Angiostrongylus vasorum is a metastrongyloid nematode with a complex indirect lifecycle. The adult L5 stage of A. vasorum resides and deposits its eggs in the right side of the heart and pulmonary arteries of dogs that act as the definitive host (Ridyard, 2005; Morgan and Shaw, 2010). The eggs hatch to first-stage larvae (L1), which penetrate the alveoli, migrate up to the oropharynx, after which they are swallowed and then excreted in the faeces. The L1s are ingested by an intermediate host, commonly snails and slugs (Helm et al, 2010), however, there is also evidence of the common frog (Rana temporaria) acting as a paratenic host (Bolt et al, 1993). The dog ingests the intermediate or paratenic host containing infective third-stage larvae (L3). L3s cross the intestinal wall and migrate to the abdominal lymph nodes, where they moult to fourth-stage larvae (L4); then enter the portal circulation, migrate via liver parenchyma and ultimately reach the right ventricle and pulmonary arteries, where they mature to the adult L5 stage. A. vasorum deposits of immunoglobulins (IgA, IgG, IgM), complement (C3), and fibrinogen have been reported in the lungs of infected dogs during the acute phase of infection (~1–2 months post-infection). Wild canids, such as red foxes (Vulpes vulpes) can be infected and serve as reservoir hosts (Sreter et al, 2003). A. vasorum has also been reported in wolves (Canis lupus), coyotes (Canis latrans), jackals (Canis aureus), and other wild canid species (Elsheikha et al, 2014).
The clinical signs relating to canine angiostrongylosis range from mild to severe depending on the worm burden (Ridyard, 2005). In general, there are three common clinical presentations. Cardiopulmonary signs are the most predominant, nevertheless coagulopathies and neurological signs are also observed (Conboy, 2011). Cases are recognised beyond UK endemic regions (Helm et al, 2010), highlighting the importance of robust knowledge of the clinical presentation, diagnosis, prevention and management of canine angiostrongylosis. A previous survey has reported that fenbendazole is the most frequently used drug, by 45% of the surveyed veterinary surgeons, for treatment of established cases of canine angiostrongylosis (Shuttleworth et al, 2018), however, fenbendazole is unlicensed for this purpose in the UK and there is no clear treatment protocol. Licensed anthelminthics, such as moxidectin/imidacloprid and milbemycin oxime are available to treat and prevent canine angiostrongylosis (Helm et al, 2010; Shuttleworth et al, 2018).
Supportive treatment options are available and can be effective. For example, oxygen supplementation and bronchodilators are reported to have been used for treatment of respiratory distress, while whole blood transfusions, packed red blood cells or fresh frozen plasma can replace erythrocytes and coagulation factors lost as a result of haemorrhagic diathesis. Some dogs can suffer from pulmonary arterial hypertension (Paradies et al, 2021), and thus diuretics (e.g. furosemide) and angiotensin converting enzyme (ACE) inhibitors (e.g. benazepril) can be used to control the effects of cardiac dysfunction. Antibiotics can be administered on the basis of culture to treat secondary infections (Helm et al, 2010; Di Cesare and Traversa, 2014). However, opportunistic bacterial infections are uncommon and ACE inhibitors are rarely needed.
