in combintion with ivermectin provided more rpid dulticidl ctivity thn ivermectin lone s well s more efficiently reducing Wolbchi numbers more effectively thn doxycycline lone. Anecdotl reports on other mcrocyclic lctones with dulticidl properties suggest similr results but no confirmtory studies hve been published Cnine Hertworm Guidelines 15

18 In cses where rsenicl therpy is not possible or is contrindicted, the use of monthly hertworm preventive long with doxycycline t 10 mg/kg BID for 4-week period might be considered. An ntigen test should be performed every 6 months nd the dog not considered clered until two consecutive NAD (no ntigen detected) hertworm ntigen tests, 6 months prt, hve been obtined. If the dog is still ntigen positive fter one yer, repet the doxycycline therpy. Exercise should be rigidly restricted for the durtion of the tretment process. AHS-RECOMMENDED TREATMENT PROTOCOL The AHS recommends multimodl pproch to treting hertworms bsed on the informtion presented bove nd depicted in the following exmple mngement protocol (Tble 2). A retrospective study of clinicl cses compring the protocol listed in Tble 2 with similr protocol without doxycycline showed decrese in respirtory complictions nd mortlity rtes when doxycycline ws included. SURGICAL EXTRACTION OF ADULT HEARTWORMS Cvl Syndrome (Dirofilril Hemoglobinuri) Cvl syndrome develops cutely in some hevily infected dogs when dult hertworms prtilly obstruct blood flow through the tricuspid vlve nd lso interfere with vlve closure. Severe pssive congestion of the liver, corse systolic murmur of tricuspid regurgittion, nd jugulr pulstions re chrcteristic fetures of the syndrome. The dignosis is bsed on sudden onset of severe lethrgy, dyspne, ple mucous membrnes, nd wekness ccompnied by hemoglobinemi nd hemoglobinuri. Cvl syndrome cn be confirmed conclusively by echocrdiogrphic visuliztion of hertworms within the tricuspid orifice nd posterior ven cv (Figure 10). The clinicl course usully ends ftlly within 2 dys if surgicl extrction of the worms is not pursued promptly. Surgicl removl of worms from the right trium nd orifice of the tricuspid vlve cn be ccomplished using light sedtion (my not be necessry), locl nesthesi, nd either rigid or flexible lligtor forceps or n intrvsculr retrievl snre introduced preferentilly vi the right externl jugulr vein. With fluoroscopic guidnce if vilble, the instrument should continue to be pssed until worms cn Figure 10. Echocrdiogrm imges courtesy of Stephen Jones, DVM (bove) nd Mtthew Miller, DVM (below). no longer be retrieved (Figure 11). Immeditely following successful opertion, the murmur should soften or dispper nd within 12 to 24 hours hemoglobinuri should dispper. Fluid therpy my be necessry in criticlly ill, hypovolemic dogs to restore hemodynmic nd renl function. Within few weeks following recovery from surgery, dulticide chemotherpy is recommended to eliminte ny remining worms, prticulrly if mny re still visible echocrdiogrphiclly. Pulmonry Arteril Infections The min pulmonry rtery nd lobr brnches cn be ccessed with flexible lligtor forceps ided by fluoroscopic guidnce. Intropertive mortlity with this technique is very low. Overll survivl nd rte of recovery of dogs t high risk of pulmonry thromboembolism is improved significntly by physiclly removing s mny worms s possible before beginning dulticide therpy. When the fcilities re vilble, worm extrction is the procedure of choice for the most hevily infected nd high-risk dogs. Before electing this method 16 Americn Hertworm Society

