Vasculitis and Angiitis

The terms vasculitis and angiitis refer to the pathologic syndrome that is characterized by vascular inflammation and necrosis. Although there have been many reported causes of vasculitis, only a few histologic manifestations of the disease have been diagnosed. Vasculitis can occur in toxic, immune-mediated, infectious, inflammatory, and neoplastic disorders. Blood vessels of any type in any organ can be affected, resulting in a wide variety of clinical signs. The nonspecific nature of histologic lesions, coupled with variable clinical presentations, makes the diagnosis of primary vasculitis quite challenging. The clinical consequences of vasculitis depend on the size, number, type, and extent of blood vessels that are affected.

Histologically, vasculitis is characterized by the presence of inflammatory cells within and around blood vessel walls. Vascular injury is associated with necrosis and degeneration of endothelial and smooth muscle cells and fibrin deposition. A collection of fibrin, immunoglobulins figs), complement, and platelets appears by light microscopy as eosinophilic material within the vessel wall and lumen and is referred to as fibrinoid. Eosinophilia secondary to degeneration of collagen and smooth muscle can also be present within the vessel wall. These histopathologic lesions distinguish vasculitis from perivascular inflammation. Vasculitides have been classified based on specific inflammatory cell infiltrates that may include neutrophils, lymphocytes, or macrophages. As the disease becomes chronic or begins to resolve, predominant cell populations may change. Vasculitis may develop from within a vessel as a result of infectious, immune-mediated or toxic injury or by extension from adjacent areas of inflammation. Infectious agents can injure endothelial cells direcdy or through the production of endotoxins and exotoxins. The exact mechanism of endothe-lial injury is not known but involves the formation of oxygen free radicals, local inflammatory mediators, and the recruitment of inflammatory cells. Exposure of subendothelial collagen during endothelial injury results in the activation of Hageman’s factor and the subsequent activation of the complement, kinin, and plasmin systems. These lead to increased vascular permeability and inflammation.

Type III hypersensitivity reactions can cause necrotizing vasculitis from the deposition of immune complexes within the vessel walls. Activation of the complement cascade may attract neutrophils, cause immune complex phagocytosis, and result in the release of lysosomal enzymes and oxygen free radicals, thereby leading to further inflammation and necrosis. In the chronic state this reaction becomes diminished, and mononuclear cells replace the neutrophilic inflammation. Immune complex reactions of this type can occur in many disease conditions such as primary immune-mediated disease or be secondary to infectious disease. Emphasis on immune complex activity can only be misleading because immune complexes are rapidly cleared from the circulation. In humans the discovery of antineutrophil cytoplasmic autoantibodies (specific for antigens in neutrophil granules and monocyte lysosomes) has allowed further identification of immune-mediated processes in which immune complexes were suspected but not identified. Cell-mediated immunopathogenic mechanisms are initiated in the blood vessel wall. This type of vasculitis is characterized by accumulations of lymphocytes and macrophages within vascular walls. Myocyte necrosis results in fibrinoid degeneration, endothelial hyperplasia, and occasionally thrombosis. A granulomatous type of reaction of the vessel wall can result, particularly in chronic cases. These changes may be accompanied by hemorrhage and ischemic changes in surrounding tissues.

The cause of secondary vasculitides is, by definition, known, and classifications are based accordingly. These conditions usually result from infectious diseases such as feline infectious peritonitis (FIP), canine coronavirus infection, parvovirus infection (rare), Rocky Mountain spotted fever (RMSF), leish-maniasis, and dirofilariasis. They may also occur in drug reactions and in immunopathogenic connective tissue and collagen diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis.

Microscopic Necrotizing Vasculitis

Microscopic necrotizing vasculitis (MNV) refers to a large heterogeneous group of clinical syndromes that share similar histologic properties. Hypersensitivity vasculitis is often referred to in dermatologic manifestations and is often clinically distinct from the multi-systemic form of necrotizing vasculitis. Termed juvenile pol-yarteritis syndrome (JPS), it has been reported in young beagle dogs. Less distinction exists between JPS and those syndromes described as idiopathic steroid-responsive vasculitides that can manifest as multisystemic or localized disease. Lesions can affect mainly arterioles, capillaries, and venules.

Clinical abnormalities of microscopic necrotizing vasculitis are often associated with phasic pyrexia, listlessness, and anorexia. In some cases, lymphadenopathy, myalgia, epistaxis, drooling, sneezing, and arthralgia may occur. In addition to the generalized signs, manifestations of specific organ lesions may occur. The most common presenting clinical signs in small animals are dermatologic lesions. Hemorrhagic maculae resembling circular petechiae and ecchymoses are common. Other lesions seen include wheals, urticaria, purpura, nodules, bullae, necrosis, and ulcers. In many cases the skin lesions are associated with pain, pruritus, or both. Less frequently encountered lesions include ulcers at the mucocutaneous junctions or of the mucous membranes, especially located on the head (external ear canal and pinnae, face), bony prominences of the limbs, and the foot pads, as well as pitting edema involving dependent areas such as limbs, ventral trunk, head, and scrotum.

Internal organ involvement with microscopic necrotizing vasculitis frequently goes undiagnosed. This is because clinical signs are vague, simultaneous multiorgan involvement often occurs, or organ manifestations are confused with those of infectious, degenerative, or traumatic conditions (e.g. pneumonia, glomerulonephritis, arthritis, spinal or neuromuscular conditions). The clinicopathologic findings of primary microscopic necrotizing vasculitis vary according to severity, duration, and specific organ. Lymphopenia, eosinopenia, hypoalbuminemia, hyper-globulinemia, and hyperfibrinogenemia occur commonly. Less consistent findings include leukocytosis with a left shift and toxic neutrophils; leukopenia; neutropenia; monocytosis; a mild normocytic, normochromic anemia; and thrombocytopenia. Serum liver enzymes and triglycerides are often elevated.

An idiopathic cutaneous and renal glomerular vasculopathy has been described in kenneled and racing greyhounds, with many characteristics similar to microscopic necrotizing vasculitis. It is characterized by fibrinoid arteritis, thrombosis, and infarction with deep, slowly healing skin ulcers and peracute renal glomerular necrosis with a predilection for afferent arterioles.

Diagnostic confirmation requires histologic examination of skin, organ, or lymph node biopsies specimen and exclusion of other immune-mediated disease. Special immunologic tests have been recommended to demonstrate a low or high concentration of complement, C3, and elevated levels of circulating immune complexes. The history may be helpful if drug hypersensitivity is suspected.

Primary periarteritis, or polyarteritis, a necrotizing vasculitis affecting small- and medium-sized muscular arteries has been identified in colonies of beagles. This polyarteritis occurs in two forms. One form occurs mainly in young beagles, in which arteritis affects major branches of coronary arteries almost exclusively. Clinical signs are usually absent. A second form of polyarteritis is associated with vague multisystemic signs (fever, depression, anorexia, neutrophilia, decreased albumin-to-globulin ratio), a stiff gait, pain on abdominal palpation (beagle pain syndrome), or a combination of these symptoms. The signs are associated with vascular lesions including disseminated, focal, or diffuse intimal thickening and acute fibrinoid necrosis of the media resulting in occlusion and thrombosis.

The differential diagnosis includes pemphigus vulgaris and foliaceus, bullous pemphigoid, SLE; dirofilariasis, specific infectious diseases, chronic neoplasia, and cold hemagglutination disease. The prognosis is usually favorable.

