Survival analysis of dogs diagnosed with canine peritoneal larval cestodiasis ( Mesocestoides spp.)

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Veterinary Parasitology 180 (2011) 256– 261

Contents lists available at ScienceDirect

Veterinary Parasitology

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urvival analysis of dogs diagnosed with canine peritoneal larvalestodiasis (Mesocestoides spp.)

alter Boycea,∗, Lisa Shendera, Laura Schultza, Winston Vickersa, Christine Johnsona,ichael Ziccardia, Laurel Beckettb, Kerry Padgettc, Paul Crosbied, Jane Sykese

Wildlife Health Center, School of Veterinary Medicine, One Shields Avenue, University of California, Davis, CA 95616, USADivision of Biostatistics, Department of Public Health Sciences, School of Medicine, One Shields Avenue, University of California, Davis, CA 95616, USACalifornia Department of Public Health, Vector-Borne Disease Section, 850 Marina Bay Parkway, Richmond, CA 94804, USADepartment of Biology, California State University, Fresno, 2555 East San Ramon Ave., Fresno, CA 93740-8034, USADepartment of Medicine and Epidemiology, School of Veterinary Medicine, One Shields Avenue, University of California, Davis, CA 95616, USA

r t i c l e i n f o

rticle history:eceived 25 August 2010eceived in revised form 11 March 2011ccepted 16 March 2011

eywords:

a b s t r a c t

Canine peritoneal larval cestodiasis (CPLC) is a poorly understood disease of dogs caused byasexual multiplication of larval Mesocestoides spp. tapeworms. In this study, we examinedthe descriptive statistics and survival characteristics of 60 dogs diagnosed with CPLC from1989 to 2009. Clinically affected dogs presented with ascites (60%), anorexia/weight loss(42%), vomiting (23%), diarrhea (9%) and tachypnea (9%), while subclinical infections (22%)were incidentally detected, typically during ovariohysterectomy or neuter. Survival at 6

esocestoidesanineestodeapewormurvival

months and 1 year post-diagnosis were 72.3% and 60.5%, respectively, and survival was notaffected by sex or age. Using Cox proportional hazard analyses, we determined that themost significant factors influencing survival were the severity of clinical signs at the timeof diagnosis and application of an aggressive treatment strategy after diagnosis. Dogs thatwere not treated aggressively were >5 times more likely to die than dogs that were treatedwith a combination of surgery/lavage and high doses of fenbendazole.

. Introduction

Adult Mesocestoides spp. tapeworms are intestinal par-sites of domestic and wild carnivores and are foundlobally, with the exception of Australia. Adult tape-orms are typically non-pathogenic. In contrast, canineeritoneal larval cestodiasis (CPLC) is a potentially life-hreatening disease that occurs when larval Mesocestoidesapeworms increase in numbers by asexually dividing or

udding within the peritoneal cavity of the dog (Crosbiet al., 1998, 2000a). A number of cases of CPLC have beenocumented from western North America and Europe,ut the published literature provides little guidance on

∗ Corresponding author. Tel.: +1 530 752 1401; fax: +1 530 752 3318.E-mail address: [email protected] (W. Boyce).

304-4017/$ – see front matter © 2011 Elsevier B.V. All rights reserved.oi:10.1016/j.vetpar.2011.03.023

© 2011 Elsevier B.V. All rights reserved.

post-treatment survival. Over the past 20 years the cor-responding author’s laboratory has confirmed a diagnosisof CPLC and made treatment recommendations for >70dogs, and consulted with practicing veterinarians on manyother cases where parasite material was not available formicroscopic and/or PCR diagnostic confirmation. Our goalin following these cases and presenting this analysis is toprovide evidence-based recommendations for treatment oflarval Mesocestoides infections.

Diagnosis of CPLC is challenging because there are noparasite stages passed in the feces and no serologic tests.Proglottids that contain viable oncospheres (eggs) must be

ingested by a suitable first intermediate host for the lifecycle to continue, but the identity of the first intermedi-ate host(s) or the complete life cycle for any species in thegenus Mesocestoides are unknown (Webster, 1949; Voge,1955; Loos-Frank, 1991; Padgett and Boyce, 2004, 2005).

