Pathophysiology

Systemic diseases that result in stasis of blood flow, hypercoagulability, and disruption of the endothelial layer in the vasculature can result in the complication of pulmonary thromboembolism (PTE). In dogs, immune‐mediated hemolytic anemia, sepsis, neoplasia, amyloidosis, hyperadrenocorticism, and dilated cardiomyopathy are associated with increased risk for PTE, while neoplasia and cardiomyopathy are found most often in cats with PTE (Johnson et al. 1999b; Norris et al. 1999). Pancreatitis is a risk factor for hypercoagulability with venous embolization in humans, and this is likely the case in dogs also.

PTE results in multiple pathophysiologic events that affect gas exchange. Physical obstruction of large pulmonary arteries by clot material increases intravascular pressure, and release of clot‐associated vasoactive factors (e.g. thromboxane) causes reactive pulmonary vasoconstriction. Elaboration of humoral mediators (e.g. serotonin, histamine, calcium, and growth factors) from platelets results in bronchoconstriction and increased airway resistance. Surfactant is a phospholipid compound comprised of hydrophilic and hydrophobic proteins that develop the surface tension‐lowering properties within the alveolus to stabilize the gas exchange region. Large surfactant aggregates are more active in lowering surface tension, and embolization reduces the ratio of large to small aggregates at the alveolus, potentiating alveolar collapse and increasing shunt fraction. Capillary leakage of plasma into the alveolus further inhibits surfactant activity through a dilutional effect. These changes contribute to loss of elastic recoil and atelectasis, decreased pulmonary compliance, and increased right‐to‐left shunting. Alveolar dead space is increased with PTE because of non‐perfused lung regions, and this leads to increased work of breathing.

History and Signalment

PTE affects any age or breed of animal because it is secondary to underlying disease processes that affect animals of different signalments. Immune‐mediated hemolytic anemia (IMHA) tends to occur in young to middle‐aged female dogs and cardiomyopathy is more common in younger cats, while pancreatitis tends to affect middle‐aged to older dogs. Therefore, the underlying disease process will determine the age of an affected animal. History and clinical signs reflect the underlying disease process, however the acute onset of respiratory distress and tachypnea in a seriously ill animal should trigger suspicion for PTE. Recent trauma or surgery might also lead to PTE.

Physical Examination

Animals with PTE often display relentless tachypnea and breathlessness that is refractory to supplemental oxygen administration. Harsh lung sounds or loud bronchovesicular sounds can sometimes be detected; however, crackles or wheezes are less common. PTE can result in mild pleural effusion and rarely, dampened heart and lung sounds might be encountered. General physical examination findings usually reflect the underlying disease process. For example, pale mucous membranes are present in animals with IMHA, a heart murmur, arrhythmia, or gallop sound would be anticipated in the patient with cardiac disease, or a pot‐bellied appearance could be found in the dog with Cushing’s disease.

Diagnostic Findings

Diagnostic testing is directed at determining the underlying cause for embolization and assessing the severity of gas exchange abnormalities. A complete blood count (CBC), chemistry panel, and urinalysis are indicated to evaluate systemic health, while pulse oximetry or arterial blood gas analysis can be used to document hypoxemia and hypocapnia. Cardiac biomarkers such as troponin have not proven helpful in the diagnosis of pulmonary embolization (Goggs et al. 2014). A coagulation panel is generally indicated in the work‐up of suspected PTE to assess the intrinsic pathway (activated partial thromboplastin time: APTT; activated clotting time: ACT), the extrinsic pathway (one‐stage prothrombin time: OSPT), and fibrin degradation products or D‐dimer (see Figure 2.1). D‐dimer, a breakdown product of cross‐linked fibrin, has some utility in assessing the risk of embolization in humans, but unfortunately this assay performs poorly in dogs, with multiple disease processes leading to an elevated D‐dimer (Epstein et al. 2013; Goggs et al. 2014). A very low or negative D‐dimer is sensitive for ruling out PTE in humans, but a normal value can sometimes be found in affected dogs (Epstein et al. 2013). Antithrombin levels are also measured in animals at risk of PTE, because loss of this anticoagulant enhances the risk for clot formation. Thromboelastography, a coagulation test that can identify hypo‐ and hypercoagulable states by assessing the speed, efficiency, and strength of clot formation, has questionable value in documentation of PTE (Goggs et al. 2014), but might prove useful in management of patients at risk for PTE and for monitoring anticoagulant therapy.