Many therapies have been advocated. Administration of all unnecessary drugs should be discontinued. In many cases immunosuppressive doses of glucocorticoids with or without an antibiotic have been used successfully. Cyclophosphamide may be administered if that fails. Dogs with lesions involving only the skin can be given sulfasalazine (Azulfidine) at an initial dose of 22 mg/lb (49 mg/kg) every 8 hours. Dose frequency can be decreased after lesions improve from three times to twice a day and, later, to once a day. Dogs receiving sulfasalazine should be observed for side effects such as fever, keratocon-junctivitis, and hematologic abnormalities.

Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a rare polysystemic disease associated with a necrotizing vasculitis of unknown cause. The disease affects predominandy segments and bifurcations of small and medium-sized muscular arteries. In humans, PAN is classified among immune-mediated collagen disorders and derives its name from purpural lesions that are palpable in the subcutaneous tissue. In contrast, palpable nodules are not a regular feature of PAN in animals. The vascular lesions consist of intimal proliferation, vessel wall degeneration, necrosis, and thrombosis in all stages of development. Polyarteritis nodosa leads to a loss of vessel wall integrity, petechial and ecchymotic hemorrhages, focal areas of tissue infarction and necrosis, aneurysm formation, nodular swelling, and thickening of the major arteries. Target tissues of canine polyarteritis nodosa include the kidneys, skin, mucous membranes, adrenals, meninges, GI tract, connective tissue, and myocardium. The lungs are usually spared.

The clinical presentation includes systemic signs (pyrexia, lethargy, reluctance to walk, vague pain, or weight loss) and a wide spectrum of organ system abnormalities (linear skin ulceration, ulceration of mucous membranes, nasal discharge, spinal pain, and signs of cardiac or renal failure (or both]). Clinicopathologic findings may include leukocytosis with a left shift and proteinuria.

The main differential diagnoses are hypersensitivity angiitis and idiopathic polyarteritis. The diagnosis is confirmed by histologic examination of a skin biopsy specimen, and the prognosis is guarded to poor. Treatment includes glucocorticoids, cyclophosphamide, or both.

Lymphomatoid Granulomatosis and Miscellaneous Vasculitides

Lymphomatoid granulomatoses and other unclassified vasculitides are characterized by a polymorpholymphocytoid, plasmacytoid, and histiocytoid granulomatous infiltration around blood vessels. Pulmonary nodular lesions of variable size due to lymphomatosis were first described in dogs. Infarction, necrosis, and cavitation occur in some of the masses. The bronchial lymph nodes can be slightly to greatly enlarged, and pulmonary thrombosis is common. The cause of this rare condition is unknown. Occasionally, similar lesions are associated with eosinophilic pneumonitis in occult dirofilariasis, although they can also occur outside of endemic areas of dirofilariasis. An immune-mediated cause is likely because, in some cases, large amounts of IgG and IgM can be demonstrated in plasma cells and macrophages. The differential diagnosis is primary or secondary ncoplasia, with which this condition is often confused. Diagnosis is rarely made clinically and requires histologic examination of biopsy material. The prognosis is usually poor. In some patients, multicentric lymphosarcoma has developed at a later date. Surgery or treatment with glucocorticoids and cytotoxic immunosuppressive drugs is only temporarily effective.


Canine Heartworm Disease: Complications And Specific Syndromes

Asymptomatic Heartworm Infection

Most dogs with heartworm infection are asymptomatic, even though many of these have heartworm disease (radiographic and pathologic lesions). Treatment is as described previously, using melarsomine in the split-dose regimen, along with a macrolide preventative.

Asymptomatic dogs may, however, become symptomatic af’er adulticidal therapy due to postadulticidal thromboembolization and lung injury (as “described elsewhere). The risk of postadulticidal thromboembolization can be imperfectly predicted by semiquantitation of the worm burden, using certain antigen tests, and by the severity of radiographic lesions. Clearly a dog with severe radiographic lesions will not tolerate thromboembolic complications well, but not all dogs with radiographic signs have heavy worm burdens. For example, a dog with moderate to severe radiographic lesions and high antigenemia may not be at high risk for postadulticidal PTE, because it is quite possible that the worms have died, explaining both the antigenemia (release from dead worms) and radio-graphic abnormalities (chronic HWD).This conclusion might also be valid in the dogs with severe radiographic lesions and negative or low antigenemia (assumes most or all worms have died, and antigen has been cleared). Alternatively, antigenic evidence of a heavy worm burden in a dog with minimal radiographic signs might still portend a severe reaction after melarsomine, because the findings suggest large worm numbers but without natural worm attrition (i.e., a relatively young infection with minimal disease). Of course, low worm burden and minimal radiographic lesions would suggest the least risk of an adverse reaction to adulticide.

It bears emphasis that with each scenario, guesswork is involved and precautions should be taken. When the risk is greatest, aspirin (5 to 7 mg/kg daily — begun 3 weeks prior to and continued until 3 weeks after adulticide) or even heparin may be used, and cage confinement is most important. The owners should be educated as to the risk, the suggestive signs, and the importance of prompt veterinary assistance in case of an adverse reaction.


The majority of dogs suffering from chronic HWI have glomerulonephritis, which can be severe. Therefore when a dog demonstrates glomerular disease, heartworm infection should be considered as a differential diagnosis. Although it is generally felt that the glomerular lesions produced by heartworm infection are unlikely to produce renal failure, a therapeutic dilemma results when one is found in a dog with proteinuria, azotemia, and HWI. Logic suggests that adulticidal therapy is indicated because heartworm infection contributes to glomerular disease, but it likewise carries risks. The approach embraced by this author is to hospitalize the patient and to administer intravenous fluids (lactated Ringer’s solution at 2 to 3 mL/kg/hr) for 48 hours (beginning 12 hours prior to the first melarsomine dose). The patient is then released, and a recheck appointment for blood urea nitrogen (BUN) and creatinine determination after 48 hours is advised. The second and third injections are tentatively scheduled for 1 to 3 months, with the treatment decision based on renal function and the overall response to initial adulticidal therapy.

Allergic Pneumonitis

Allergic pneumonitis, which is reported to affect 14% of dogs with HWD, is a relatively early development in the disease course. In fact, the pathogenesis probably involves immunologic reaction to dying microfilariae in the pulmonary capillaries. Clinical signs include cough and sometimes dyspnea and other typical signs of HWD, such as weight loss and exercise intolerance. Specific physical examination findings may be absent or may include dyspnea and audible crackles in more severe cases. Radiographic findings include those typical of heartworm disease but with an infiltrate, usually interstitial, but occasionally with an alveolar component, often worse in the caudal lung lobes. Eosinophils and basophils may be found in excess in peripheral blood and in airway samples. Corticosteroid therapy (prednisone or prednisolone at 1 to 2 mg/kg per day) results in rapid attenuation of clinical signs, with radiographic clearing in less than a week. The dose can then be stopped in 3 to 5 days if clinical signs subside. Although microfilaricidal therapy is typically not indicated because infections are often occult, macrolide prophylaxis is indicated to avoid further infection. Adulticidal therapy can be used after clinical improvement.