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Proglottids do not appear to be infective to dogs, mice, orlizards (Padgett and Boyce, 2004), and thus do not serve asthe source of CPLC infections. Reptiles and rodents serveas second intermediate hosts by harboring tetrathyridia, alarval stage of the parasite, which can be found throughoutthe body of these hosts (Voge, 1955; Padgett and Boyce,2004). When infected lizards or rodents are ingested by adog, tetrathyridia may develop into adult tapeworms in thesmall intestine.

Larval Mesocestoides organisms in the peritoneal cav-ity of dogs may resemble tetrathyridia found in reptilesand rodents, with 4 suckers, or they may be acephalic,lacking suckers (Voge and Berntzen, 1963; Specht andVoge, 1965; Widmer and Specht, 1992; Crosbie et al.,2000a,b). It is unknown if tetrathyridia and acephalic lar-vae found in the peritoneal cavity represent tetrathyridiathat migrated through the intestinal wall following inges-tion of the second intermediate host, or if they representan aberrant stage resulting from dogs accidentally ingest-ing the first intermediate host. Infected dogs may appearhealthy and harbor relatively few larvae, or they maypresent with abdominal distention resulting from ascitesand larval parasites in their peritoneal cavity (Crosbieet al., 1998). Subclinical infections are often diagnosed dur-ing routine spay or neuter surgeries. Diagnosis in dogsthat develop abdominal distention is typically first madeafter abdominocentesis or exploratory surgery (Carusoet al., 2003). Because parasites must be recovered fromthe peritoneal cavity to confirm a diagnosis of CPLC, manyperitoneal infections likely go undetected or misdiagnosed.

In this study we evaluated risk factors influencing sur-vival after diagnosis of CPLC. Data from 60 infected dogswere analysed to test the hypotheses that a more aggres-sive treatment approach would lead to high survival rates,and that dogs presenting with more severe clinical signswould have a decreased probability of survival. In themajority of these cases, we had recommended that dogsbe treated with a combination of surgery/lavage and pro-longed high doses of fenbendazole (FBZ) (100 mg/kg BID for28 days). Because this was not a controlled trial, these rec-ommendations were not always followed, and dogs weretreated with various approaches including the use of praz-iquantel (PZQ) in a small number of animals. However, thispaper focuses on the use of FBZ since small sample sizesprecluded us from evaluating whether PZQ or any otheranthelmintic influenced survival.

2. Materials and methods

2.1. Sample collection and formation of predictorvariables

Cases of CPLC were opportunistically identified from1989 to 2009 in the corresponding author’s laboratoryfollowing requests for assistance from private veteri-nary practitioners, commercial diagnostic laboratories, or

upon patient admission to the University of California,Davis, Veterinary Medical Teaching Hospital. A diagnosis ofMesocestoides spp. infection was confirmed for all cases inthis study by microscopic examination, and in many casesby PCR testing (Crosbie et al., 2000a). Data collected from

logy 180 (2011) 256– 261 257

examination of records and interviews with veterinariansand clients included breed, age, sex, weight, spay/neuterstatus, signs noted at presentation, treatment history, andsurvival after diagnosis.

Cases were assigned a disease severity score (SevScore)based on clinical signs recorded at the time of diagnosis.If an animal was apparently healthy, it received a scoreof 0. Otherwise it received 2 points for the presence ofascites, and 1 point each for the presence of any of the fol-lowing signs: vomiting, diarrhea, tachypnea, and weightloss/anorexia. Individual scores were additive with a max-imum value of 6 points. Ascites was more heavily weighted(2 points) because it was a more direct indicator of para-site mass or numbers. Each case was allocated a treatmentscore (TxScore) with values ranging from 0 to 3. An animalreceived a score of 0 if no treatment had been provided, anda score of 1–3 if one, two, or three of the following treat-ment options were used: surgery/lavage, a prescription forthe anthelmintic drug FBZ at any dose, and FBZ given at adosage of 100 mg/kg and/or for >28 days duration (termedhigh dose). Some veterinarians/clients used FBZ at lowerdoses or for shorter periods than the high dose we recom-mended, and our scoring system allowed us to evaluatewhether this influenced survival. If a dog was prescribedan anthelmintic other than FBZ, such as PZQ, then it didnot receive any points for anthelmintic treatment, mean-ing dogs given PZQ were grouped with dogs receiving nodrug treatment. This decision was justified since our rec-ommended treatment for CPLC for most of the study periodwas FBZ at 100 mg/kg per os, twice daily for 28 consecutivedays (Crosbie et al., 1998), and we had only a small numberof cases where PZQ or another anthelmintic was used.