There are three indications for using anti-inflammatory medications as supportive treatments: management of inflammation; anaphylaxis; and immune-mediated thrombocytopenia (IMTP). First, pulmonary inflammation arises from the deposition of eggs, migration of larvae, and the presence of adult worms in pulmonary vessels, which can lead to secondary fibrosis of the lungs and verminous pneumonia (Søland and Bolt, 1996; Gredal et al, 2011). Corticosteroids have an anti-inflammatory effect (Liyanage et al, 2017), hence could be used to ameliorate A. vasorum induced inflammation (Tebb et al, 2007; Koch and Willesen, 2009), similarly NSAIDs can also reduce inflammation (Lascelles et al, 2005). Furthermore, anaphylaxis can occur in canine angiostrongylosis following anthelmintic treatment, as a result of the rapid release of A. vasorum antigens after death of the worms. Levamisole increases this risk because it kills nematodes comparatively fast (Søland and Bolt, 1996). It is an acute hypersensitivity response which can be fatal (Shaker et al, 2020). Therefore, the short-term use of immunosuppressive doses of corticosteroids, has been suggested alongside anthelmintic treatment, to prevent or reduce the anaphylaxis risk (Søland and Bolt, 1996; Whitley et al, 2005; Helm et al, 2009; Willesen et al, 2008). Additionally, IMTP is reported to be a possible cause of bleeding in A. vasorum infections (Gould and McInnes et al, 1999). IMTP occurs when macrophages destroy platelets (Lewis and Meyers, 1996), thus immunosuppressive doses of corticosteroids can be used (Koch and Willesen, 2009; Helm et al, 2010) as they could disrupt the platelet destruction (Rozanski et al, 2002). However, this is a rare indication for corticosteroid use because thrombocytopenia in A. vasorum infections is typically as a result of consumptive processes/chronic disseminated intravascular coagulation, rather than IMTP. Unlike corticosteroids, NSAIDs do not have immunosuppressive effects so are not used in the management of anaphylaxis and IMTP.
Despite these significant indications for use there has been little research on anti-inflammatory drugs as a supportive treatment for canine angiostrongylosis, hence evidence of their effectiveness is lacking. While corticosteroids are used as a supportive treatment (Koch and Willesen, 2009) there is limited research on their administration. NSAIDs also have anti-inflammatory actions (Lascelles et al, 2005), however, they are not commonly used as a supportive treatment presumably to avoid the risk of coagulopathy (Barr and Bell, 2020). The aim of this study was to determine the prevalence of anti-inflammatory drug use, in a small cohort of veterinarians, as a supportive treatment for canine angiostrongylosis in addition to the rationale for their use in supportive therapy. A further aim was to determine whether there are differences in prescribing tendencies or rationale between a known endemic (South East England), and as yet non-endemic (Yorkshire), region of the UK. It is hypothesised that the prevalence and reasoning for the use of antiinflammatory drugs will be inconsistent. It is also postulated that veterinarians from the South East will be more aware of A. vasorum treatment, as they are likely to have encountered more cases in this endemic area.
Methods
Population of interest
The survey population included veterinarians from Yorkshire and South East England. These two regions were selected because of the incidence variability in A. vasorum cases. According to the Bayer lungworm map (Bayer, 2020), Yorkshire has the lowest prevalence, and the South East has the second highest. London, the most prevalent, was excluded as this study sought to compare regions of a similar surface area and veterinary practices covering several counties.
Survey design
The survey was produced online, making it easily accessible by a URL link. The initial page introduced the research aim, and the short completion time of 5–10 minutes was highlighted to encourage participation. It also stated that all data would be anonymised and consent for usage was required. The survey comprised ten questions over four sections. Demographics and practice name were requested, so agerelated differences in prescribing tendencies between veterinarians could be identified, and practice responses tracked. Information on practice policies relating to A. vasorum treatment were collated along with disease frequency, followed by if they would use corticosteroids, NSAIDs, or both as a supportive treatment for canine angiostrongylosis and their reasoning. Closed questions were used to obtain a clear response to provide quantitative research findings. Open questions followed allowing reasoning to be elicited. An optional prize draw was offered to a randomly chosen participant to encourage participation.
Piloting and administration of the survey
To evaluate the survey a small pilot survey was conducted, comprising two veterinarians, including a parasitologist. This elicited important feedback resulting in removing three questions for irrelevancy and similarity. Additionally, one question was re-worded, and another had its multiple-choice options modified. In total 24 veterinary practices were chosen from each region, South East England and Yorkshire, and were stratified according to their practice type (independent, corporate-owned or referral). Ten independent, 11 corporate-owned, and three referral practices were contacted from both regions to identify any policy differences for the management of A. vasorum. Of the 24 practices from each region, 11 agreed to participate from Yorkshire (five independent, four corporate-owned and two referral), and 13 from the South East (five independent, seven corporateowned and one referral). These were randomly chosen from a list of practices per county from the RCVS website (RCVS, 2020). Yorkshire comprises four counties, namely the East Riding of Yorkshire (n = five practices), North Yorkshire (n = six practices), South Yorkshire (n = seven practices), and West Yorkshire (n = six practices), whereas South East England comprises nine counties, namely Berkshire (n = three practices), Buckinghamshire (n = two practices), East Sussex (n = four practices), Hampshire (n = six practices), Kent (n = one practice), Oxfordshire (n = two practices), Surrey (n = four practices), and West Sussex (n = two practices). The remaining South East county, the Isle of Wight, was excluded from this study. The survey received ethical approval from the University of Nottingham School of Veterinary Medicine and Science and was forwarded to these practices for circulation in October 2020, providing 7 days for completion.
