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Background Intracardiac heartworm (IH) disease is a serious condition that can become life threatening if the patient develops caval syndrome. We aim to describe the management and outcome of IH in dogs evaluated by Medvet’s New Orleans cardiology service from November 2015 to December 2021. Methods Records of 27 dogs with IH were examined retrospectively. Follow-up information was obtained from phone conversations with referring veterinarians and owners. Results Nine of 27 dogs had a previous diagnosis of heartworm disease and were undergoing “slow kill” treatment; 12/27 dogs' heartworm disease was a new diagnosis, and 6/27 had either scheduled or started adulticide therapy. Nine dogs had heartworm extraction. No dogs died during the heartworm extraction procedure. Four of 9 dogs have died (survival time 1; 676; 1815 and 2184 days). One dog died the day after the procedure secondary to continued respiratory distress; the other three died of non-cardiac causes. Five of nine are alive (median follow-up 1062 (range 648–1831) days. Eleven dogs had IH resolution. In 7/11 this occurred while undergoing stabilization for heartworm extraction. In 4/11 heartworm extraction was not recommended because of low IH burden. All dogs with IH resolution were discharged from the hospital. Four of 11 have died (survival time 6; 22, 58 and 835 days), and 6/11 are alive (median follow-up 523 (range 268–2081) days. One was lost to follow-up after 18 days. Five dogs were medically managed. In one of five dogs, extraction was not recommended because of low IH burden. In four of five extraction was recommended but declined. One of five has died (survival 26 days), and four of five are alive (follow-up 155, 371, 935 and 947 days). Two dogs were killed at the time of diagnosis. Fifteen of 27 dogs were considered to have caval syndrome. Conclusion The results suggest that patients with IH resolution have a good long-term prognosis. Most often IH resolution occurred while the dog was undergoing stabilization for heartworm extraction. When IHs are present, heartworm extraction should still be considered the treatment of choice and recommended as first-line therapy whenever possible. Graphical Abstract

Background Since the advent of ivermectin (along with melarsomine and doxycycline), heartworm has come to be viewed as a solved problem in veterinary medicine, diminishing investment into non-clinical research on Dirofilaria immitis . However, heartworm infections continue to pose problems for practitioners and their patients and seem to be increasing in frequency and geographic distribution. Resistance to preventative therapies (macrocyclic lactones) complicates the picture. The use of chemotherapy for other kinds of pathogens has benefitted enormously from research into the basic biology of the pathogen and on the host-pathogen interface. A lack of basic information on heartworms as parasites and how they interact with permissive and non-permissive hosts greatly limits the ability to discover new ways to prevent and treat heartworm disease. Recent advances in technical platforms will help overcome the intrinsic barriers that hamper research on D. immitis , most notably, the need for experimentally infected dogs to maintain the life cycle and provide material for experiments. Impressive achievements in the development of laboratory animal models for D. immitis will enhance efforts to discover new drugs for prevention or treatment, to characterize new diagnostic biomarkers and to identify key parasite-derived molecules that are essential for survival in permissive hosts, providing a rational basis for vaccine discovery. A ‘genomics toolbox’ for D. immitis could enable unprecedented insight into the negotiations between host and parasite that enable survival in a permissive host. The more we know about the pathogen and how it manipulates its host, the better able we will be to protect companion animals far into the future. Graphical Abstract

Background Immune complexing of target antigen to high affinity host antibody is recognized to impact the sensitivity of commercial heartworm antigen tests. Published information describing the effect of heat on interfering canine host antibodies is lacking. Immune complex dissociation (ICD) by heat treatment of serum for samples initially testing negative for heartworm antigen increases sensitivity of commercial antigen tests, particularly for single sex or low adult infection intensities. In this study the stability and nature of the targeted epitope and mechanism of heat ICD were examined. Methods Canine IgG was isolated using protein-A columns from serum originating from four dogs evaluated after necropsy: one dog with evidence of previously cleared infection and three dogs with confirmed heartworm infections. These dogs were expected to have an excess of antibodies based on negative antigen test and to have no or low antigen optical density, respectively, following heat treatment. Interference of antigen detection on (non-heated) positive serum was evaluated, following 1:1 mixing of antibody/PBS solutions previously heated at 25 °C, 65 °C, 75 °C, 85 °C, 95 °C and 104 °C, compared to positive serum/PBS control measured by optical density using a commercial heartworm antigen ELISA and protein quantification. Live heartworms incubated in media for 72 h provided excretory/secretory antigen for antigen stability studies following heat, endopeptidase digestion and disulfide bond reduction. Results Mixing antigen-positive heartworm serum with antibody solutions demonstrated a significant inhibition of antigen detection for antibody solutions previously heated at 25 °C and 65 °C relative to positive serum/PBS control. Antigen detection optical density was restored at or above the control when positive serum was mixed with solutions previously heated at 75 °C, 85 °C, 95 °C and 104 °C. Significant changes occurred in protein levels for antibody solutions heated at 75 °C, 85 °C, 95 °C and 104 °C. Relative stability of antigen from live heartworms in culture was demonstrated following heat, chemical and enzymatic treatment. Conclusions Significant changes in protein levels and antigen binding ability occurred in IgG solutions heated above 65 °C. The findings confirm heat denaturation of antibodies as the suspected mechanism of heat ICD at 104 °C for antigen diagnosis of heartworm. No significant change occurred in antigen detection following heat, chemical or enzymatic digestions supporting a heat-stable linear nature of the epitope. Graphical Abstract

