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Heartworm disease caused by Dirofilaria immitis is a serious and underdiagnosed cardiovascular condition in domestic ferrets. Hemodynamic changes caused by parasitization in ferrets cause a potentially fatal syndrome, but its clinical findings and treatment have not yet been standardized. The objective of this study was to describe the clinical case of a successful surgical extraction in a ferret infected by D. immitis. The patient was a 2-year-old, 1.5 kg asymptomatic male domestic ferret. The infection was diagnosed using a commercial test for the detection of D. immitis antigens. Subsequently, their clinical status was evaluated using serological and imaging diagnostic tests, and it was finally decided to perform surgical extraction of the adult worms. The ferret was anesthetized and placed in the left lateral decubitus position to perform a venotomy in the right jugular vein. Endoscopic extraction basket-shaped devices were used in the right atrial cavity under fluoroscopic guidance following the Seldinger endovascular surgery technique. With careful handling, two adult parasites were manually removed. A transthoracic echocardiogram performed after the procedure confirmed the absence of heartworms. The ferret recovered without complications and was discharged within 24 h. In the clinical review, 30 days after surgery, no notable alterations or symptoms were observed. This case report describes the first complete surgical removal of adult D. immitis parasites in a naturally infected ferret.

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The mosquito-borne zoonotic nematode parasites Dirofilaria immitis and Dirofilaria repens primarily affect dogs. In recent years, their distribution has expanded due to various factors influencing vector-borne pathogens. This study aimed to investigate the comparative prevalence of infection in dogs and humans within a hyperenzootic region of Europe, and to estimate the proportional relationship between infection prevalence in dogs and humans, within the concept of "One Health". To this end, 604 blood samples from dogs and 625 serum samples from humans living in the Thrace region of northeastern Greece were collected. The dog samples were examined for Dirofilaria spp. microfilariae using Kott's test and for D. immitis antigen using a commercial serological test. The human sera were analyzed for both parasites by Western blot. The overall prevalence of infection in dogs was 177 (29.3%), with 173 (28.6%) testing positive for D. immitis and 7 (1.2%) for D. repens, including 6 (1%) cases of mixed infection. Specific IgG antibodies were detected in 42 (6.7%) human samples, with 24 (3.8%) positive for D. immitis and 18 (2.9%) for D. repens. The infection proportion in humans was 23.4% of the corresponding canine infections, indicating a high risk of human infection in this hyperenzootic region.

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Angiostrongylus vasorum, commonly known as the French heartworm, is a metastrongyloid parasitic nematode that infects wild and domestic canids. In North America, A. vasorum is endemic to the Canadian island of Newfoundland, but has been expanding to new areas including Nova Scotia, Prince Edward Island, and West Virginia (USA). Two cases of A. vasorum are reported from the state of Tennessee. The first case in a black bear (Ursus americanus) and the second case in a coyote (Canis latrans). The black bear was found dead in Sevier County in November of 2022, while the coyote was trapped and euthanized as part of a predator control program in Campbell County in January of 2023. Histology of the lungs revealed both animals had verminous pneumonia. DNA was extracted from the lungs of both, and PCR was performed using NC1 and NC2 primers. Sequencing results of the PCR products from the bear and coyote samples indicated that they were 95% and 96% similar, respectively, to European strains of A. vasorum. This report marks the first time A. vasorum has been reported in Tennessee as well as only the second and third report of autochthonous A. vasorum infection in the United States and the first report in an ursid. These two cases confirm the spread of A. vasorum further into North America. This nematode is highly pathogenic to wild and domestic canids, and thus these cases represent an emerging threat to both and underscore the need for further surveillance for the parasite.