Data analysis
The survey responses were recorded in Microsoft® Excel (Microsoft Corporation, 2016) and graphs were compiled.
Results
Response rate
Ten of 24 practices responded, giving a 42% practice response rate. Five responded from the South East (three corporate-owned and two independent), and five also responded from Yorkshire (one corporate-owned, two independent and two referral). One veterinarian responded from each of the 10 practices and the respondent age categories comprised 22–30 years old (50%), 31–40 years old (10%), 41–50 years old (20%) and 51–60 years old (20%).
Practice policies
Respondents from the South East on average see canine angiostrongylosis cases annually (60%), less than once per year (20%), or never (20%) (Figure 1). In contrast, fewer respondents from Yorkshire encountered angiostrongylosis annually (40%), and significantly 60% had never encountered angiostrongylosis (Figure 2). Only 30% of practices were found to have a protocol or professional guidelines relating to the treatment of A. vasorum (Figure 3), of which one-third were corporate-owned and two-thirds were independent. One respondent was unaware if their practice had a protocol. Two of three practices with a treatment protocol would prescribe 7 days of fenbendazole, with one of these practices citing a dose of 50 mg/kg for fenbendazole and that paracetamol would also be administered at 10 mg/kg twice daily. The remaining practice would prescribe Advocate® (Elanco UK AH Ltd), containing the active ingredients imidacloprid and moxidectin (National Office of Animal Health (NOAH), 2020).
Corticosteroids in the treatment of canine angiostrongylosis
Only one veterinarian, from the South East, would always administer corticosteroids to a dog with canine angiostrongylosis (10%), citing prevention of anaphylaxis as the rationale. The majority (70%) would sometimes with reasons cited to reduce inflammation (2/7), if NSAIDs proved ineffective (1/7), or that it would be case dependent (4/7), including severity of clinical signs. For example, one respondent would consider administering 0.5 mg/kg prednisolone once daily if the patient had respiratory distress and severe pneumonia. Whether the action of corticosteroids in the short-term, however, is predominantly anti-inflammatory or immunosuppressive will depend on the dose used. Corticosteroids are typically used for weeks at anti-inflammatory doses (0.5 mg/kg) to reduce bronchial inflammation and associated clinical signs. In contrast, much higher doses (1 mg/kg or greater) are used over shorter periods of time for immune suppression to control anaphylaxis or IMTP.
Those that would never administer corticosteroids (20%) claimed either they had never considered it or that immunosuppressive actions may negatively impact the outcome. The regional differences for corticosteroid use are illustrated in Figure 4.
NSAIDs in the treatment of canine angiostrongylosis
Only one veterinarian surveyed would always administer NSAIDs to a dog with canine angiostrongylosis (10%), citing reducing pain, inflammation, and pyrexia as their reasoning. Those who would sometimes administer NSAIDs (30%) claimed it would depend on the clinical signs or burden, including the severity of inflammation. The majority (60%) said they would never administer NSAIDs, with four of six mentioning the coagulopathy risk. The remaining two respondents had either not considered it or would use corticosteroids instead. The regional differences for NSAID use are illustrated in Figure 4.