Thoracic radiographs can be relatively unremarkable (Figure 8.1) and a variety of pulmonary infiltrates have been reported in dogs with thromboembolization, as well as mild pleural effusion. Review of thoracic radiographs will sometimes reveal pulmonary vascular abnormalities such as uneven distribution of perfusion or blunted pulmonary arteries. Detection of these abnormalities would facilitate early diagnosis in an animal with risk factors for PTE.

Confirmation of embolization is difficult and requires perfusion scanning with 99‐ technetium‐labeled macroaggregated albumin (Figure 8.2), ventilation/perfusion scanning, or computed tomography pulmonary angiography (CTPA). Perfusion scanning could be a valuable clinical tool because it can be done in the awake animal; however, it is only available at specialty hospitals and requires radiation isolation after the scan, which could compromise care in an unstable patient. This technique has documented that pulmonary embolization is common in dogs after cemented total hip replacement (Liska and Poteet 2003); but it has not been evaluated for use in animals with cardiopulmonary disease or other risk factors for PTE. CTPA is used commonly in human medicine and has been employed in veterinary patients to establish filling defects in the pulmonary vasculature consistent with PTE (Goggs et al. 2014) but CT is not widely used because anesthesia is required to obtain a detailed, high speed helical scan with contrast injection. Echocardiography might be helpful in increasing suspicion for the diagnosis of PTE because a clot could be visible in the right atrium or pulmonary artery, or indirect evidence of right ventricular overload might be seen, such as right ventricular dilation, flattening of the right ventricular septum, or a high probability of pulmonary hypertension (PH).

Treatment

Control of the primary disease process is essential in managing PTE. Oxygen therapy is recommended for all animals initially, although the respiratory pattern may not improve dramatically because of alterations in central respiratory control, associated either with the physiology of embolization or due to central infarcts. Animals that do not have intrapulmonary shunting will show improved hemoglobin saturation with oxygen while on supplementation; however, not all dogs with PTE are oxygen responsive (Johnson et al. 1999b).

Classically antiplatelet drugs would be indicated for venous clots such as PTE, while anticoagulants would be used for arterial emboli. Thromboembolism results in hypercoagulability due to both tissue factor activation of clotting and platelet activation, therefore multi‐pronged treatment is utilized to reduce clotting and limit further deposition of fibrin on existing clots. Selection of specific medications often depends on the availability of drugs in an appropriate formulation and dose, the method of delivery preferred, side effects of the medications, and client finances.

Heparin bound to antithrombin inactivates some clotting factors – thrombin factor (IIa), factors Xa, IXa, XIa, and XIIa – and prevents further accumulation of fibrin on a clot. Subcutaneous heparin at an initial starting dose of 200–300 U/kg subcutaneously (SQ) two to three times a day (BID–TID) is administered to prolong the APTT two to three times the normal value, and dosing is tailored to the individual for maximal efficacy in clot reduction. However, in most hospitals, the use of heparin has been supplanted by administration of low‐molecular‐weight heparins (LMWH). Examples of LMWH agents include enoxaparin (Lovenox®, Sanofi‐Aventis, Bridgewater, NJ) and dalteparin (Fragmin®, Pfizer, New York). This class of drug acts similarly to heparin in inhibiting further clot formation, but has greater inhibition of factor X versus factor II, and therefore does not prolong the APTT or theoretically result in hemorrhagic tendencies. Monitoring of drug efficacy requires an anti‐factor Xa assay. Experimental studies in dogs have revealed improved antithrombotic efficacy of LMWH over unfractionated heparin, and use of enoxaparin (0.8 mg/kg SQ TID) in dogs with IMHA was well tolerated (Panek et al. 2015), although the extent to which embolization was prevented is unclear. In cats, LMWH given at standard doses (enoxaparin at 1 mg/kg SQ BID) resulted in plasma levels that approach the human therapeutic range 4 hours after dosing, while administration of dalteparin (100 IU/kg BID) resulted in less predictable levels (Alwood et al. 2007; Vargo et al. 2009). Enoxaparin was rapidly cleared, suggesting that more frequent administration could be required for effective anticoagulation in cats.