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OBJECTIVE: To describe the clinical presentation, diagnostic findings, and medical management of the first suspected autochthonous case of a dog in the US diagnosed with Angiostrongylus vasorum, the French heartworm. ANIMAL: A 10-month-old Goldendoodle born in Oregon and residing in Washington State. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The dog presented for evaluation of intermittent vomiting and diarrhea. Bloodwork revealed leukocytosis with mild lymphocytosis, monocytosis, eosinophilia, and basophilia. Larvae were detected on a fecal flotation, and fecal PCR confirmed A vasorum. TREATMENT AND OUTCOME: Administration of milbemycin oxime PO once a week for 4 weeks was initiated with recommendation to continue monthly treatment at label dose. The patient improved over the course of treatment. CLINICAL RELEVANCE: This case highlights the clinical and diagnostic findings and medical management of A vasorum, also known as the French heartworm, in a dog in the US. Few cases of A vasorum have been reported in wild foxes in North America, mostly in eastern Canada and 1 within the eastern US. Here we report for the first time an autochthonous case of A vasorum in a domestic dog in the US and the first report of any canid in the western US. This case highlights the importance of considering A vasorum as a differential for respiratory disease, gastrointestinal disease, or inexplicable eosinophilia in canine veterinary patients in the US and raises awareness for veterinary practitioners to incorporate appropriate preventative and diagnostic measures for their canine patients.

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Dirofilaria immitis is a filarial parasitic nematode of veterinary significance. With the emergence of drug-resistant isolates in the USA, it is imperative to determine the likelihood of resistance occurring in other regions of the world. One approach is to conduct population genetic studies across an extensive geographical range, and to sequence the genomes of individual worms to understand genome-wide genetic variation associated with resistance. The immature life stages of D. immitis found in the host blood are more accessible and less invasive to sample compared to extracting adult stages from the host heart. To assess the use of immature life stages for population genetic analyses, we have performed whole genome amplification and whole-genome sequencing on nine (n = 9) individual D. immitis microfilaria samples isolated from dog blood. On average, less than 1% of mapped reads aligned to each D. immitis genome (nuclear, mitochondrial, and Wolbachia endosymbiont). For the dog genome, an average of over 99% of mapped reads aligned to the nuclear genome and less than 1% aligned to the mitochondrial genome. The average coverage for all D. immitis genomes and the dog nuclear genome was less than 1, while the dog mitochondrial genome had an average coverage of 2.87. The overwhelming proportion of sequencing reads mapping to the dog host genome can be attributed to residual dog blood cells in the microfilariae samples. These results demonstrate the challenges of conducting genome-wide studies on individual immature parasite life stages, particularly in the presence of extraneous host DNA.

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Dirofilariosis is a zoonotic disease that mainly affects dogs and cats, with a high risk to public health. The island of Gran Canaria (Spain) has been shown to be a hyperendemic area of infection and, therefore, a model for studying the evolution of the disease. The objective of this study was to track the prevalence and distribution of heartworm in dogs, cats, and residents of Gran Canaria from 1994 to 2020, using published and unpublished data. Blood samples from 5841 dogs, 1203 cats, and 1604 humans were collected in the years analyzed, considering geographical and isoclimatic factors. In 1994, a prevalence of Dirofilaria immitis of 67.02% in dogs was reported, while in 2020 it was 15.81%. In cats, the seroprevalence in 2010 was 33.03%, compared to 17.20% in 2020. The incidence of D. immitis in humans in 2008 was 18.66%, while in 2020 it was 8.27%. For all study groups, temperate cold zone (TC) and temperate mild zone (TM) climates had the highest prevalence. Throughout these 20 years, the prevalence of heartworm disease has decreased. Despite this, it continues to be a hyperendemic island. This study highlights the importance of using the "One Health" perspective and the risks of contagion of the disease.