Discussion
Prevalence of use of anti-inflammatory drugs
One of the aims of this survey was to determine the current prevalence of use of anti-inflammatory drugs as a supportive treatment for canine angiostrongylosis. Four responding veterinarians who would sometimes administer corticosteroids cited that it would depend on the clinical presentation, indicating that corticosteroid use would depend on the infection's severity. The survey results also showed only 30% of practices had a treatment protocol, highlighting that in most practices A. vasorum treatment is dependent on the veterinarian managing the case. This choice may not be dependent on the clinical presentation as one responding veterinarian declared they would always administer corticosteroids to prevent anaphylaxis. No clear trends were identified between the different practice types or regional area relating to the likelihood of having a treatment protocol. Two of the three practices with a treatment protocol were from the South East, where the A. vasorum caseload is higher (Bayer, 2020), so arguably having an existing treatment protocol may be more likely, however further research would need to be conducted to validate this on a larger scale.
One website mentions the use of corticosteroids and aspirin as a supportive treatment for canine angiostrongylosis (Barr and Bell, 2020), although recommends that aspirin or any NSAIDs are not administered alongside potential coagulopathy disorders. This is important since coagulopathies are a common presentation in canine angiostrongylosis (Yamakawa et al, 2009) and NSAIDs may impair platelet aggregation, via inhibiting cyclooxygenase and blocking the formation of thromboxane A2, prolonging the bleeding time (Schafer, 1999; Lascelles et al, 2005). In the survey, 40% of veterinarians claimed they would never administer NSAIDs for this very reason, however, 60% did not acknowledge the increased bleeding risk. Of these, four of six would always or sometimes administer NSAIDs as a supportive treatment, which could clearly exacerbate the dog's recovery.
Overall, the results showed more veterinarians 80% (8 out of 10) would always or sometimes administer corticosteroids compared with NSAIDs 40% (4 out of 10). Figure 4 shows the only regional difference is one veterinarian from Yorkshire would always administer NSAIDs, whereas one veterinarian from South East England would always administer corticosteroids. The South East have more reported A. vasorum cases (Bayer, 2020), so may be more aware of effective treatment options, as a result of having more experience in managing cases. To confirm if there is a significant regional difference, a survey using a larger sample size is warranted. Interestingly, 40% (4 out of 10) of veterinarians indicated they would sometimes administer corticosteroids to a dog according to the severity of clinical signs. This can be the magnitude of any coagulopathies/thrombocytopenia, presenting neurological signs, or the degree of respiratory distress. In addition, the perception of a high worm burden might be the trigger to introduce prednisolone at the time of initiating therapy to reduce the chances of acute decompensation following worm death.
Management of inflammation, anaphylaxis and immune-mediated thrombocytopenia
The survey responses showed 20% would sometimes administer corticosteroids to reduce A. vasorum associated inflammation, suggesting it would depend on the inflammation's severity. Similarly, 10% would always and 10% would sometimes administer NSAIDs as a treatment for inflammation. One respondent claimed if NSAIDs proved ineffective they would administer corticosteroids. Only one respondent would administer corticosteroids to prevent anaphylaxis. In one study, prednisolone (1 mg/kg daily) was used to prevent anaphylaxis (Brennan et al, 2004). In other studies, dexamethasone alone (0.25 mg/kg once) (Boag et al, 2005) or (0.15 mg/kg once) (Tebb et al, 2007), or dexamethasone (0.1 mg/kg daily) combined with prednisolone (0.25–0.5 mg/kg 2x daily, tapered) (Boag et al, 2005) were used to reduce pulmonary inflammation, treat hypercalcaemia and prevent anaphylaxis. Other survey respondents may be unaware of the potential anaphylaxis, or that corticosteroids could be used as a preventative. Alternatively, they might think evidence behind corticosteroids preventing anaphylaxis is lacking or that the anaphylaxis risk is minimal, given this remains unknown (Di Cesare and Traversa, 2014). IMTP was not mentioned by the survey respondents, suggesting that some veterinarians remain unaware of its link to canine angiostrongylosis. Alternatively, they may consider IMTP treatment when it occurs rather than during initial treatment since it is an uncommon finding in A. vasorum infections.