Rivaroxaban (Xarelto®, Janssen Pharmaceuticals, Beerse, Belgium), an oral direct‐acting anti‐Xa anticoagulant, is another agent that has been utilized in management and prophylaxis of PTE. In dogs with IMHA administered rivaroxaban at 0.9 mg/kg PO daily, no adverse effects were noted, although no differences were detected in rate of thrombosis or survival in comparison to those treated with clopidogrel and aspirin (Morassi et al. 2016). Apixaban, another direct factor Xa inhibitor, did not result in clinical bleeding when used in combination with clopidogrel in healthy Beagle dogs (Gagnon et al. 2021); however in sick, hospitalized patients, close clinical monitoring is advised in dogs administered any factor Xa inhibitor to avoid life‐threatening gastrointestinal hemorrhage. Rivaroxaban was assessed as safe and well‐tolerated in healthy cats when administered at 1.25–5.0 mg/day (Dixon‐Jiminez et al. 2016), although studies in cats with embolic disease are lacking.

Antiplatelet therapy could also reduce the risk of clotting. A low dose of aspirin is used to inhibit cyclooxygenase activity without reducing endothelial cell production of prostacyclin. However, some dogs are genetically non‐responsive to aspirin, which could impact the efficacy of this drug. Aspirin does not appear to be very effective in cats and it is difficult to dose. Drugs in the thienopyridine class are irreversible adenosine diphosphate (ADP) receptor/P2Y12 inhibitors that reduce platelet activation. One such drug, clopidogrel (Plavix®, Sanofi, Paris, France) is safe and effective at inhibiting platelets in healthy cats at oral dosages of 18.75–75 mg once daily (Hogan et al. 2004), and various experimental studies in dogs at 2–4 mg/kg/day have shown that it reduces clotting. The efficacy of these drugs to treat or prevent embolization in animals with clinical disease remains uncertain.

With increasing certainty of the diagnosis of PTE or worsening condition of the patient, more aggressive therapy with a fibrinolytic agent such as tissue plasminogen activator (TPA) can be considered, and TPA has proven effective in limiting physiologic derangements associated with systemic embolization (Diaz et al. 2022). The efficacy of this therapy has not been fully established in animals with PTE, and in human medicine, fibrinolytic therapy is reserved for patients with hemodynamic instability.

Prognosis

Development of PTE is associated with a guarded prognosis, and mortality is high. Because of poor success in the treatment of PTE, prophylactic anticoagulant therapy should be considered in animals with diseases that have been shown to predispose to the condition. Clopidogrel is advised for platelet inhibition. LMWH and rivaroxaban are more costly but can also be used for prophylaxis when the risk of embolization is high.

Pathophysiology

Canine heartworm disease is a condition with essentially worldwide distribution, depending on the presence of the mosquito vector. It is most common in warm, humid environments, with the highest infection rates along the east coast of the USA, Gulf States, and Mississippi river valley. Southern Europe, Japan, China, India, South America, and Southeast Asia also have a large number of heartworm cases, as do other regions of the world where preventative medications are not widely used. Mosquitos deposit third‐stage larvae of Dirofilaria immitis under the skin. The larvae migrate into the right heart and pulmonary arterial system, where they develop into adult worms and begin producing microfilaria 5–7 months after infection. High worm burden is common in infected dogs, and disease results from obstruction of pulmonary arteries followed by right ventricular failure due to pressure overload. Heartworms also trigger pulmonary endothelial damage that can stimulate clot formation, with subsequent thromboembolization. Physical damage to the adult worm or death of the adult can lead to worm embolization. Heartworms also trigger a pulmonary hypersensitivity response that results in eosinophilic inflammation in the parenchyma. Antigen–antibody complex deposition in the kidneys can lead to a protein‐losing nephropathy, and heartworm infection can also cause hepatocellular damage.

Dirofilarial organisms commonly harbor the endosymbiont bacterium Wohlbachia, which helps the tissue larvae develop and survive and also aids adults in reproduction. This Gram‐negative, intracellular organism is thought to contribute to the inflammatory response of heartworm infection through activation of neutrophils and monocytes, and it could play a role in the pulmonary vascular pathology induced by heartworm infection. Thus, treatment of Wohlbachia is often employed to lessen the inflammatory response to death of dirofilarial organisms during heartworm treatment.

History and Signalment

Heartworm disease can be detected in dogs with no clinical complaints, or owners may note coughing, exercise intolerance, or an abnormal breathing pattern. Dogs with severe infections develop hemoptysis and signs of right‐sided heart failure, PH, or pulmonary embolization that can include respiratory distress, abdominal distention, and syncope.