Eosinophilic Granulomatosis

A more serious, but rare, manifestation, pulmonary eosinophilic granulomatosis, responds less favorably. This syndrome is characterized by a more organized, nodular inflammatory process, associated with bronchial lymphadenopathy and, occasionally, pleural effusion. With pulmonary granulomatosis, cough, wheezes, and pulmonary crackles are often audible; when very severe, lung sounds may be muffled and associated with dyspnea and cyanosis. Treatment with prednisone at twice the dose for allergic pneumonitis is reported to induce partial or complete remission in 1 to 2 weeks. The prognosis remains guarded because recurrence within several weeks is common. Prednisone may be combined with cyclophosphamide or azathioprine in an effort to heighten the immunosuppressive effect. The latter combination appears to be the most effective Adulticide therapy should be delayed until remission is attained. As the prognosis for medical success is guarded; surgical excision of lobar lesions has been advocated.

Pulmonary Embolization

Spontaneous thrombosis or postadulticidal thromboembolization associated with dead and dying worms — the most important heartworm complication — may precipitate or worsen clinical signs, producing or aggravating PHT, right heart failure or, in rare instances, hemoptysis and pulmonary infarction. Acute fatalities may result from fulminant respiratory failure, exsanguination, DIC, or may be unexplained and sudden (arrhythmia or massive pulmonary embolism). The most common presentation, however, is a sudden onset of lethargy, anorexia, and cough 7 to 10 days after adulticidal therapy — often after failure to restrict exercise. Dyspnea, fever, mucous membrane pallor, and adventitial lung sounds (crackles) may be noted on physical examination. Thoracic radiographs reveal significant pulmonary infiltrates, most severe in the caudal lung lobes.

The degree of worsening, as compared with pretreatment radiographs, is typically dramatic. The infiltrate, typically alveolar, is most severe in the caudal lobes, and occasionally areas of consolidation are noted. Laboratory abnormalities vary with the severity of signs but may include leukocytosis, left shift, monocytosis, eosinophilia, and thrombocytopenia. The degree thrombocytopenia may provide prognostic information.

Medical management of thromboembolic lung disease is largely empiric and somewhat controversial. It is generally agreed that strict cage confinement, oxygen administration via oxygen cage or nasal insufflation (50 to 100 mL/kg), and prednisone (1 mg/kg/day for 3 to 7 days) are indicated in the most severe cases. KMW Some advocate careful fluid therapy (see recommendations for CS), measuring CVP to avoid precipitation of heart failure, to maximize tissue perfusion and combat dehydration. The use of heparin (75 IU/kg subcutaneously three times a day until platelet count has normalized [5 to 7 days]) and aspirin (5 to 7 mg/kg/day) has been advocated y some but remains controversial.

Other therapeutic strategies might include cough suppressants, antibiotics (if fever is unresponsive), and, although speculative at this time, vasodilators (amlodipine, hydralazine, diltiazem). If vasodilatory therapy is used, one must monitor blood pressure because hypotension is a potential side effect. Clinical improvement may be rapid and release from the hospital considered after several days’ treatment. For less severely affected dogs, careful confinement and prednisone at home are often adequate.

Congestive Heart Failure

Right heart failure results from increased right ventricular afterload (secondary to chronic pulmonary arterial disease and thromboemboli with resultant PHT). When severe and chronic, pulmonary hypertension may be complicated by secondary tricuspid regur-gitation and right heart failure. Congestive signs (ascites) are worsened in the face of hypoproteinemia. Calvert suggests that up to 50% of dogs with severe pulmonary vascular complication to heartworm disease will develop heart failure. Clinical signs variably include weight loss, exercise intolerance, ashen mucous membranes with prolonged capillary refill time, ascites, dyspnea, jugular venous distension and pulsation, arrhythmias with pulse deficits, and adventitial lung sounds (crackles and possibly wheezes). Dyspnea may be due to pulmonary infiltrates (PIE or PTE, but not cardiogenic pulmonary edema), abdominal distension, or pleural effusion.

Treatment aims include reduction of signs of congestion, reducing PHT, and increasing cardiac output. This involves dietary, pharmacologic, and procedural interventions. Moderate salt restriction is logical and probably useful in diminishing diuretic needs. This author chooses a diet designed for senior patients or early heart disease, because salt restriction should only be moderate. Diuretics may be useful in preventing recurrence of ascites but are typically not able to mobilize large fluid accumulations effectively. This then requires periodic abdominal or thoracic paracentesis (or both) when discomfort is apparent. Furosemide is typically used at 1 to 4 mg/kg daily, depending on severity and patient response Additional diuretics, which provide a supplemental effect by using differing parts of the nephron, include spironolactone (1 to 2 mg/kg orally twice a day) and chlorothiazide (2 mg/kg orally daily to every other day). The ACE-inhibitors (eg., enalapril, benazepril, lisino-pril, ramipril), by their effect on the renin-angiotensin-aldosterone system, may be of use as mixed vasodilators, in blunting pathologic cardiac remodeling, and in reducing fluid retention, particularly cases of refractory ascites. Adulticide therapy is delayed until clinical improvement is noted. No evidence indicates that digoxin improves survival in HWD. Because of the risk of toxicity and pulmonary vasoconstriction associated with its use, it is not routinely used by is author in the management of HWD-induced heart failure However, digoxin may be beneficial in the presence of supraventricular tachycardia or refractory heart failure Aspirin, theoretically useful because of its ability to ameliorate some pulmonary vascular lesions and vasoconstriction, may be used 5 mg/kg/day orally.

The arterial vasodilator, hydralazine, has been shown by Lombard to improve cardiac output in a small number of dogs with heartworm disease and heart failure. It has also been demonstrated to reduce pulmonary artery pressure and vascular resistance right ventricular work, and aortic pressure without changing cardiac output or heart rate in dogs with experimental heartworm disease (but without heart failure). Clinical experience has shown perceived improvement with the vasodilators diltiazem and amlodipine as well. Research and clinical experience suggest that hydralazine, amlodipine, and diltiazem might have a role in this setting, but further studies are necessary to define their role, if any. In heart failure the author uses hydralazine at 0.5 to 2 mg/kg orally twice a day, diltiazem at 0.5 to 1.5 mg/kg orally three times a day, or amlodipine at 0.1 to 0.25 mg/kg/day orally. The risk of hypotension with these therapies must be realized and blood pressure monitored.

Often heart failure follows adulticidal therapy, but if it is present prior to adulticidal therapy, the difficult question arises as when (or whether) to administer melarsomine. If clinical response to heart failure management is good, adulticidal therapy may be offered in 4 to 12 weeks, as conditions allow. Melarsomine is generally avoided if heart failure is refractory. Antiarrhythmic therapy is seldom necessary, although slowing the ventricular response to atrial fibrillation with digoxin, Diltiazem, or both () may be necessary in some cases.

Caval Syndrome

Heartworm CS is a relatively uncommon but severe variant or complication of HWD. Most studies have shown a marked sex predilection, with 75% to 90% of CS dogs being male. It is characterized by heavy worm burden (usually >60, with the majority of the worms residing in the right atrium and venae cavae) and a poor prognosis.

Studies performed in the author’s laboratory indicate that retrograde migration of adult heartworms to the cavae and right atrium, from 5 to 17 months after infection, produces partial inflow obstruction to the right heart and, by interfering with the valve apparatus, tricuspid insufficiency (with resultant systolic murmur, jugular pulse, and CVP increase). Affected dogs also exhibit pre-existent heartworm-induced PHT, which markedly increases the adverse hemodynamic effects of tricuspid regurgitation. These combined effects substantially reduce left ventricular preload and hence cardiac output. Cardiac arrhythmias may further compromise cardiac function.