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Macrocyclic lactones (MLs) are the only drug class currently licensed for heartworm disease prophylaxis. Macrocyclic lactones kill third- and fourth-stage larvae of Dirofilaria immitis, thus preventing the development of adult worms in dogs, which are responsible for heartworm disease, a potentially life-threatening condition. Despite considerable overlap in terms of endectocide spectrum, several important differences distinguish moxidectin from other MLs. Moxidectin has beneficial pharmacokinetic characteristics, such as a longer half-life and greater tissue distribution compared to ivermectin. Additionally, moxidectin has a greater margin of safety compared to ivermectin in dogs with ABCB1 (previously MDR1) gene-defect, which is commonly recognized in collies and other breeds. Multiple laboratory studies have shown that moxidectin is more effective than other commonly used heartworm preventives against resistant strains of D. immitis. This improved efficacy benefits individual dogs and helps reduce the risk of spreading resistant strains within the community. Despite the presence of proven resistant strains in the United States, non-compliance with preventive measures remains a major factor contributing to the diagnosis of heartworm disease in dogs. In retrospective analyses, the oral moxidectin combination product Simparica Trio® (sarolaner, moxidectin, and pyrantel) was associated with increased compliance, resulting in more time of protection compared to dogs receiving flea/tick and heartworm preventive products separately. Compliance with the extended-release moxidectin injectables ProHeart® 6 and ProHeart® 12 was higher than with monthly heartworm preventives, as they provide 6 months or a full year of protection with one single injection, respectively, and revenues remain in the veterinary clinics as injectable moxidectin cannot be sourced through online retailers.

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Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

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A bioassay-guided chemical investigation of a bacterium, Streptomyces sp. CMB-MRB032, isolated from sheep feces collected near Bathurst, Victoria, Australia, yielded the known polyketide antimycins A4a (1) and A2a (2) as potent inhibitors of Dirofilaria immitis (heartworm) microfilaria (mf) motility (EC50 0.0013-0.0021 µg/mL), along with the octapeptide surugamide A (3) and the new N-methylated analog surugamide K (4). With biological data suggesting surugamides may also exhibit activity against D. immitis, a GNPS molecular network analysis of a library of microbes sourced from geographically diverse Australian ecosystems identified a further five taxonomically and chemically distinct surugamide producers. Scaled-up cultivation of one such producer, Streptomyces sp. CMB-M0112 isolated from a marine sediment collected at Shorncliff, Qld, Australia, yielded 3 along with the new acyl-surugamides A1-A4 (5-8). Solid-phase peptide synthesis provided additional synthetic analogs, surugamides S1-S3 (9-11), while derivatization of 3 returned the semi-synthetic surugamide S4 (12) and acyl-surugamides AS1-AS3 (13-15). The natural acyl-surugamide A3 (7) and semi-synthetic acyl-surugamide AS3 (15) were shown to selectively inhibit D. immitis mf motility (EC50 3.3-3.4 µg/mL), however, unlike antimycins 1 and 2, were inactive against the gastrointestinal nematode Haemonchus contortus L1-L3 larvae (EC50 > 25 µg/mL) and were not cytotoxic to mammalian cells (human colorectal carcinoma SW620, IC50 > 30 µg/mL). A structure-activity relationship (SAR) study on the surugamides 3-15 revealed that selective acylation of the Lys3-ε-NH2 correlates with anthelmintic activity.

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An 8-year-old neutered male Maltese dog presented with a month-long history of progressive nonambulatory tetraparesis. MRI revealed a well-defined, centrally nonenhanced, T1-weighted hypointense, extradural structure located in the vertebral canal at the level of the C5 vertebral body. CT demonstrated a hypoattenuating, space-occupying structure in the same area. Surgery revealed a long, narrow parasite in the epidural space. An adult Dirofilaria immitis was confirmed by multiplex polymerase chain reaction (PCR) assay. This is a novel report describing the MRI and CT features of cervical epidural dirofilariasis in a dog.

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The diagnosis of skin lesions involving the eyes can be challenging, especially when uncommon etiologies are considered. We present a case of a 52-year-old female initially diagnosed with blepharoconjunctivitis but later found to have a subcutaneous heartworm infection. The patient experienced recurrent episodes of unilateral palpebral edema, pain, pruritus, and a sensation of a foreign body in her eye. Upon examination, a vermiform structure with peristaltic movements was observed, raising suspicion of subcutaneous dirofilariasis and prompting further investigations. Serological tests confirmed the presence of anti-Dirofilaria spp. antibodies. Surgical removal of the worm led to the resolution of symptoms. This case highlights the importance of considering uncommon etiologies, such as subcutaneous heartworm infection, in patients presenting with atypical migratory skin lesions or ocular manifestations when there is no definite diagnosis and the condition does not respond to usual medical treatment.