The exact date of euthanasia or death was recorded formost fatal outcomes, thus the precise number of days alivepost-diagnosis could be ascertained. In some cases onlyapproximate information was available such as “dog died inNovember 2001” or “dog died in 2005”. We assigned deathdates using the midpoint of the known interval (15th of themonth to approximate dates for the former example, andJune 15th for the latter situation).

2.2. Descriptive and bivariate analyses

All statistical analyses were conducted using R statis-tical software (version 10.2; R Development Core Team,2009). Predictor variables (risk factors) included sex, age,weight, altered status (intact or spayed/neutered), SevS-core, and TxScore. A Fisher’s exact test was employed to testfor associations between categorical variables. The propor-tion of dogs surviving at 6 months and 1 year post-diagnosiswas calculated.

2.3. Survival analyses

We conducted univariate and multivariate logisticregression (data not shown) to identify variables that were

related to post-diagnosis survival at 6 months and 1 year forinclusion in survival analyses. Based on these preliminaryanalyses, we constructed univariate and multivariate Coxproportional hazards models. However, because samplesizes were very low for variables of interest in the mul-

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Table 1Descriptive statistics of 60 cases of canine peritoneal larval cestodiasis caused by Mesocestoides spp. that were diagnosed from 1989 to 2009.

Percent (n = 60) Mean clinicalseverity scorea

(n = 60)

Mean treatmentscoreb

(n = 56)

Percent survivalto 6 months (n)

Percent survivalto 1 year (n)

Male 41.7% 2.4 2.1 73.7% (14/19) 56.3% (9/16)Female 58% 2.0 2.2 71.4% (20/28) 63.0% (17/27)Spayed/neutered 65% 2.8 2.2 65.7% (23/35) 57.6% (19/33)Intact 35% 1.0 2.1 91.7% (11/12) 70.0% (7/10)Sizec

Large 28.3% 2.5 2.1 50% (7/14) 38.5% (5/13)Medium 53.3% 2.2 2.2 88.5% (23/26) 73.9% (17/23)Small 18.3% 1.5 2.1 57.1% (4/7) 57.1% (4/7)

a Clinical severity scores ranged from 0 to 6. Apparently healthy animals received a score of 0; clinically affected dogs received 2 points for the presenceof ascites, and 1 point each for vomiting, diarrhea, tachypnea, and weight loss/anorexia.

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b Treatment scores ranged from 0 to 3. Untreated animals received a sose, and FBZ given at a dosage of 100 mg/kg and/or for >28 days durationeceived scores of 0 for anthelmintic treatment.

c Small = <6.8 kg, medium = 6.8–22.7 kg, large = >22.7 kg

ivariate models, we focus our discussion and presentationn the univariate survival analyses from this point forward.

For our analyses, we censored dogs lost to follow-ups well as those dogs that presumably died from causesther than Mesocestoides (n = 3). Dogs that died >5 yearsfter diagnosis (n = 4) were also censored since they rep-esented such a small proportion of the total cases (7%)nd their death may not have been due to Mesocestoidesnfection. Sample sizes were not large enough to evalu-te the effect of all levels of SevScore (0–6) and TxScore0–3) on survival, leading us to create dichotomized valuesor these two risk factor variables. We characterized theeverity of clinical signs at the time of diagnosis as low ifevScore was 0, 1, or 2, and high if SevScore was 3, 4, or 5no case received a score of 6). We classified treatment ofases as non-aggressive if TxScore was 0 or 1, and aggres-ive if TxScore was 2 or 3. The variables in each model weressessed for the proportional hazards assumption usinghe “cox.zph” function, which calculates the proportional-azards assumption for each covariate by correlating theorresponding set of scaled Schoenfeld residuals with auitable transformation of time (Fox, 2002). Hazard ratiosere considered significant if the calculated Wald statistic

ad a P value of < 0.05. Likelihood-ratio, Wald, and Scorelog-rank) tests were performed to test the null hypothesishat the � coefficient for the model was equal to zero (i.e.,hat the variable had no effect on the survival outcome).

able 2urvival analysis (Cox proportional hazard models) for potential risk factors influeaused by Mesocestoides spp.