This constellation of events precipitates a sudden onset of clinical signs, including hemolytic anemia caused by trauma to red blood cells (RBCs) as they pass through a sieve of heart-worms occupying the right atrium and venae cavae, as well as through fibrin strands in capillaries if disseminated intravascular coagulation has developed. Intravascular hemolysis, metabolic acidosis, and diminished hepatic function with impaired removal of circulating pro-coagulants contribute to the development of DIC. The effect of this traumatic insult to the erythron is magnified by increased RBC fragility, due to alterations in the RBC membrane in dogs with HWD. Hemoglobinemia, hemoglobinuria, and hepatic and renal dysfunction also are observed in many dogs. The cause of hepatorenal dysfunction is not clear, but it probably results from the combined effects of passive congestion, diminished perfusion, and the deleterious effects of the products of hemolysis. Without treatment, death frequently ensues within 24 to 72 hours due to cardiogenic shock, complicated by anemia, metabolic acidosis, and DIC.

A sudden onset of anorexia, depression, weakness, and occasionally coughing are accompanied in most dogs by dyspnea and hemoglobinuria. Hemoglobinuria has been considered pathognomonic for this syndrome. Physical examination reveals mucous membrane pallor, prolonged capillary refill time, weak pulses, jugular distension and pulsation, hepatosplenomegaly, and dyspnea. Thoracic auscultation may disclose adventitial lung sounds; a systolic heart murmur of tricuspid insufficiency (87% of cases); loud, split S2 (67%); and cardiac gallop (20%). Other reported findings include ascites (29%), jaundice (19%), and hemoptysis (6%). Body temperature varies from subnormal to mildly elevated.

Hemoglobinemia and microfilaremia are present in 85% of dogs suffering from CS. Moderate (mean PCV, 28%) regenerative anemia characterized by the presence of reticulocytes, nucleated RBC, and increased mean corpuscular volume (MCV) is seen in the majority of cases. This normochromic, macrocytic anemia has been associated with the presence of target cells, schistocytes, spur cells, and spherocytes. Leukocytosis (mean white blood cell (WBC] count, approximately 20,000 cells/cm) with neutrophilia, eosinophilia, and left shift has been described. Dogs affected with disseminated intravascular coagulation are characterized by the presence of thrombocytopenia and hypofibrinoginemia, as well as prolonged one stage prothrombin time (PT), partial thromboplastin time (PTT), activated coagulation time (ACT), and high fibrin degradation product concentrations. Serum chemistry analysis reveals increases in liver enzymes, bilirubin, and indices of renal function. Urine analysis reveals high bilirubin and protein concentrations in 50% of cases and more frequently, hemoglobinuria.

CVP is high in 80% to 90% of cases (mean, 11.4 cm H20). Electrocardiographic abnormalities include sinus tachycardia in 33% of cases and atrial and ventricular premature complexes in 28% and 6%, respectively. The mean electrical axis tends to rotate rightward (mean, +129 degrees), with an S1,2,3 pattern evident in 38% of cases. The S wave depth in CV6LU (V<) is the most reliable indicator of right ventricular enlargement (>0.8 mv) in 56% of cases. Thoracic radiography reveals signs of severe heartworm disease with cardiomegaly, main pulmonary arterial enlargement, increased pulmonary vascularity, and pulmonary arterial tortuousity recognized in descending order of frequency (). Massive worm inhabitation of the right atrium with movement into the right ventricle during diastole is evident echocardiographically. This finding on M-mode and two-dimensional echocardiograms is nearly pathognomonic for CS in the appropriate clinical setting. The right ventricular lumen is enlarged and the left diminished in size, suggesting pulmonary hypertension accompanied by reduced left ventricular loading. Paradoxical septal motion, caused by high right ventricular pressure, is commonly observed. No echocardiographic evidence of left ventricular dysfunction exists. Cardiac catheterization documents pulmonary, right atrial, and right ventricular hypertension and reduced cardiac output.

Prognosis is poor unless the cause of the crisis — the right atrial and caval heartworms — is removed. Even with this treatment, mortality can approximate 40%.

Fluid therapy is needed to improve cardiac output and tissue perfusion, to prevent or help to reverse DIC, to prevent hemoglobin nephropathy, and to aid in the correction of metabolic acidosis. Overexuberant fluid therapy, however, may worsen or precipitate signs of congestive heart failure. In the author’s clinic, a left jugular catheter is placed and intravenous fluid therapy instituted with 5% dextrose in water or one-half strength saline and 2.5% dextrose. The catheter should not enter the anterior vena cava because it will interfere with worm embolectomy. A cephalic catheter may be substituted for the somewhat inconvenient jugular catheter, but this does not allow monitoring of CVP. The intravenous infusion rate for fluids is dependent on the condition of the animal. A useful guideline is to infuse as rapidly as possible (up to 1 cardiovascular volume during the first hour) without raising the CVP or without raising it above 10 cm H20 if it was normal or near normal at the outset. Initial therapy should be aggressive (10 to 20 mL/kg/hr for the first hour) if shock is accompanied by a normal CVP (<5 cm HzO), and it should be curtailed to approximately 1 to 2 mL/kg/hr if CVP is 10 to 20 cm HzO. Whole blood transfusion is not indicated in most cases because anemia usually is not severe, and transfused coagulation factors may worsen DIG Sodium bicarbonate is not indicated unless metabolic acidosis is severe (pH, 7.15 to 7.20). Broad-spectrum antibiotics and aspirin (5 mg/kg daily) should be administered. Treatment for disseminated intravascular coagulation is described elsewhere in this text.

The technique for surgical removal of caval and atria] heartworms was developed by Jackson and colleagues. This procedure should be undertaken as early in the course of therapy as is practical. Often, sedation is unnecessary, and the procedure can be accomplished with only local anesthesia. The dog is restrained in left lateral recumbency after surgical clipping and preparation. The jugular vein is isolated distally. A ligature is placed loosely around the cranial aspect of the vein until it is incised, after which the ligature is tied. Alligator forceps (20 to 40 cm, preferably of small diameter) are guided gently down the vein while being held loosely between the thumb and forefinger. The jugular vein can be temporarily occluded with umbilical tape. If difficulty is encountered in passage of the forceps, gentle manipulation of the dog by assistants to further extend the neck will assist in passage of the forceps past the thoracic inlet; medial direction of the forceps may be necessary at the base of the heart. Once the forceps have been placed, the jaws are opened, the forceps are advanced slightly, the jaws are closed, and the worms are removed. One to four worms are usually removed with each pass. This process is repeated until five to six successive attempts are unsuccessful. An effort should be made to remove 35 to 50 worms. Care should be taken not to fracture heartworm during extraction. After worm removal, the jugular vein is ligated distally, and subcutaneous and skin sutures are placed routinely. Other catheters, such as urethral stone basket catheters, horsehair brushes, snares and flexible alligator forceps have also been used. Fluoroscopic guidance, when available, is useful in this procedure.

Successful worm retrieval is associated with a reduction in the intensity of the cardiac murmur and jugular pulsations, rapid clearing of hemoglobinemia and hemoglobinuria, and normalization of serum enzymatic aberrations. Immediate and latent improvement in cardiac function occurs over the next 24 hours. It is important to realize that removal of worms does nothing to reduce right ventricular afterload (PHT), and hence fluid therapy must be monitored carefully before and after surgery to avoid precipitation or worsening of right heart failure. Cage rest should be enforced for a period of time suitable for individual care.