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BACKGROUND: Dirofilaria immitis, commonly known as heartworm (HW), is a parasitic nematode transmitted by various mosquito species, leading to heartworm disease (HWD) in dogs. Diagnosis of HW typically involves antigen or microfilariae detection, or visualization of adult worms through imaging or post mortem examination. Polymerase chain reaction (PCR) and micro RNA (miRNA) detection have been explored for HW diagnosis. METHODS: Three dogs, previously experimentally infected with HW, underwent blood sampling every 4 weeks for 7 months. Samples were assessed for antigen presence after heat treatment, PCR amplification, and microfilaria examination using Giemsa-stained thick smears. Additionally, whole blood aliquots underwent miRNA deep sequencing and bioinformatic analysis. RESULTS: Heartworm antigen was detectable after heat treatment at 20 weeks post-inoculation and via PCR at 24 weeks, with microfilariae observed in peripheral blood smears at 28 weeks. However, deep miRNA sequencing revealed that the miRNA candidate sequences are not consistently expressed before 28 weeks of infection. CONCLUSIONS: While ancillary molecular methods such as PCR and miRNA sequencing may be less effective than antigen detection for detecting immature larval stages in an early stage of infection, our experimental findings demonstrate that circulating miRNAs can still be detected in 28 weeks post-infection.

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Although Dirofilaria immitis in dogs is considered enzootic in northern Greece, the available data on the occurrence of infection in southern parts of the country demonstrate its scarcity. The aim of this study was to update the current knowledge on D. immitis infection in dogs in areas of Greece previously considered non-enzootic (Central Greece, Attica, Peloponnese, North Aegean, South Aegean, Crete and the Ionian islands). In total, 1528 dog blood samples were collected from the aforementioned areas and examined by Dirochek® ELISA (Synbiotics). Additionally, data published until 2022 on the prevalence of infection in these areas were compared to the data of this study. The 'Wilson' Score interval method (Epitools) was employed. Overall, 10.8% of dogs were positive for D. immitis. In detail, the prevalence was 21.7, 13.7, 10.7, 5.4, 4.7, 6.2 and 17.0% for D. immitis, in Central Greece, Attica, Peloponnese, North Aegean, South Aegean, Crete and the Ionian islands, respectively. Infection with D. immitis is recorded for the first time in Crete. The probability of a dog becoming infected has increased 4.1 times since 2022 in previously non-enzootic areas. This study denotes the spread of D. immitis and highlights the necessity for preventive measures.

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Heartworm disease caused by the nematode Dirofilaria immitis is one of the most important parasitoses of dogs. The treatment of the infection is long, complicated, risky and expensive. Conversely, prevention is easy, safe, and effective and it is achieved by the administration of macrocyclic lactones (MLs). In recent years, D. immitis strains resistant to MLs have been described in Southern USA, raising concerns for possible emergence, or spreading in other areas of the world. The present study describes the first case of ML-resistant D. immitis in a dog in Europe. The dog arrived in Rome, Italy, from USA in 2023. Less than 6 months after its arrival in Italy, the dog tested positive for D. immitis circulating antigen and microfilariae, despite it having received monthly the ML milbemycin oxime (plus an isoxazoline) after arrival. The microfilariae suppression test suggested a resistant strain. Microfilariae DNA was examined by droplet digital PCR-based duplex assays targeting four marker positions at single nucleotide polymorphisms (SNP1, SNP2, SNP3, SNP7) which differentiate resistant from susceptible isolates. The genetic analysis showed that microfilariae had a ML-resistant genotype at SNP1 and SNP7 positions, compatible with a resistant strain. It is unlikely that the dog acquired the infection after its arrival in Europe, while it is biologically and epidemiologically plausible that the dog was already infected when imported from USA to Europe. The present report highlights the realistic risk of ML-resistant D. immitis strains being imported and possibly transmitted in Europe and other areas of the world. Monitoring dogs travelling from one area to another, especially if they originate from regions where ML-resistance is well-documented, is imperative. Scientists, practitioners, and pet owners should be aware of the risk and remain vigilant against ML-resistance, in order to monitor and reduce the spreading of resistant D. immitis.