Background The American Heartworm Society canine guidelines recommend treatment with doxycycline prior to adulticide administration to reduce levels of Wolbachia and its associated metabolites, which are known to be a leading cause of pulmonary pathology. Studies have determined that doxycycline administered at 10 mg/kg BID for 28 days is an effective dose for eliminating Wolbachia , but what has not been determined is the clinical relevance of this elimination. The current guidelines also recommend a 30-day wait period following administration of doxycycline to allow for clearance of metabolites, such as Wolbachia surface protein, and for further reduction in heartworm biomass before administration of adulticide. Reducing the doxycycline dose and eliminating the wait period may carry practical benefits for the animal, client, and practitioner. Methods To investigate these treatment practices, Dirofilaria immitis adults were surgically transplanted into each of 45 dogs, which were divided into nine study groups of five dogs each. Seventy-five days after transplantation, two groups each were administered 5, 7.5, or 10 mg/kg BID doxycycline orally for 28 days and 6 µg/kg ivermectin monthly, with three untreated groups serving as controls. Study animals were necropsied and examined prior to treatment as well as 30 and 60 days post-treatment. Results Mean worm weight was unaffected by dosage but exhibited a significant increase at 30 days and significant decrease at 60 days post-treatment, including in control groups. Histopathology lesion scores did not significantly differ among groups, with the exception of the lung composite score for one untreated group. Liver enzymes, the levels of which are a concern in doxycycline treatment, were also examined, with no abnormalities in alanine aminotransferase or alkaline phosphatase observed. Conclusions No consistent worsening of tissue lesions was observed with or without the AHS-recommended 30-day wait period, nor did reduced dosages of doxycycline lead to worsening of pathology or any change in efficacy in depleting worm weight. Mean worm weight did significantly increase prior to, and decrease following, the wait period. Future work that also includes adulticide treatment (i.e. melarsomine) will study treatment recommendations that may improve both animal health and owner compliance. Graphical abstract

Background : Veterinary knowledge regarding feline heartworm has been increasing significantly over the past two decades. Necropsy surveys of shelter cats have shown feline adult heartworm infection prevalence to be 5–20% of the rate in unprotected dogs; however, other studies have shown feline heartworm antibody prevalence up to 33%, reflecting higher exposure rates and potential immature adult infections. Thus, the true prevalence of feline heartworm infection is likely underestimated due to the limitations of current diagnostic techniques, inadequate testing protocols, and the high likelihood of cats exhibiting transient clinical signs or dying without confirmation of infection. Diagnosing Feline Heartworm Disease (FHWD), also referred to as Heartworm Associated Respiratory Disease (HARD), is one of the conundrums of veterinary medicine. The purpose of this study was to evaluate and characterize the occurrence of Heartworm Associated Respiratory Disease [HARD] in shelter cats, naturally-infected with D.immitis . Methods Fifty shelter cats slated for euthanasia between December 2009 and June 2010 were investigated by gross necropsy, radiography, serology, and lung histopathology using techniques that have been established in experimental models of cat heartworm infection. The relationship between pulmonary vascular disease and serological markers for heartworm was also examined using correlations and statistical modeling. Serology included standard heartworm antigen test and a commonly used heartworm antibody test. Also included were heat-treated heartworm antigen test and two additional heartworm antibody tests previously evaluated on experimentally-infected cats. Results None of the cats were heartworm antibody (HW Ab) positive on a commonly used HW Ab test used by many reference laboratories even though 20% of the study cats were heartworm antigen (HW Ag) positive on heat-treated samples. Two additional HW Ab test were positive on 26% and 22% of the study cats. The combination of heat-treated HW Ag, HW Ab tests, and histopathology indicated 34% of the study cats had HARD. Conclusions Utilizing both, the above tests, and thoracic radiographs, enhanced the ability to predict vascular disease, possibly caused by infection with immature and adult heartworms and supported the premise that cats develop heartworm disease at the same rate as dogs. Graphical Abstract