Variable Level

Sex Female

Male

Spayed/neutered No

Yes

Clinical severitya Low

HighAggressive treatmentb No

Yes

a Clinical severity scores (0–6) were categorized as low (≤2) or high (≥3)b Treatment scores (0–3) were categorized as non-aggressive (≤1) or aggressiv

0, and treated dogs received 1 point each for surgical lavage, FBZ at anyreated with any anthelmintic other than FBZ (n = 7), such as praziquantel,

3. Results

3.1. Case demographics and descriptive statistics

From 1989 to 2009, there were sixty (60) cases ofCPLC that had sufficient data for inclusion in this study.The majority (n = 50) of these dogs were from California,although there were also three cases from Oregon, andone each from the states of Washington, Arizona, Florida,and Oklahoma. In addition, there were single cases fromCanada, Italy, and Spain, and each of these dogs had spentat least some time in the western United States. Descrip-tive statistics are provided in Table 1, but we did nottest for differences in sex, age, weight, or altered sta-tus at the time of diagnosis because these cases wereidentified opportunistically and we lacked correspond-ing controls. The mean age and weight at diagnosis were7 years (range 4 months–18 years) and 15.4 kg (range3.6–37.2 kg), respectively. Cases included dogs belong-ing to 34 breeds or mixed breeds, and 35% of the caseswere represented by four breeds: corgis (n = 6), Labradorretrievers (n = 5), golden retrievers (n = 5), and terrier mixes(n = 5). Clinically affected dogs presented with ascites (60%),

anorexia/weight loss (42%), vomiting (23%), diarrhea (9%)and tachypnea (9%). The majority of subclinical infections(22%) were incidentally detected typically during ovario-hysterectomy (spay) or neuter. Bivariate examination of

ncing time-to-death after diagnosis of canine peritoneal larval cestodiasis

HazardRatio

95% CI P value

1.01.59 0.67–3.81 0.2941.02.4 0.81–7.24 0.1131.03.96 1.59–9.88 0.0031.00.16 0.06–0.39 0.000

e (≥2)

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predictor variables revealed two significant correlations.Weight and spay/neuter status were significantly associ-ated (point biserial correlation, P = 0.022), as were age andaltered status (point biserial correlation, P = 0.014).

3.2. Survival analyses

Logistic regression revealed that SevScore and TxScoresignificantly influenced survival at both 6 months and 1year, while other predictor variables (sex, age, weight,spay/neuter status) did not. These results were consistentwith and confirmed by proportional hazards analysis (bothunivariate and multivariate). The hazard ratio associatedwith aggressive treatment was 0.16, meaning that dogswith more aggressive treatment had only 16%, or < 1/5th,the hazard of death as compared to those dogs whoreceived moderate or no treatment (Table 2). A dog withmoderate to severe clinical signs had a 3.59-fold greaterhazard of death at any given point in time than did a dogwith none to mild clinical signs. For each univariable model,the likelihood ratio, Wald, and Score (log rank) statisticswere in close agreement (data not shown), further substan-tiating rejection or lack-of-rejection of the null hypothesisthat the � coefficient was equal to zero. The proportionalhazards assumption was met for all analyses.

4. Discussion

This analysis of 60 confirmed cases provides the mostcomprehensive evaluation of CPLC to date, and is the firststudy with sufficient sample sizes to examine statisti-cal factors influencing survival post-diagnosis. There arenumerous other reports of CPLC infections; however, mostof these papers only present case information on one tofour cases (Williams et al., 1985; Bonfanti et al., 2004; Topluet al., 2004; Venco et al., 2005; Witherle et al., 2007; Papiniet al., 2010). The largest previous published study was con-ducted by Crosbie et al. (1998), and we incorporated datafrom those 11 cases into this study to increase our statisticalpower.