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Previous reports of macrocyclic lactone (ML) resistance in Dirofilaria immitis, the parasitic nematode which causes heartworm disease, have mainly been from the southern Mississippi Delta region. Southeast Missouri (SEMO), forming the northern boundary of this region, has not previously been well studied. The area is an ideal propagation region for heartworm infection and possibly for the spread of ML resistance. To assess whether D. immitis isolates infecting domestic canines in SEMO exhibit evidence of resistance to MLs, domestic canines, presented to veterinary facilities testing positive for heartworms through antigen and microfilariae (MF) examination, were utilized in the study. Using a descriptive epidemiological cross-sectional study, from March 2021 through February 2022, blood sample collection from 96 canines living in SEMO testing positive for heartworms were analyzed. MiSeq technology was utilized to sequence specific genetic markers associated with susceptibility/resistance for MLs in D. immitis isolates. Genomic data revealed most D. immitis isolates had genotypic profiles consistent with resistance to MLs. Of the 96 samples tested, 91 (94.8%) had a resistant genotype, 4 (4.2%) had a mixed genotype, and 1 sample (1%) genotyped as susceptible. While detailed and reliable medical histories were not available for most canines, detailed medical history from 2 canines indicated evidence of phenotypic resistance that was consistent with their genotypes. However, in vivo preventive tests are needed to confirm a high frequency of phenotypic ML resistance in D. immitis from this region. Increasing resistance patterns to MLs indicate the approach to heartworm prevention/treatment protocol should be reconsidered. New measures may be required to stop heartworm disease.

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Dirofilaria immitis infection is routinely detected in dogs during veterinary care in tropical and subtropical regions worldwide. Parasitological tests for the detection of this infection are routinely performed only in areas with a high prevalence. Baixada Fluminense, a region in Rio de Janeiro, was considered heartworm-free until local veterinarians began to receive blood exams results indicating the presence of microfilariae (MF). A laboratory database was hence used to collect data from 2017 to 2020 to understand the extent of spread of the parasite in this area. The results of complete blood count analysis and MF or heartworm antigen detection tests conducted on canine samples sent from veterinary clinics in Baixada Fluminense (Magé, Duque de Caxias, Guapimirim, Nova Iguaçu, and São João de Meriti municipalities) were included. In total, the results of 16,314 hematological tests were considered. The overall prevalence of D. immitis was 3.4% (554/16,314), considering that only one test result was obtained per animal on the same day. This study is highly relevant because it indicates the spreading geographic distribution of the worms, heightens awareness among local health professionals and the general population, and encourages compliance with prophylactic measures to prevent further spread of parasite.

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BACKGROUND: Macrocyclic lactones (MLs) are the only class of drugs currently commercially available that are effective for preventing heartworm disease. The data presented in this article provide information on the efficacy of oral moxidectin against JYD-34, a known ML-resistant Dirofilaria immitis isolate, when dogs are treated under various dosing regimens. METHODS: Fifty-two purpose-bred Beagle dogs were used in five laboratory studies. All dogs were inoculated with 50 D. immitis third-stage larvae (L3) (JYD-34 isolate) 30 days prior to the first treatment. Dogs were randomized to treatment (four to five animals in each group) with one, three, or five monthly doses of oral moxidectin ranging from 6 to 100 µg/kg body weight. In each study, control dogs were not treated. Five to 6 months after L3 inoculation, dogs were euthanized, and adult worms were counted to evaluate efficacy of the dosing regimens. RESULTS: Adult heartworms were recovered from all control dogs, with an overall geometric mean of 29.7 worms (range 15.2 to 38.0, individual counts ranged from 8 to 51). Five monthly doses of 6 µg/kg provided 83.3% and 90.2%, efficacy, and the same number of monthly doses of 9 µg/kg demonstrated 98.8% and 94.1% efficacy. Three monthly doses of 30 and 50 µg/kg demonstrated 97.9% and 99.0% efficacy, respectively, while a single dose of 100 µg/kg demonstrated 91.1% efficacy. CONCLUSIONS: Five monthly doses of 9 µg/kg provided similar or only marginally lower efficacy against JYD-34, a known ML-resistant isolate, compared to substantially higher doses administered for 3 months. This underscores the importance of duration of exposure to moxidectin when facing ML-resistant isolates. Repeated administration of lower doses of moxidectin are an alternative to higher doses in the prevention of heartworm disease associated with less susceptible or resistant isolates.