Physical Examination

Dogs sometimes lack any physical evidence of heartworm disease. In dogs with mild disease, tracheal sensitivity can be present. With progressive severity of infection, dogs can appear cachectic and display manifestations of right‐sided heart failure, including ascites or hepatomegaly, icterus, jugular venous distension, a heart murmur or gallop sound, loss of lung sounds due to pleural effusion, or crackles associated with parenchymal disease.

Diagnostic Findings

Peripheral eosinophilia is commonly detected on a CBC in infected dogs. Chemistry panel and urinalysis should be closely scrutinized for evidence of liver dysfunction (indicated by an increase in alanine transaminase) and renal involvement (indicated by elevated blood urea nitrogen, increased creatinine, or the presence of proteinuria). When proteinuria is detected, a urine protein‐to‐creatinine ratio is recommended to gain an appreciation of the severity of glomerulonephritis.

Microfilaria can be detected by a modified Knott’s or filter test; however, microfilaremia will be found only in infected dogs that are not on heartworm‐preventive medication. Therefore, because most dogs are on some form of preventive, an antigen test is the recommended screening test. The test will be positive 6–7 months after infection, although a false‐negative antigen test can be encountered with infection by immature worms or by all male worms. In addition, formation of an antigen–antibody complex can interfere with identification of heartworm antigen in point‐of‐care tests. These immune complexes might be related to the inherent immune response of the individual dog or might result from administration of avermectins or doxycycline. A heat‐precipitated antigen test should be performed when there is a high suspicion of heartworm disease in a dog with a negative antigen test. When a positive antigen test is obtained, whole blood should be assessed for microfilaria.

Radiographic findings in canine heartworm disease vary depending on the severity of disease. Pulmonary arteries become progressively enlarged, blunted, and tortuous, parenchymal infiltrates progress, and right ventricular enlargement develops (Figure 8.3). Echocardiography detects the walls of the heartworm as parallel lines (Figure 8.4) and can demonstrate signs of right ventricular overload, including right ventricular dilatation, tricuspid regurgitation, and PH.

Treatment

Prior to adulticidal treatment, the severity of disease should be staged and clinical signs stabilized as indicated. Class 1 dogs are mildly affected, with few clinical signs and normal radiographic and laboratory findings. Class 2 dogs are moderately affected with cough or respiratory difficulty, have right heart enlargement on radiographs, and have abnormal laboratory values such as anemia or elevated liver enzymes. Class 3 dogs are severely affected with signs of right heart failure, severe radiographic abnormalities, and marked laboratory abnormalities. Class 4 dogs are those with caval syndrome.

Melarsomine dihydrochloride is the approved adulticidal treatment for canine heartworm disease. The American Heartworm Society recommends use of doxycycline (10 mg/kg PO BID) for 1 month and a macrocyclic lactone for 2 months (an avermectin or milbemycin) prior to a split‐dose protocol. This protocol entails administration of one deep intramuscular injection followed 1 month later by two intramuscular injections on alternate sides of the spine 24 hours apart. To perform the injection, a region on the spine between the third and fifth lumbar vertebrae is clipped and prepared with a surgical scrub. Following injection of melarsomine (2.5 mg/kg), the dog is confined in the hospital, with monitoring of respiratory rate and effort as well as for any other adverse effects. For dogs with persistent clinical signs and a positive antigen test after the set of two injections, a second treatment can be given in 4 months. Class 3 dogs appear to be at higher risk for embolization and can require further stabilization with oxygen, diuretics, vasodilators, inotropes, and corticosteroids as indicated prior to adulticidal treatment. Use of anticoagulants is controversial. Class 4 dogs are those with caval syndrome, and melarsomine is not recommended for these dogs. Stabilization and physical removal of worms by an interventional cardiologist are required.

All owners should be cautioned about the possibility of embolic disease following treatment and should understand the need for cage confinement for 1–2 months after treatment to limit the occurrence of this complication. Monthly preventive medication is continued in dogs with occult infection. If microfilaria are present, the initial dose of preventive medication should be given to the dog while hospitalized to monitor for adverse effects. Treatment recommendations for canine heartworm disease are continually updated and can be found at www.heartwormsociety.org.