Worm embolectomy through a jugular venotomy is frequently successful in stabilizing the animal, allowing adulticide therapy to be instituted to destroy remaining heartworms in a minimum of 1 month. Careful scrutiny of BUN and serum liver enzyme concentrations should precede the latter treatment. Aspirin therapy is continued for 3 to 4 weeks after adulticide therapy. Substantial improvement in anemia should not be expected for 2 to 4 weeks after worm embolectomy. Macrolide preventative therapy, as described previously, is administered at the time of release from the hospital.

Aberrant Migration

Although heartworms in the dog typically inhabit the pulmonary arteries of the caudal lung lobes, they may find their way to the right ventricle, and rarely (see Caval Syndrome) the right atria and venae cavae. Much less frequently, immature L5 may aberrantly migrate to other sites, including the brain, spinal cord, epidural space, anterior chamber of the eye, the vitreous, the subcutis, and the peritoneal cavity. In addition, the worms may inhabit the systemic circulation, producing systemic thromboembolic disease. Treatment of aberrantly migrating heartworms requires either nothing (e.g., peritoneal cavity), surgical excision of the offending parasite, adulticidal therapy, or symptomatic treatment (e.g., seizure control with brain migration). The method for surgical removal from internal iliac and femoral arteries has been described.


Lymphoproliferative and Myeloproliferative Disorders

Leukemia is the abnormal proliferation of hematopoietic cells that encompasses both lymphoproliferative and myeloproliferative disorders and is considered rarer in the horse than in other species. Leukemia can be classified based on the (1) type of abnormal cell: lymphoid or myeloid; (2) degree of tumor differentiation: acute or chronic; and (3) number of specific types of abnormal cells that are circulating in the peripheral blood: aleukemic, subleukemic, or leukemic. In addition, tumor cells can be further characterized by histochemical and immunohistologic methods. The lymphoproliferative (lymphoma, lymphoid leukemia, and plasma cell myeloma) and myeloproliferative (the myeloid leukemias and erythrocytosis) disorders of the horse are reviewed in this post.


Plasma Cell Myeloma

Plasma cells are terminally differentiated B cell lymphocytes. Malignant transformation can result in three categories of tumors: chronic B cell lymphocytic leukemia, B cell lymphoma (considered above), and plasma cell tumors. Plasma cell tumors occur rarely in the horse; most of the reported information is derived from individual cases and a retrospective series of 10 cases (). No risk factors have been established, and affected animals have ranged from 3 months to 22 years of age. Solitary plasmacytoma is the term used for a single extramedullary tumor. However, the most common form of plasma cell tumors in horses involves the bone marrow and is called multiple myeloma.

Plasma Cell Myeloma: Clinical Signs

Clinical signs are associated with the sites of tumor invasion and include limb edema, ataxia, lameness, epistaxis, lymphadenopathy, weight loss, and anorexia. Secondary infections that commonly involve the lower respiratory or urinary tract may develop. Anemia and hyperglobulinemia are the most common abnormal laboratory findings. With myelophthisic disease, the anemia may be severe and accompanied by leukopenia and thrombocytopenia. Hypoalbuminemia may accompany hyperglobulinemia. A monoclonal gammopathy is detected in nearly all cases by serum electrophoresis and reflects the malignant transformation and clonal expansion of a single plasma cell lineage. The monoclonal protein, called a paraprotein, may be a complete or partial immunoglobulin, the majority of which are in the IgG class. Analysis of urine may reveal proteinuria, and the heat-precipitation method has confirmed the presence of light chains (Bence Jones protein) in the urine of a few horses. Occasionally, hypercalcemia may be found as a paraneoplastic condition.

Diagnosis of Plasma Cell Myeloma

In human patients, definitive diagnosis is based on the demonstration of bone marrow plasmacytosis (>10% of cells) or an extramedullary plasmacytoma and one of the following: (1) a serum monoclonal gammopathy; (2) detection of a urine monoclonal protein; or (3) osteolytic lesions. The majority of equine cases have a monoclonal gammopathy; however, cases in which the serum globulin content was within normal limits have been described. Further examinations should include skeletal survey radiographs of the long bones and cervical vertebrae and biochemical tests to detect renal or hepatic involvement.

Prognosis and Treatment of Plasma Cell Myeloma

Most horses die or are euthanized within 4 months of developing clinical signs, but longer survival times have been reported in a few horses treated with antineoplastic agents. Melphalan (Alkeran), prednisone, and cyclophosphamide have been used in the treatment of multiple myeloma in an 18-year-old Quarter Horse mare. Diagnosis was confirmed 1 week before foaling. Chemotherapy was started after the foal was weaned at 4 days of age; however, dosages were not reported, and plasmapheresis was also performed. The mare was euthanized 7 months after diagnosis because of severe chronic laminitis. A 20-year-old horse with multiple myeloma was also treated with melphalan (7 mg/mz PO q24h for 5 days, and then every 3 weeks). The horse’s condition remained stable for 1 year after diagnosis.

Myeloid Leukemias

Myeloproliferative disorders are characterized by medullary and extramedullary proliferation of bone marrow constituents, including the erythroid, granulocytic, monocytic, and megakaryocytic cell series. Myelodysplastic syndromes are characterized by refractory cytopenia, which generally progresses to acute myeloid leukemia. Classification schemes for myeloid leukemia are based on the degree of differentiation of the transformed cell line. For example, chronic myeloid leukemia involves neutrophils and late precursor cells, whereas acute myeloid leukemia involves myeloblast cells. In general, chronic leukemias are less aggressive than acute leukemias. Reports of myeloproliferative disorders of horses are rare and are dominated by acute leukemias of the granulocytic cell series.

Clinical Signs of Myeloid Leukemias

In a review of 11 reported cases of myelogenous leukemia in the horse, the ages ranged from 10 months to 16 years, and both genders and various breeds were affected. Common clinical findings included ventral and peripheral edema, petechiae, weight loss, depression, and enlarged lymph nodes. Less common findings were fever, epistaxis, pneumonia, exercise intolerance, and colic. All were found to be anemic and thrombocytopenic and had circulating neoplastic cells; the majority had neutropenia and a gammopathy. Secondary infections seem more common in this form of hematopoietic disorders, presumably as a result of immunosuppression. Two horses with myelomonocytic leukemia developed pulmonary aspergillosis.

Diagnosis of Myeloid Leukemias

Bone marrow examination confirms the diagnosis. Confirmation of cell lineage may be morphologically obvious. When needed, further characterization is possible with histochemical and immunohistologic or flow cytometric identification of cell-surface antigens or enzyme content.

Myeloid Leukemias: Prognosis and Therapy

Myelogenous leukemias are notoriously resistant to common antineoplastic agents. However, chemotherapy has been attempted in at least two cases of equine acute myelomonocytic leukemia. These horses were given cytosine arabinoside, based on a low-dose protocol (10 mg/m2 q12h for 3 weeks) adopted from human cancer medicine. The aim of this therapy is to promote terminal differentiation of the neoplastic cell line and diminish clonal expansion. Newer modalities are being tested in human patients and include the use of hematopoietic cytokines and bone marrow transplantation, but no reports of similar use in equine cancer patients exist.



Lymphoma is the general term denoting malignant transformation of lymphoid cells, but it is often used in equine medicine in place of the term lymphosarcoma, which is specifically the malignant transformation of lymphoid cells into solid (or sarcomatous) tumors. Lymphoid leukemia (or “true” leukemia) denotes the malignant transformation of lymphoid cells within the bone marrow. Both forms of lymphoid neoplasia may be accompanied by circulating neoplastic cells.