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A 9-year-old dog was presented with weight loss, respiratory effort, and an enlarged abdomen. Imaging studies and exploratory surgery showed pulmonary and splenic masses and bi-cavitary effusion, later classified as hemorrhage. Cytology of the peritoneal and pleural fluids also revealed several microfilariae. Immunologic and molecular analyses confirmed Dirofilaria immitis infection and histopathology of the spleen indicated a cavernous endothelial proliferation with undefined etiology (hemangiosarcoma vs reaction to parasite infestation). The nematode larvae are speculated to have entered body cavities via erratic migration or via hemorrhage and visceral lesions to be related to parasitism. Nematode infection should be considered as a differential diagnosis for internal bleeding of undetermined origin.

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Dirofilaria immitis is a mosquito-borne nematode-causing canine heartworm disease, with adult worms localized in the pulmonary arteries and right heart. In rare cases, ectopic migration might occur, and adults and blood circulating microfilariae can be found in unusual organs or fluids (e.g., eyes, abdominal cavity, bone marrow, and urine). A 17-year-old mixed-breed female dog was presented in a private veterinary clinic in Italy for hematuria and dysuria. Physical examination showed cardiac mitral murmur with marked respiratory distress and cyanotic mucous membranes after handling. Abdominal ultrasounds revealed a non-specific chronic cystopathy, while the echocardiography showed enlargement of the right heart associated with tricuspid insufficiency and mitral regurgitation, with the presence of an adult filariae in the right ventricular chamber. Circulating microfilariae were observed in the blood smear and molecularly identified as D. immitis. Unusual microfilaruria was detected in the urine sediment. Data presented raise awareness about the occurrence of microfilariae in unusual locations, such as the bladder, suggesting the need of a thorough clinical and laboratory assessment where D. immitis is endemic.

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NexGard®PLUS (moxidectin, afoxolaner, and pyrantel pamoate), is an oral combination product for dogs indicated for the prevention of heartworm disease, the treatment and prevention of flea and tick infestations, and the treatment of gastro-intestinal nematode infections. The safety of this product in dogs was evaluated in three studies. Study #1 was a margin-of-safety study conducted in puppies, dosed six times at 28-day intervals at 1X, 3X, or 5X multiples of the maximum exposure dose (equivalent to 24 µg/kg moxidectin, 5 mg/kg afoxolaner, and 10 mg/kg pyrantel). In Study #2, the product was administered to ABCB1-deficient collie dogs at a 1X dose twice at a 28-day interval, and at a 3X or 5X dose once. Study #3 evaluated the safety of the product at 1X and 3X doses administered three times at 4-week intervals, to dogs harboring adult Dirofilaria immitis. In the three studies, the safety was evaluated on the basis of multiple clinical observations and physical examinations, including a complete assessment of toxicity to macrocyclic lactones, and on comprehensive clinical and anatomical pathology evaluations in Study #1. No clinically significant combination product-related effects were observed in any of the three studies. No signs of macrocyclic lactone toxicity were observed in the ABCB1-deficient collie dogs. Some mild and self-resolving instances of emesis or diarrhea were occasionally observed in the 3X and 5X dosed dogs. NexGard® PLUS was demonstrated to be safe following multiple administrations in puppies, in ABCB1-deficient collie dogs, and in microfilaremic dogs infected with adult D. immitis.

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