A non‐arsenical treatment option that can be pursued utilizes topical 10% moxidectin/2.5% imidacloprid twice monthly for 3 months and then monthly along with doxycycline (10–15 mg/kg/day for 15 days) for Wohlbachia (Ames and Atkins 2020). Using this protocol, most dogs had converted to heartworm antigen negative status within 13 months and lacked detectable microfilaria. Exercise restriction is also warranted when using this slow kill protocol.

Any circulating microfilaria or developing larvae (L3 and L4) are eliminated over 6–9 months through administration of heartworm‐preventive medications. Ivermectin and milbemycin oxime are oral preparations given monthly and administered year round to help limit the spread and expansion of heartworm in the environment. Milbemycin is preferred for Collies or any Collie‐type dogs that might have the deletion mutation of the mdr1 (multi‐drug‐resistance‐1) gene. Selamectin and moxidectin are topically administered drugs that prevent heartworm disease. Moxidectin is also available as an injectable product that provides 6 months of prevention.

Prognosis

Dogs with mild to moderate heartworm disease have a good prognosis for uneventful treatment and full recovery, although melarsomine can be associated with various toxicities, including injection site reaction and neurologic signs (Hettlich et al. 2003). Dogs with class 3 and 4 disease are at increased risk for embolization during and after treatment and can develop long‐term cardiopulmonary disease associated with pulmonary arterial damage.

Heartworm‐preventive medications remain highly efficacious against heartworm infection, although they are not always 100% effective and emerging resistance to medications is becoming increasingly apparent (Snyder et al. 2011; Blagburn et al. 2016). Lack of owner compliance or failure to ingest the appropriate dose plays a role in development of infection despite use of preventative medication. This might be reduced by use of extended‐release injectable formulations, however, inherent resistance of new strains of heartworm cannot be completely ruled out.

Pathophysiology

The initial life cycle of heartworm in the cat is similar to that in the dog, with deposition of L3 larvae under the skin, followed by development into adult worms in the pulmonary artery approximately 4 months after infection. However, in the cat, infection with only one to two or up to six adult worms is typical and single‐sex infection is common. This feature, along with an augmented host response to the microfilaria, might explain the lack of microfilaremia in most cats. Antibody production can be detected within 2–3 months of infection, and heartworm antigen is present from 6 to 8 months post‐infection.

Arrival of immature adult worms in the pulmonary circulation has been proposed to stimulate an immune response within the vasculature that leads to clinical signs of cough or respiratory difficulty (Dillon et al. 2017). This has been referred to as heartworm‐associated respiratory disease (HARD), and clinical signs diminish as the worms mature. Similar to the dog, Wohlbachia species could play a role in the development of pulmonary pathology and resultant clinical signs in cats.

Cats do not attract mosquitos to the same extent as dogs and only 15–25% of cats develop infection after injection with D. immitis larvae. Many infected cats display no clinical signs and will self‐cure within 2–3 years; however, serious consequences have been reported with feline heartworm disease. Sudden death might result from an anaphylactic response to internal filarial antigens released with worm death (Litster et al. 2008). Interestingly, aberrant migration of heartworm larvae is relatively common in the cat, and cerebral infection is another potential cause for sudden death in cats.

The prevalence of heartworm disease in the cat relative to the dog is difficult to assess because documentation of disease remains elusive due to features of the tests themselves as well as the lack of routine screening. In an endemic area of Italy, prevalence of heartworm infection in cats was approximately 10% that of dogs (Venco et al. 2011), while in southern Florida in the USA, the ratio was approximately 1 case in cats for every 7 in dogs (Hays et al. 2021). The difficulty in confirming a diagnosis of heartworm disease in the cat was acknowledged in both studies. A recent serosurvey of heartworm exposure reported antibody positivity in 3.5% of healthy cats lacking clinical signs of disease, with the highest seropositivity in the western United States (Murillo et al. 2023). Seroprevalence of antigen positivity in North America also varies with geographic location. The highest number of positive results on a standard point‐of‐care enzyme‐linked immunosorbent assay (ELISA) was found in cats from the Hawaii, central west region, and southern USA (up to 1.6%) and the lowest (0%) in cats from Canada (Levy et al. 2017).