Lymphoma is one of the most common internal neoplasms of the horse, but the prevalence of lymphoma in horse populations is relatively low — ranging from 0.002% to 0.05%, based on United States abattoir surveys and from 0.2% to 3.0%, based on necropsy surveys. No established risk factors for equine lymphoma exist, and the etiology is unknown. A breed or sex predilection does not appear to be a factor, and the majority of patients are between 4 and 10 years of age. However, individual cases of lymphoma in a fetus and in horses younger than 1 year or older than 20 years of age have been reported.

Clinical Signs of Lymphoma

A diverse spectrum of clinical signs has been associated with lymphoma. The signs and progression of disease relate to the sites of tumor involvement and are not specific to lymphoma. The most common clinical signs are decreased appetite, depression, weight loss, fever, lymphadenopathy, and dependent edema. In a study of 20 cases of lymphoma confirmed by histology, the clinical findings included — in descending order of frequency — weight loss, fever, peripheral lymphadenopathy, abdominal mass, upper or lower respiratory signs, ocular signs, colic, and diarrhea.

Numerous lymphoma tumor locations have been reported and include peripheral and internal lymph nodes, spleen, liver, kidney, intestine, heart, lung, nasopharynx, eye and adnexa, skeletal muscle, skin, reproductive organs, and central and peripheral nervous system. Four anatomic forms of lymphoma are well described: multi-centric — 50%; alimentary — 19%; mediastinal — 6%; and extranodal — 25%. Combinations of these four classic forms of lymphoma occur in approximately 50% of cases.

Multicentric, or generalized, lymphoma is the most commonly reported form and involves multiple peripheral and internal lymph nodes and other organs. The most commonly involved peripheral lymph nodes are the mandibular, caudal cervical, retropharyngeal, and superficial inguinal. The most commonly involved abdominal lymph nodes are the mesenteric, colonic, and deep iliac. Splenomegaly occurs in 25% of the cases, and hepatomegaly or perirenal masses are found infrequently. The multiple sites of involvement probably represent metastasis via the blood and lymphatic circulatory systems. Notably, this is the most common form to be associated with circulating neoplastic lymphocytes, referred to as the “leukemic phase” of lymphoma. Clinical signs reflect dysfunction of affected organs, and the course of the disease is typically rapid once signs become evident.

The alimentary type is the most acute form of lymphoma. It causes rapid deterioration and involves the small intestine and associated mesenteric lymph nodes. Distant metastasis appears slow to develop. Alimentary lymphoma is commonly detected in horses from 2 to 5 years of age. Signs are considered nonspecific and include weight loss, decreased appetite, fever, dependent edema, and diarrhea or abdominal pain of varying severity and duration. Affected horses may have a blunted oral glucose tolerance response and reduced serum albumin concentration, which suggests intestinal malabsorption. Immune-mediated hemolytic anemia and hyperglobulinemia have also been reported to accompany this condition.

Lymphoma of the mediastinal lymph nodes typically occurs in adult horses. The most common clinical signs are referable to compression of intrathoracic structures and include pleural effusion, tachypnea, dyspnea, and dependent edema. Less common findings include a persistent cough, tachycardia, jugular vein distention, and forelimb lameness. Neoplastic cells may be observed in the pleural fluid and the paraneoplastic syndrome of hypercalcemia has been associated with this form of lymphoma.

The most common extranodal sites of tumor development are — in descending order — the skin, upper respiratory tract, eyes or adnexa, and central nervous system. Lymphoma of the skin — the cutaneous form — is the least common form of lymphoma in horses, although it represented the most common form in one report. Tumors are readily identified as nonpainful, dermal, or subdermal masses that are firm and well circumscribed and may be haired, nonhaired, or ulcerated. Horses may have a solitary mass or multiple masses that range in size from a few millimeters up to several centimeters in diameter. The most commonly affected regions include the shoulder, perineum, axilla, and trunk. Clinical signs are referable to internal metastasis and may not be present during the initial examination. Tumors may develop rapidly or slowly and may spontaneously regress and reappear. However, cutaneous lymphoma generally manifests as a slowly progressive extension of an internal malignancy and involves multiple or single, nonulcerated dermal or subdermal masses of neoplastic lymphocytes (i.e., a sarcomatous form). The most rare form of cutaneous lymphoma is termed mycosis fungoides, which differs from the sarcomatous form in that it represents a diffuse infiltration with neoplastic lymphocytes of the dermis or subdermis. This rare form of cutaneous lymphoma is also chronic and progressive and, without appropriate histologic examination of the skin, may be easily mistaken for other diffuse non-neoplastic dermatoses.

Extranodal lymphoma of the eye or adnexa most commonly involves the palpebral conjunctiva and eyelids and may be associated with exophthalmus, exposure keratitis, uveitis, chemosis, and conjunctivitis. Lymphoma has been occasionally reported to involve the upper respiratory tract, thus causing signs of upper airway obstruction with and without nasal discharge. A single recent report involved tumor infiltration of the tongue. Reports of peripheral nerve sheath and epidural infiltration also exist and may be considered rare differentials for lameness and ataxia, respectively. Metastatic periarticular involvement that causes lameness has also recently been reported.

Diagnosis of Lymphoma

Diagnosis of lymphoma can be difficult, and ante mortem confirmation occurs in less than 60% of cases. The key to ante mortem diagnosis is a persistent diagnostician. Neoplasia must always be considered in an adult horse with recurrent inflammatory and febrile episodes that are unresponsive to antimicrobial therapy. The physical examination should include transrectal abdominal palpation and careful thoracic auscultation and percussion. However, the definitive diagnosis of lymphoma requires the observation of neoplastic cells in aspirates or biopsy specimens of lymph nodes and other masses or in centesis samples of body cavity fluids, bone marrow aspirates, or peripheral blood.

Cytologic observations consistent with neoplastic transformation of lymphoid cells include mitotic figures, prominent nucleoli, and binucleation, but evaluation of tissue architecture is equally important in the detection of neoplastic transformation and can only be obtained with biopsy. The observation of neoplastic lymphocytes in the peripheral blood is uncommon and may be a late manifestation of lymphoma in the horse, thus indicating dissemination and bone marrow involvement. When neoplastic cells are observed in the peripheral blood, the leukemia is characterized as subleukemic or leukemic if the total white blood cell count is normal or increased, respectively. Lymphoma is aleukemic when neoplastic cells are not present in peripheral blood. Furthermore, the leukemia may be characterized by the appearance of the transformed cells: acute or lymphoblastic leukemia if immature; chronic or lymphocytic leukemia if mature.

Since publication of the last edition of this text, significant strides have been made in classifying lymphomas using antibodies to cell surface antigens (). Probably the greatest anticipated utility of immunophenotyping equine lymphomas is in the prognostication and choice of anti-neoplastic agent(s), as has been realized in human and small animal veterinary medicine. In addition, immunophenotyping should aid in determining the cell lineage of more poorly differentiated equine tumors, in the correct classification as T cell versus B cell lymphomas, in recognizing phenotypic-specific distri-bution patterns, and in determining the apparent proliferation rates of lymphoid tumors. For example, immunophenotyping has lead to the discovery of a previously unrecognized form of equine lymphoma — the T cell-rich, B cell lymphoma, a form that appears to be prone to subcutaneous tumors. This phe-notype may be a major form of lymphoma in horses and represents 11 out of 24 (or 46%) B cell lymphoma cases and about 33% of all lymphomas.