We found that CPLC is a life-threatening disease with aguarded prognosis; survival at 6 months and 1 year post-diagnosis were only 72.3% and 60.5%, respectively (Table 1).Without a background hospital population for comparison,it was not possible to examine specific breed predispo-sitions. However, corgis appeared to be overrepresented(10% of our patient population), given the low popularityof this breed in the United States relative to Golden andLabrador retrievers (each 8.5% of our patient population)(American Kennel Club, 2009).

Our results indicated that clinical severity and treat-ment regime both significantly influenced survival out-come. The most common clinical signs at the time ofdiagnosis were ascites (60%) and anorexia/weight loss(42%), and the severity of clinical signs at the time of diag-nosis had a significant influence on survival. Ascites is an

important diagnostic and prognostic indicator since thevolume of fluid is related to parasite multiplication andaccumulation. For example, in one severe case, we deter-mined that >10 million larvae were present in 4 l of fluidrecovered by peritoneal lavage. Severe ascites can also

logy 180 (2011) 256– 261 259

compromise respiration (15% of dogs were tachypneic),potentially because fluid containing parasites interfereswith normal movement of the diaphragm.

The factors influencing initial infection and subsequentparasite multiplication in the peritoneal cavity of dogsare unknown, but studies with rodents suggest that glu-cocorticoid administration and male sex may increasesusceptibility (Hermánek, 1991; Poulin, 1996). If parasitesmultiply more readily in intact male dogs, we would expectthese dogs to have more severe clinical signs and decreasedsurvival. However, we did not find any significant relation-ship between survival and either sex or spay/neuter status.It is also possible that severely affected dogs are immuno-compromised and unable to control parasite multiplicationin the peritoneal cavity. Although a number of dogs withhigh clinical severity scores had a history of glucocorticoidadministration (given for other disorders), we lacked suffi-cient sample sizes and data to draw any conclusions aboutthe influence of immunity or glucocorticoid administrationon host survival.

As expected, aggressive treatment strongly influencedthe likelihood of survival, and dogs that were treated usinghigh doses of FBZ, or by both peritoneal lavage/surgery andusing any dose of FBZ, had <1/5th the risk of dying com-pared to those that were not similarly treated (Table 2).Closed peritoneal lavage, where a large bore needle orcatheter is inserted into the peritoneal cavity to drain fluidand parasites, is most useful when parasites and fluid arefound free in the peritoneal cavity. However, when par-asites are sequestered in “pockets” or cysts, it may benecessary to locate and drain cysts by guided ultrasound. Incases where lavage is impractical (larval invasion of tissues,massive fibrous adhesions), it may be necessary to surgi-cally remove parasites and associated tissues. All of thesemethods were used in the cases we studied, although wedid not differentiate between these methods when assign-ing treatment scores, and we did not have sufficient samplesizes to compare different methods for physically removingparasites (i.e., lavage vs. surgery).

Praziquantel is commonly used to treat adult tape-worms in the small intestine, but in our limited experiencewe have not found it to be effective against Mesocestoideslarvae in the peritoneal cavity (data not shown). Becausewe doubted the usefulness of PZQ and we lacked sufficientsample size to compare between anthelmintics, we clas-sified those few dogs (n = 7) that were treated with PZQas untreated in this analysis. This conservative approachshould have made it more difficult to demonstrate a signif-icant treatment effect on survival if PZQ were an effectivetreatment for Mesocestoides infection. A recent case reportconcluded that PZQ was more effective than FBZ in treatingperitoneal cestodiasis (Papini et al., 2010). However, thereare several reasons to question this conclusion includingsmall sample size (n = 1), the dog was treated with both FBZand PZQ, and viable larvae may have still been present aftertreatment since efficacy was evaluated only by abdomi-

nal ecography. The use of FBZ as the treatment of choicefor CPLC is well supported by our data. Although FBZ hasa number of limitations (described below), and there is aneed for better treatment options, it would be difficult torecommend treatment with PZQ or another anthelminthic

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60 W. Boyce et al. / Veterinary

or CPLC, given the improved survival noted for dogs thateceived FBZ (scored as aggressive treatment) in our study.