History and Signalment

Both indoor and outdoor cats can be infected with heartworm through mosquito exposure, although outdoor cats are at higher risk. Young to middle‐aged cats are affected most commonly, but cats of any age can be infected. The majority of cats do not develop disease associated with heartworm, but it has been recognized as a cause of a multitude of clinical signs, including chronic cough, acute respiratory distress, chronic tachypnea, vomiting unrelated to eating, neurologic signs related to aberrant migration, and lethargy. Unfortunately, sudden death can also occur, and in some cats respiratory or gastrointestinal signs are noted immediately before death.

Pathophysiology

Vascular infection with the metastrongyloid worm Angiostrongylus vasorum is responsible for the disease known as French heartworm disease. The worm is endemic in certain parts of the UK, Europe, Africa, and South America and has spread to Newfoundland, Canada (Chapman et al. 2004; Bourque et al. 2008). Angiostrongylus has been characterized by progressive spread across the world. The red fox is likely an important reservoir of infecting organisms (Elsheikha et al. 2014). Angiostrongylus infects dogs and foxes as its definitive host and is spread through ingestion of intermediate or paratenic hosts, including slugs, snails, and frogs that contain infective third‐stage larvae. Larvae are released in the dog’s intestine, migrate to intra‐abdominal lymph nodes, and gain access to the portal circulation. L4 travel to the pulmonary artery, right heart, or pulmonary arterioles, where development into the adult stage is completed. The pre‐patent period is typically 40–60 days but can be in excess of 3 months. Adults produce eggs that hatch to first‐stage larvae, penetrate the alveoli, are coughed up and swallowed, and then pass in the feces to be taken up by the intermediate host. Maturation into infective L3 then occurs in the intermediate host.

Respiratory disease results from the inflammatory response induced by migration of the larvae, which causes granulomatous interstitial pneumonia and thrombotic disease (Bourque et al. 2008). Right heart failure appears to be less common than that seen with D. immitis, perhaps because of the smaller size of Angiostrongylus (1.5–2 cm). A hemorrhagic diathesis has also been reported with Angiostrongylus infection, resulting in epistaxis, hemoptysis, petechiae, and ecchymoses. The precise mechanism for this is unclear, but it may be related to a consumptive coagulopathy. Neurologic signs have also been reported (due to hemorrhage or infection by A. cantonensis or other species), and granulomatous lesions can occur in the liver and kidneys, reflecting systemic infection by the parasite.

History and Signalment

Outdoor dogs and those that hunt are exposed to possible infection more commonly than other dogs; however, both urban and rural dogs can be affected (Chapman et al. 2004). Infection seems more common in younger dogs (<1 year of age) and dogs are presented for a combination of signs, including coughing, exercise intolerance, respiratory distress, evidence of hemorrhage (ecchymotic hemorrhages, hemoptysis, gingival bleeding), and/or syncope. Non‐specific findings such as lethargy, anorexia, and weight loss are also common.

Physical Examination

Dogs with a bleeding diathesis will display ecchymotic hemorrhage in the subcutis, conjunctiva, sclera, or mucous membranes. Overt bleeding from mucosal surfaces may be present. With severe bleeding, anemia can develop, resulting in pale mucous membranes. Pneumonia is responsible for tachypnea and respiratory difficulty. Abnormal or harsh lung sounds may be auscultated. Rarely cardiac failure, PH, or myocarditis can develop resulting in a murmur or gallop sound or an arrhythmia.

Diagnostic Findings

Eosinophilia or neutrophilia can be detected on a CBC and hyperglobulinemia is relatively common (Chapman et al. 2004). A platelet count should be assessed in dogs suspected of angiostrongylosis, because thrombocytopenia is common and can be as severe as that encountered in immune‐mediated thrombocytopenia. A coagulation panel (OSPT, APTT) is recommended given the possibility for infection to result in a coagulopathy, and a thromboelastogram can be helpful for identifying a hypocoagulable state. Thoracic radiographs generally show a bronchoalveolar pattern that is often concentrated in the caudodorsal lung fields. The pulmonary pattern depends on the duration of infection and reflects the pulmonary hypersensitivity response to larval migration. Fibrotic lesions can develop over time. Right ventricular enlargement can be found when severe pulmonary artery obstruction occurs, but this is rare. Echocardiography is useful for identifying PH (see later).