Paraneoplastic syndromes are the indirect systemic effects of cancer and may have profound consequences on disease expression. The cause of these syndromes is often unknown but generally thought to be mediated by soluble substances released from the neoplastic cells. A few of the paraneoplastic syndromes that may be relevant to horse cancer patients include cachexia, hypercalcemia, hypoglycemia, hypertrophic osteopathy, anemia, disseminated intravascular coagulation, leukocytosis, hyperproteinemia, fever, and various neurologic abnormalities. Adjunct therapy aimed at diminishing paraneoplastic syndromes may have a profound effect on patient comfort and clinical course ().

Anemia is a common finding and occurs in 30% to 50% of horses with lymphoma. Typically, the anemia is mild, normochromic, and normocytic and reflects bone marrow suppression. Immune-mediated hemolytic anemia may be suspected based on a positive direct Coombs’ test. Thrombocytopenia can be profound and has resulted in bleeding diathesis. The number of leukocytes and lymphocytes in the peripheral blood is often within normal limits. With leukocytosis, mature neutrophilia and increased serum fibrinogen activity are most commonly observed and indicate the presence of inflammation. Leukopenia and pancytopenia are uncommon findings.

Common alterations of plasma proteins include increased fibrinogen, total protein, and globulin concentrations. Gammopathy may reflect chronic inflammation but may also reflect neoplastic clonal expansion of B cell lymphocytes (see later section on plasma cell myeloma). Hypoalbuminemia may occur in response to a profound gammopathy or from gastrointestinal loss and rarely from end-stage liver failure as a consequence of hepatic involvement. Both selective (immunoglobulin M [IgM]) and generalized immunoglobulin deficiencies have been occasionally associated with lymphoid neoplasia in horses. Biochemical alterations that may be seen include hypercalcemia, increased liver enzyme activity, and azotemia.

Prognosis and Treatment of Lymphoma

In the majority of patients, rapid deterioration follows the onset of clinical signs associated with internal disease. Horses with lymphoma limited to cutaneous involvement, however, have survived for several years with and without chemotherapeutic intervention. Immunosuppressive glucocorticoid therapy (0.02-0.2 mg/kg dexamethasone [Azium] IV, IM, or PO q24h) may be palliative for steroid-responsive malignancies and may also suppress immune-mediated sequelae, including hemolytic anemia and thrombocytopenia. Cutaneous lesions may regress in 2 to 6 weeks, at which time the dose may be gradually reduced. If glucocorticoid administration is tapered too quickly or is discontinued, more aggressive lymphoid tumors may reappear. Signs of acute laminitis have been observed during glucocorticoid therapy in equine cancer patients and were the grounds for discontinuing therapy.

Few reports discuss use of a specific antineoplastic agent in the treatment of equine lymphoma. The expense and possible toxicity of chemotherapy in the horse are the most common reasons cited for nontreatment. However, the use of a multiple-agent induction protocol in horses with lymphoma has been reported () and is summarized here. Cytosine arabinoside (Cytosar-U; 200-300 mg/m2 SQ or IM) is given once every 1 or 2 weeks. Chlorambucil (Leukeran; 20 mg/m2 PO) is given once every 2 weeks. Prednisone (Deltasone; 1.1-2.2 mg/kg PO) is given every other day throughout the treatment period. Alternatively, cyclophosphamide (Cytoxan; 200 mg/m2 IV given once every 2-3 weeks) is substituted for chlorambucil. Antineoplastic agents are given on alternating weeks but have been given on the same day without apparent consequence. Response to induction therapy should occur within 2 to 4 weeks, but if a response is not observed, adding vincristine (Oncovin; 0.5 mg/m2 IV once a week) to the induction protocol has been recommended.

With remission, the induction protocol is used for a total of 2 to 3 months and then is switched to a maintenance protocol. The first cycle of maintenance therapy increases the treatment interval for each antineoplastic agent by one week; prednisone, however, is given for the duration of therapy and is gradually reduced in dose. After 2 to 3 months on the first cycle, if the horse is still in remission, the second cycle is begun, adding one more week to the treatment intervals of each agent. Several cycles of maintenance therapy can be given; however, most horses in remission are treated for a total of 6 to 8 months.

Other reported protocols include single-agent use of l-asparaginase (Elspar; 10,000-40,000 IU/m2 IM once every 2-3 weeks) or cyclophosphamide (as described previously) and combinations of either cytosine arabinoside or cyclophosphamide with prednisone.

Unfortunately, the likelihood that remission rates and survival times for specific chemotherapeutic protocols and well characterized lymphoid neoplasms in horses (based on a suitably large number of cases) will soon be available is not high. Nevertheless, anecdotal reports suggest remission is possible in some cases of equine lymphoma.


Treatment of Thrombocytopenia

No treatment for primary bone marrow megakaryocyte hypoplasia exists. (Treatment for DIC is discussed in: “Hemostatic Disorders.”) Treatment for IMTP is similar to immune-mediated hemolytic anemia. Medication withdrawal should be implemented with adjustment of antibiotic or drug therapy to a molecularly dissimilar agent. Attempts should be made to identify and treat potential underlying diseases. In life-threatening cases, whole blood or platelet rich plasma transfusion is indicated. Dexamethasone (0.05-0.1 mg/kg IV q24h) is generally indicated to decrease Fc binding, phagocytic removal, and antibody production. When the platelet count is greater than 100,000/μl, the dose of steroid should be reduced 0.01 mg/kg/day with close monitoring for disease recurrence. Prednisolone (1 mg/kg IM ql2h) may be attempted, but not all horses respond favorably to this protocol. Steroids should not be discontinued until the platelet count has been within normal limits for at least 5 days. If steroid therapy has been implemented for greater than 2 weeks, every-other-day administration should be implemented in the tapering dose protocol. Splenectomy has been reported in humans and dogs, but long-term outcome has not been reported in the horse. The vinca alkaloid, vincristine at a dose of 0.01 to 0.025 mg/kg IV weekly, has been used with steroid therapy to increase the peripheral platelet count with some success. Because vincristine has immunosuppressive activities, neutropenia may develop; this is an indication for drug discontinuation. Although anecdotal evidence suggests some improvement of thrombocytopenia with the use of azothiaprine (3-5 mg/kg PO q24h) and cyclophosphamide (300 mg/m2 body surface area), no data are currently available to support their routine use. Complications associated with immunosuppressive therapies may include laminitis and profound immunosuppression that lead to secondary sepsis. Concentrated immunoglobulin therapy has been used for human patients with profound IMTP. The mechanism is multifaceted; however, blocked Fc receptor binding, steric hinderance of immune complex adherence, enhanced T lymphocyte suppressor activity, and reduced B lymphocyte function are proposed actions of excessive Ig administration. The recommended dose is 200 to 1000 mg IgG/kg per day for 2 to 5 days or approximately 6 L plasma per dose for a 450-kg horse. Although equine plasma transfusion carries a reduced risk of adverse effects when compared with glucocorticoids, the cost associated with treatment may be prohibitive. A less expensive alternative to equine plasma is lyophilized equine IgG (Lyphomune, Diagnon Corporation; Rockville, Md.); however, its use in IMTP has been limited in horses.