Background In recent years, the usefulness of echocardiography and serum biomarkers in the diagnosis of pulmonary hypertension (PH) in dogs with heartworm disease has been studied. Previously, N-terminal pro B-type natriuretic peptide (NT-proBNP) has shown high concentrations in dogs with heart disease and/or PH as well as its usefulness as a prognostic indicator, but it has never been evaluated in the diagnosis and prognosis of PH in dogs with heartworm disease. The aim was to evaluate the serum concentrations of NT-proBNP in dogs infected by Dirofilaria immitis to determine its usefulness as a tool to detect precapillary PH. Methods NT-proBNP was determined in 50 heartworm-infected dogs. Presence/absence of PH was determined echocardiographically, using the Right Pulmonary Artery Distensibility Index (RPAD Index) and the systolic flow of tricuspid regurgitation mainly, together with other echocardiographic measurements following the guidelines of the American College of Veterinary Internal Medicine (ACVIM) for the diagnosis of PH. Other epidemiological parameters (breed, age, sex, status: client-owned or shelter dogs) and clinical parameters (microfilaremia, parasite burden, presence of symptoms, body condition) were collected as well. Results Moderate-severe PH was present in 40% of the dogs (RPAD Index < 29.5%), NT-proBNP concentrations being significantly higher compared with dogs that did not have PH. A cutoff for NT-proBNP of ≥ 1178.45 pmol/l showed a sensitivity of 64.3% and a specificity of 95.5% for the presence of moderate-severe PH. Older dogs and dogs from shelters showed significantly higher NT-proBNP concentrations. Dogs with symptoms and low body condition presented significantly higher NT-proBNP concentrations as well. Conclusions The determination of NT-pro-BNP concentration can be a useful tool in the diagnostic work-up of dogs with heartworm disease and associated PH and can help to identify animals in the more advanced stage of this disorder. Graphical abstract

Dogs with heartworm disease may present for procedures that require anesthesia. This article is a brief, practical review of anesthetic techniques for dogs with heartworm. Dogs with heartworm, such as in a shelter that undergo spay and neuter procedures, may be safely anesthetized prior to heartworm treatment. The dog presenting with caval syndrome may require emergent anesthesia for extraction of the heartworms; anesthetic drugs and potential adverse effects are discussed. The anesthetic agents that have been used are discussed.

Heartworm disease caused by Dirofilaria immitis is a vector-borne disease that affects canids and felids, both domestic and wild, throughout the world. It is a chronic disease which causes vascular damage in pulmonary arteries, and in advanced stages, the presence of pulmonary hypertension and right-sided congestive heart failure can be evidenced. Moreover, pulmonary thromboembolism is caused by the death of the worms, which can be lethal for the infected animal. Furthermore, it is the causative agent of human pulmonary dirofilariosis, being a zoonotic disease. The aim of this review was to update the current epidemiological situation of heartworm in Europe in dogs, cats, wild animals, and vectors insects, and to analyse the factors that may have contributed to the continuous spread of the disease in the last decade (2012–2021). In Europe, the disease has extended to eastern countries, being currently endemic in countries where previously only isolated or imported cases were reported. Furthermore, its prevalence has continued to increase in southern countries, traditionally endemic. This distribution trends and changes are influenced by several factors which are discussed in this review, such as the climate changes, presence of vectors in new areas, the appearance of new competent vector species in the continent, increased movement of pets that travelled to or originated from endemic countries, the urbanisation of rural areas leading to the formation of so-called “heat islands”, or the creation of extensive areas of irrigated crops. The continuous expansion of D. immitis must be monitored, and measures adapted to the situation of each country must be carried out for adequate control.