Infection with this helminth can be confirmed through the use of a fecal Baermann analysis for L1 stages. However, larvae will not be present in the pre‐patent period and a single fecal test has poor sensitivity for documenting infection. Pooling of feces over 3 days has been advised. FLOTAC, a flotation‐based fecal examination that uses a high‐specific‐gravity solution, has improved sensitivity for documenting parasite eggs and larvae (Schnyder et al. 2011). An antigen‐based serum ELISA is sensitive and specific, and this test will be positive approximately 5 weeks post‐infection. Dogs with D. immitis can cross‐react on this test. Serologic assessment of antibodies to Angiostrongylus is available and can be of use in select cases. Quantitative polymerase chain reaction on bronchoalveolar lavage fluid can be used to confirm the diagnosis when other tests are negative (Canonne et al. 2016), although dogs might not always be stable enough for collection of an airway sample.

Treatment

Successful treatment of Angiostrongylus infection has been reported with a single dose of 0.1 ml/kg imidacloprid 10%/moxidectin 2.5% spot‐on solution or with fenbendazole (25–50 mg/kg PO for 20 days; Chapman et al. 2004; Willesen et al. 2007). Milbemycin oxime combined with praziquantel is also effective when administered orally PO for 4 weeks. Moxidectin and milbemycin can be used monthly to prevent Angiostrongylus infection. Depending on the severity of clinical signs and pulmonary infiltrates, additional therapy with corticosteroids, intravenous fluid support, and oxygen can be required. Cases with serious coagulopathies can require fresh frozen plasma or blood transfusions.

Prognosis

Dogs with low worm burdens can remain sub‐clinical. Animals with severe radiographic changes, marked respiratory difficulty, or syncope have a guarded prognosis for recovery. It appears that dogs surviving to discharge experience few residual effects of disease.

Pathophysiology

PH is defined by a peak pulmonary arterial systolic gradient that exceeds 32 mmHg. Typically, probability of the diagnosis is based on echocardiographic interrogation of the velocity of a tricuspid regurgitant jet along with subjective changes in the right ventricle and pulmonary artery (Reinero et al. 2020). Classifications of PH include pulmonary arterial hypertension (usually of idiopathic origin), pulmonary venous hypertension associated with increased left atrial pressure, PH associated with respiratory disease, PH associated with thrombosis, PH caused by parasitic disease, and miscellaneous causes of PH. Idiopathic pulmonary arteriopathy resulting in PH has been reported rarely in the veterinary literature (Glaus et al. 2004; Zabka et al. 2006). Pulmonary venous hypertension associated with left heart disease is relatively common, although the elevation in pulmonary artery pressure (PAP) is often mild to moderate. PH associated with respiratory disease results from increased vascular resistance and occurs with a number of disease processes.

In veterinary medicine, the most well‐recognized cause of PH is canine heartworm disease, which represents a form of embolic or vascular obstructive PH. PH has been described in association with a variety of respiratory diseases, including pneumonia in young dogs, chronic tracheobronchial disease, and suspected interstitial lung disease (Johnson et al. 1999a; Pyle et al. 2004; Jaffey et al. 2019; Johnson and Stern 2020). It also occurs in some dogs with brachycephalic obstructive airway disease. The proportion of dogs with these primary conditions that develop PH is unknown, although it has been estimated that greater than 40% of West Highland White Terriers with presumed idiopathic pulmonary fibrosis and ~40% of dogs with mitral valve disease causing increased left atrial pressure and pulmonary venous hypertension will have elevation in PAPs (Schober and Baade 2006; Borgarelli et al. 2015). It seems likely that genetic and environmental influences play a role in the generation of vascular injury and subsequent PH in these common conditions.

PH also occurs in cats although it is not as clinically recognizable in cats as it is in dogs, perhaps because cardiac chambers are not often visibly enlarged radiographically or because syncope is less commonly witnessed in cats. Similar underlying disease processes can result in PH in cats, including congenital heart disease (VSD, PDA, ASD) and chronic left‐sided congestive heart failure due to cardiomyopathy (Vezzosi and Schober 2019) as well as pulmonary fibrosis, thromboembolic disease, infectious or parasitic pneumonia, and feline bronchial disease.

PH has also been described as pre‐capillary, resulting from a disease in the pulmonary arterial bed, and post‐capillary, which relates to pulmonary venous hypertension. Pre‐capillary PH occurs in conditions associated with normal left atrial pressure, while post‐capillary PH develops when left atrial pressure is high, such as in mitral valve disease or cardiomyopathy. This categorization suggests active (arterial) versus passive (venous) influences on pulmonary vascular pressures; however, some conditions are associated with both pre‐ and post‐capillary influences.