19 Tble 2. AHS-Recommended Mngement Protocol Dy Dy 0 Dy 1 Dys 1 28 Dy 30 Dy 60 Dy 90 Dy 91 Dy 120 Dy 271 Tretment Dog dignosed nd verified s hertworm positive: Positive ntigen (Ag) test verified with microfilri (MF) test If no microfilrie re detected, confirm with 2 nd Ag test from different mnufcturer Begin exercise restriction. The more pronounced the signs, the stricter the exercise restriction If the dog is symptomtic: Stbilize with pproprite therpy nd nursing cre Prednisone prescribed t 0.5 mg/kg BID 1st week, 0.5 mg/kg SID 2nd week, 0.5 mg/kg EOD 3rd nd 4th weeks Administer hertworm preventive. If microfilrie re detected, pretret with ntihistmine nd glucocorticosteroid, if not lredy on prednisone, to reduce risk of nphylxis Observe for t lest 8 hours for signs of rection Administer doxycycline 10 mg/kg BID for 4 weeks. Reduces pthology ssocited with ded hertworms Disrupts hertworm trnsmission Administer hertworm preventive. Administer hertworm preventive. First melrsomine injection 2.5 mg/kg intrmusculrly (IM) Prescribe prednisone 0.5 mg/kg BID 1st week, 0.5 mg/kg SID 2nd week, 0.5 mg/kg EOD 3rd nd 4th weeks. Decrese ctivity level even further. Cge restriction/on lesh when using yrd Administer hertworm preventive. Second melrsomine injection 2.5 mg/kg IM Third melrsomine injection 2.5 mg/kg IM Prescribe prednisone 0.5 mg/kg BID 1st week, 0.5 mg/kg SID 2nd week, 0.5 mg/kg EOD 3rd nd 4th weeks. Continue exercise restriction for 6 to 8 weeks following lst melrsomine injections. Test for presence of microfilrie. If positive tret with microfilricide nd retest in 4 weeks Estblish yer-round hertworm prevention. Antigen test 6 months fter completion; screen for microfilrie Cnine Hertworm Guidelines 17

20 of tretment, however, echocrdiogrphic visuliztion of the right hert nd pulmonry rteries should be performed to determine tht sufficient number of worms re in ccessible loctions. ALTERNATIVE THERAPIES Long-term Mcrocyclic Lctone Administrtion Slow-kill methods using continuous monthly dministrtion of prophylctic doses of ny mcrocyclic lctone re NOT RECOMMENDED. While effective in reducing the life spn of juvenile nd dult hertworms, it ppers tht the older worms re less susceptible, tking longer to die. The dulticidl effect of mcrocyclic lctones hs been shown to tke more thn 2 yers of continuous dministrtion before dult hertworms re 95% eliminted, nd the timing for rigid exercise restriction is unknown with this pproch. Throughout this period, the infection would persist nd pthology would continue to progress. Another importnt concern in using mcrocyclic lctones in monotherpy of hertworm-positive dogs s stnd-lone therpy is the potentil for selection of resistnt subpopultions of hertworms. Herbl Therpies No nturl or herbl therpies hve been shown to be sfe nd effective prevention or tretment for hertworm disese. CONFIRMATION OF ADULTICIDE EFFICACY Clinicl improvement is possible without completely eliminting the dult hertworms. Worms tht do survive dulticide tretment re invribly the ntigen-producing femles. Most microfilremic dogs with post-dulticide, femle unisex infections become occult within 6 to 9 months, with or without microfilricide tretment, nd prticulrly if they were treted with doxycycline nd re on mcrocyclic lctone preventive during nd fter dulticidl therpy. Consequently, clinicl improvement nd successful clernce of microfilrie from the blood do not verify complete dulticide effect. Recurrence of microfilremi 6 months lter my be due to incomplete clernce of dult worms, mturtion of immture worms if preventive ws not given during dulticide therpy, or new infection due to lpse in chemoprophylxis. Figure 11. Surgicl removl of worms. Photogrphs courtesy of C. Thoms Nelson, DVM. Hertworm ntigen testing is the most relible method of confirming the efficcy of dulticidl therpy. If ll of the dult femle worms hve been killed, hertworm ntigen should become undetectble by 6 months post tretment. However, this single test result does not verify tht the dog is negtive for hertworms, s lrvl nd/or juvenile hertworms my be present in the dog nd n insufficient mount of ntigen is being produced by these young worms to elicit positive test result. This is especilly criticl if mcrocyclic lctone ws not dministered prior to or initited concurrently with dulticidl therpy. If hertworm-positive dog is immeditely treted with dulticide nd mcrocyclic lctone is not given until 3 to 4 weeks fter the lst dose of dulticide, the dog should hve negtive ntigen test 7 months fter the initil dose of mcrocyclic lctone before being considered clered of dult worms. 18 Americn Hertworm Society