Safety of anti-inflammatory drugs
Long-term administration of corticosteroids can lead to iatrogenic hyperadrenocorticism (Bexfield et al, 2006). Longer-term use of corticosteroids leads to inhibition of the hypothalamic-pituitary-adrenal axis (Bexfield et al, 2006). As a result of this, a tapered dosing schedule allows the recovery of endogenous corticosteroid production (Guignat et al, 2008). This approach avoids the risk of iatrogenic adrenal insufficiency and the clinical consequences thereof (Guignat et al, 2008). It is therefore vital to determine if and to what extent the efficacy of corticosteroids outweighs the adverse effects. As previously highlighted NSAIDs have been reported to alter some aspects of the clotting cascade (Lascelles et al, 2005), which could make the outcome of having IMTP significantly worse.
One survey respondent confirmed they would not administer corticosteroids to treat inflammation because of the immunosuppressive actions. This highlights the varied role of corticosteroids in the management of inflammatory disease. In canine angiostrongylosis the use of corticosteroids is aimed at reducing inflammation and not inducing immunosuppression. However, in cases presenting with IMTP the dose would be higher and aimed at immunosuppression. The range of doses would, therefore, include 0.5 mg/kg to 2 mg/kg daily. The former being anti-inflammatory, which would be chosen in cases of canine angiostrongylosis when attempting to reduce inflammation, and in particular the acute deterioration that may occur when initiating therapy with anthelminthics. The latter dose would be selected when specifically attempting to treat the secondary IMTP. It is therefore apparent that among certain veterinary demographics this information needs to be more clearly delivered via undergraduate teaching and post-graduate continuing professional development (CPD) courses. Further confusion and an inadequate knowledge base on which prescribing is occurring with canine angiostrongylosis is highlighted by the same respondent, indicating they would administer NSAIDs without acknowledging the risk of exacerbating any pre-existing coagulopathy.
Limitations and further studies
One notable limitation of this study is the inability to determine the true prevalence of the use of anti-inflammatory drugs as a supportive treatment for canine angiostrongylosis. Other limitations are inherent to the retrospective design of the study, including the reliance on veterinarians to respond to a defined set of questions as opposed to direct face-to-face interviews, which allows discussion of open-ended questions. Thus, specific information on corticosteroid dose administered, recognition of differing actions at different doses, and the exact number of cases seen by veterinarians annually could not be obtained. Also, conclusions of the present study are limited by the relatively small number of participants. The two regions selected were based on prevalence of cases of canine angiostrongylosis according to the Bayer lungworm map during September 2020 (Bayer, 2020). The number of reported cases were 848 in the South East and 84 in Yorkshire. However, cases are reported voluntarily so the true prevalence is likely to be considerably greater than those reported. The low response rate provided a small sample size which could not be considered representative of the regional population. Therefore, meaningful conclusions could not be extrapolated and significant variations between ages, regions and practice type were unidentified. No responses emerged from the 60+ age category and the 22–30 age group was overrepresented, thus opinions from more experienced veterinarians may have been lacking. In future work, a prospective, or at the very least, a retrospective study with survival data, is required to determine any beneficial use of corticosteroids and thus when all veterinary professionals should utilise them as a supportive treatment for canine angiostrongylosis to control A. vasorum associated inflammation, anaphylaxis and IMTP.
Conclusions
The low number of respondents meant that the true prevalence of the use of anti-inflammatory drugs as a supportive treatment for canine angiostrongylosis could not be calculated. It could depend on the infection's presentation, or simply at the discretion of the veterinarian as some practices lack a clear treatment protocol. It is suggested that practices covering endemic areas are more likely to hold treatment protocols given the prevalence within these areas. Overall, more veterinarians would administer corticosteroids over NSAIDs. They would administer corticosteroids depending on the clinical situation, to reduce inflammation, or prevent anaphylaxis, but IMTP was never mentioned. One respondent would not administer corticosteroids because of their immunosuppressive effects, although these are desirable in some aspects of the clinical syndrome induced by canine angiostrongylosis. The use of NSAIDs was mainly to reduce inflammation, while the majority would never administer them, significantly some veterinarians would despite the increased coagulopathy risk. The disparate survey responses indicate an intrinsic lack of understanding for if, when and why, antiinflammatory drugs should be administered as a supportive treatment for canine angiostrongylosis, conceivably because of the lack of conclusive research evidence and uncertainties about the treatment effects. It is therefore imperative that further research is conducted to address these questions and serve to direct future efficacious therapeutics for canine angiostrongylosis.