We did not attempt to evaluate or quantify the in vivoarvacidal effects of FBZ since surgical exploration of theeritoneal cavity after treatment would have been nec-ssary to confirm the absence of parasites. A peritonealspirate that contains larvae is meaningful. However, aegative aspirate is not conclusive proof of anthelminticfficacy, since aspirates can miss pockets of larvae and thisechnique will not recover larvae that have infiltrated tis-ues. We did not have sufficient sample sizes to compare allf the various dosages of FBZ that were used by veterinari-ns in these 60 cases. Our impression over the past 20 yearsas been that dogs treated with lower doses of FBZ, or givenBZ for shorter periods of time, were more likely to haveositive peritoneal aspirates after treatment. The utility ofiving high, prolonged doses of FBZ, or using FBZ at anyose in combination with surgery/lavage, to achieve clin-

cal improvement was confirmed by the highly significantnfluence of TxScore on survival. However, we strongly sus-ect that FBZ sometimes failed to completely eliminate allf the parasites, in agreement with reports of parasitostatics. parasiticidal effects (Jura et al., 1998; Lucio-Forster et al.,007). Even after 28 days of high dose treatment, someogs suffered a reoccurrence of clinical disease with lar-ae again recovered from their peritoneal cavity monthsr years later. Rather than consider these reoccurrencess separate cases, we combined them, using the diagno-is date of the initial occurrence, and the death date fromhen the dog finally succumbed to disease after its secondiagnosis. We felt this combination of data entry was jus-ified since we could not distinguish between reinfectionnewly acquired from the environment) and reoccurrencef an existing infection.

Fenbendazole is most commonly used in dogs at0 mg/kg daily for 3 days for treatment of a varietyf intestinal parasites. The reported benefits of usingrolonged high doses of benzimidazoles for humanchinococcus infection (reviewed by Reuter et al., 2000),oupled with the relative safety of FBZ, helped formhe basis for our recommendation that dogs be given00 mg/kg per os, twice daily, for 28 consecutive days.lthough FBZ has a high margin of safety (LD50 >10 g/kg),ogs undergoing high dose treatment (an off-label use)hould be monitored for adverse reactions (Lucio-Forstert al., 2007). A few dogs in our study exhibited adverse reac-ions to FBZ, but most were able to tolerate re-initiation ofBZ treatment after a break of several days. Daily, life-longnthelmintic treatment (i.e., mebendazole at 50 mg/kg,ID) has been found to be necessary to control parasiteultiplication in some humans infected with Echinococcus

Reuter et al., 2000). These findings, coupled with the resultf this study, support our current recommendation thatogs that remain persistently infected with Mesocestoidese given FBZ at 50–100 mg/kg daily for life. We anticipatehat the benefits of this approach outweigh the risks since

umans given continuous high doses of benzimidazolesad minimal adverse reactions, and periodic breaks in con-inuous treatment further reduced the potential for toxicityReuter et al., 2000). However, one significant disadvantagef using prolonged high doses of FBZ is the high cost of

logy 180 (2011) 256– 261

treatment, which may reach several hundred dollars (U.S.)per month.

In summary, CPLC is a potentially life-threatening con-dition that is best managed by aggressive treatment. Weencourage others to conduct well-designed trials that willimprove the survival of dogs with CPLC. Because it was notpossible to conduct a more extensive study testing a rangeof doses, it is conceivable that lower dosages of FBZ mighthave been equally effective. Until better treatment optionsare available, we stress that FBZ combined with peritoneallavage/surgery is scientifically defensible and significantlyincreases survival in clinically and subclinically affecteddogs.

Conflict of interest

All authors declare no conflict of interest.

Acknowledgements

We thank Grace Lee, Maureen Dannen, Robin Houston,and Lacie Carlisle for expert technical assistance and themany veterinarians and clients whose cooperation madethis study possible. This research was supported in partwith funding from the U.C. Davis School of VeterinaryMedicine Center for Companion Animal Health.

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