Background Compliance failure with administration of heartworm (HW) disease preventives has been reported as the main contributor to HW disease incidence in medicalized dogs. This study aimed to evaluate purchase compliance with different canine HW preventive products in the USA. Methods Anonymized transaction data from clinics throughout the USA served as the basis for two retrospective analyses. We first examined the monthly equivalent doses of HW preventive purchases from clinics that had implemented extended-release moxidectin injectables ProHeart ® 6 (PH6) and/or ProHeart ® 12 (PH12) compared to clinics that prescribed monthly HW preventatives (MHWP) only. In the second analysis, the purchase compliance in practices that dispensed only flea and tick (FT) and HW products separately but did not dispense combination products (dual-therapy practices) was compared to the purchase compliance with the combination product Simparica Trio ® (sarolaner, moxidectin, and pyrantel chewable tablets), purchased in clinics having implemented combination therapy in their formulary (combination-therapy practices). In both analyses, the numbers of monthly doses dispensed annually per dog were calculated. Results Transaction data from 3,539,990 dogs in 4615 practices were included in the first analysis. In dogs administered PH12 or PH6, the numbers of monthly equivalent doses were 12 and 8.1, respectively. In both clinic types, the average annual number of MHWP doses totaled 7.3. In the second analysis, a total of 919 practices were identified as combination-therapy practices and 434 as dual-therapy-only practices. A total of 246,654 dogs (160,854 dogs in dual-therapy practices and 85,800 dogs in combination-therapy practices) were included in the calculation of the average annual number of monthly doses, which totaled 6.8 (HW preventive products) and 4.4 (FT products) in dual-therapy practices compared to 7.2 months for both FT and HW preventives with Simparica Trio ® across both practice types. Conclusions The injectable HW preventive PH12 is the only product that provides 12 months of heartworm disease prevention in a single veterinarian-administered injection. When choosing a monthly preventive, the combination therapy was associated with a greater purchase compliance compared with FT and HW products being dispensed separately. Graphical Abstract

Background Assessment of the safety of heartworm preventatives in dogs with pre-existing patent heartworm ( Dirofilaria immitis ) infections is necessary because rapid adult worm and microfilarial death can lead to severe clinical complications, including thromboembolism and anaphylactic shock in dogs. The aim of this study was to determine the clinical safety of Simparica Trio ® (sarolaner, pyrantel, moxidectin) in heartworm-infected dogs and the degree of microfilaricidal and adulticidal activity of three consecutive monthly treatments of Simparica Trio. Methods Twenty-four laboratory Beagle dogs were implanted with 10 male and 10 female D. immitis (ZoeKY isolate), and once infection was patent, they were randomized equally among three groups to receive no treatment, 1× or 3× the maximum recommended label dose of Simparica Trio. Dogs in the treated groups received Simparica Trio on days 0, 28 and 56. In-life assessments included body weight, physical examinations, clinical observations, daily general health observations, a quantitative estimate of food consumption and blood collections for pharmacokinetic (PK) analysis, microfilariae (MF) counts and D. immitis antigen testing. At the end of the study the heart, lungs and pleural and peritoneal cavities were examined for adult D. immitis worms. Results Simparica Trio was generally well tolerated. Emesis occurred at low frequency in all groups including control. Abnormal stool occurred occasionally in the 1× and 3× groups throughout the 3-month study. Fever (> 104 °F/40 °C) was recorded in one 1× and one 3× dog 1 day after the first dose and resolved by the following day. No severe hypersensitivity reactions occurred. The mean number of circulating microfilariae (MF) counts in the control group increased from 12,000/ml at study start (Day 0) to > 20,000/ml at Day 28 and remained > 20,000/ml for the duration of the study. The least squares means of circulating MF were reduced by 69.8% on Day 1 and 97.4% on Day 7 for the 1× group and remained at > 99% lower than the control group for the remainder of the study. Similarly, least squares means of circulating MF were reduced by 85.3% on Day 1 and 93.9% on Day 7 for the 3× group and remained > 98% lower than the control group for the remainder of the study. At the end of the study, the mean number of implanted adult worms recovered was < 10 per sex in all groups with 90%, 85% and 75% of live adult heartworms recovered in control, 1× and 3× treatment groups, respectively. Low numbers of dead adult worms were recovered in 1× and 3×, with none in control. Following each dose, the moxidectin and sarolaner AUC and C max had close to dose proportional increases. Conclusions This study demonstrated that Simparica Trio (sarolaner, pyrantel, moxidectin) was well tolerated when administered to heartworm-positive dogs at 1× and 3× the maximum recommended dose at 28-day intervals for 3 consecutive months. Simparica Trio significantly reduced microfilaria counts in both treatment groups, without significant clinical consequences. At the doses administered, Simparica Trio had minor adulticidal activity but resulted in no clinical sequelae. Graphical Abstract