Whole blood transfusion or platelet-rich plasma can be used to treat thrombocytopenic patients that have persistent hemorrhage. Platelet-rich plasma is harvested by centrifuging fresh blood for a short time at a slow speed (3 to 5 minutes at 250 g). Blood or plasma should be collected into plastic bags because glass activates platelets, and either product should be used immediately. Platelet transfusion is a transient life-saving procedure, and the ultimate outcome depends on the individual case.

Cases of secondary IMTP that result from drug administration often resolve rapidly after drug withdrawal, except in cases associated with chrysotherapy (gold salts), which may require months to years to resolve. Many cases of equine IMTP recover in approximately 3 to 4 weeks. Cases that are secondary to EIA or neoplasia carry a poor to grave prognosis. Reports exist in which chronic recurrent thrombocytopenia has continued for an extended period of time and required intermittent steroid administration.


Immune-Mediated Hemolytic Anemia

Immune-mediated hemolytic anemia () results from cross-reacting antibodies that induce enhanced red blood cell removal. Autoimmune (primary immune-mediated hemolytic anemia) hemolysis results from loss of self-tolerance and is relatively rare in horses. Most commonly, hemolysis results from adherence of cross-reacting antibodies to erythrocyte surface antigens (secondary immune-mediated hemolytic anemia). The presence of these molecules on red blood cells causes intravascular destruction by complement activation (IgM-mediated) or — most commonly — extravascular removal by macrophages. It is important for the reader to consider that any infectious agent — especially equine infectious anemia, Babesia organisms, and Anaplasma phagocytophila; exogenous substances such as penicillin and phenylbutazone; or neoplasia — may cause alterations in epitopes of the erythrocyte membrane or neoantigens that contribute to enhanced removal by immune mechanisms. Therefore identification of the inciting cause is important for complete resolution of the hemolytic crisis.

Several possibilities may explain the onset of cellular destruction. The basic mechanisms involve a change in the red blood cell or an alteration in immunologic control of self-recognition. For example, a change in the red blood cell membrane may form a novel antigen that evokes an immune response. Drugs, neoplasia, or infection may induce changes in red cell antigens. Infectious agents that express similar antigens as host red blood cell antigens result in pathogen-induced immune-mediated hemolysis, termed molecular mimicry. An example of molecular mimicry is human infection with Epstein-Barr virus. Genetic predispositions may cause a failure of self-tolerance. Failure of autoregulation has been suggested to result from reduced suppressor lymphocyte control. Finally, failure of appropriate erythropoiesis may result from precursor erythrocytes being targeted by the immune response in a manner similar to that of circulating red blood cells. The goal of the clinician should be to focus on identifying any potential inciting causes because this will allow for appropriate case management with the best prognosis for efficient and complete disease resolution.

Immune-Mediated Hemolytic Anemia: Clinical Signs and Diagnosis

Horses with immune-mediated hemolytic anemia most commonly present with signs of extravascular hemolysis, but intravascular hemolysis is possible, especially when IgM antibodies or complement is involved. Spherocytes may be present on cytology of peripheral blood smears. Diagnosis based on autoagglutination will suggest surface-bound antibody. Dilution of the sample with saline (1:1) will indicate whether true agglutination is present. If erythrocytes still agglutinate after dilution, they can be considered positive for surface-bound antibody molecules. Tests that are used for the diagnosis when autoagglutination is absent are the direct and indirect Coombs’ test; the direct test is more sensitive. The Coombs’ reagent is polyclonal sera directed against equine IgG, IgM, IgA, and C3 and is used in serial dilutions. The endpoint of the Coombs’ test is agglutination, but it can also be used to test for antibody- or complement-mediated lysis. Direct Coombs’ test may yield a false-negative result if an incomplete set of reagents is used, if blood is not tested at both 4° C and 37° C, or if severe hemolysis has resulted in removal of the majority of antibody-coated RBCs from circulation. As previously described, a new direct immunofluorescence assay that uses class-specific antibodies to equine IgM, IgG, and IgA and flow cytometry has an increased sensitivity to detect red cell antibodies for the diagnosis of immune-mediated hemolytic anemia.

Treatment of Immune-Mediated Hemolytic Anemia

Therapy will be determined based on the level of anemia. In severe cases, whole blood transfusion may be indicated. Specific guidelines are given under Blood and Blood Component Therapy (see: “Blood and Blood Component Therapy”). Current drug administration should be discontinued. If, based on confirmed sepsis, antimicrobial therapy is required, drug therapy should be continued with a molecularly dissimilar drug. After blood samples for diagnostic tests (i.e., Coombs’ test or direct immunofluorescence assay) are obtained, immunosuppressive therapy may be considered. Most affected horses require immunosuppression with corticosteroids. Because immunosuppression carries the risk of potentiating infectious agents, underlying infectious disease conditions such as equine infectious anemia should be ruled out. Glucocorticoid therapy benefits the patient in the short term by reducing the function of macrophages to recognize antibodies complexed to red blood cells and in the long term by altering antibody production by B-lymphocytes. Dexamethasone used at 0.05 to 0.2 mg/kg IV q24h has been reported to have the greatest efficacy in treating immune-mediated hemolytic anemia in horses. The packed cell volume should be monitored carefully during the course of steroid therapy, and if the patient does not respond quickly, the frequency of administration may be increased to twice daily. In some instances, it may take up to a week for the full effect of steroid therapy to be reflected by a rise in packed cell volume. Once the packed cell volume is stable at greater than 20%, the steroid therapy should be carefully tapered by 0.01 mg/kg/day, while the horse is closely monitored for recurrence of hemolytic crisis. The major adverse reactions to long-term administration of corticosteroid in horses are laminitis, tendon laxity or weakness, and immunosuppression that leads to secondary infections. Therefore the goal is to reduce to the lowest effective dose as soon as possible. Alternate day therapy should be administered for the last week of therapy. Some individuals may require therapy for several weeks until disease resolution occurs. Although only a single equine case report has been published, the use of azathioprine (5 mg/kg PO q24h) and cyclophosphamide (300 mg/m2 body surface area) was successful in managing a case of refractory immune-mediated hemolytic anemia.


Treatment of Cutaneous Lymphosarcoma

Glucocorticoids remain the mainstay of treatment of cutaneous T cell-rich, B cell lymphoma. Tumor regression is typically noted following the systemic administration of dexamethasone (0.02-0.2 mg/kg IV, IM or PO q24h) or prednisolone (1-2 mg/kg PO q24h). In these authors’ experience, dexamethasone proves more effective than prednisolone in treating lymphosarcoma. Once cutaneous lesions have regressed in size and number, the glucocorticosteroid dose can be gradually tapered. However, a rapid decrease or discontinuation of glucocorticosteroid administration may result in recurrence of cutaneous lesions. Relapses are anecdotally reported to be sometimes more refractory to treatment. Long-term maintenance therapy may be required in these cases. These authors prefer to use a dose of 0.04 mg/kg of dexamethasone (approximately 20 mg for an average-size horse) once daily until significant regression of tumors has occurred; the dose then is reduced to 0.02 mg/kg daily and then to every 48 hours. Intralesional injections of betamethasone or triamcinolone can also be performed with success; this may be impractical when presented with a large number of cutaneous lesions. Topical application of corticosteroid preparations may result in clinical improvement in cases with ulceration; however, results of its use have not been reported. In addition to im-munosuppression, laminitis is a potential side effect of corticosteroid administration.

Exogenous progestins may demonstrate an antiproliferative effect on lymphosarcoma tumors. The exact mechanism of action has not been determined; however, it is believed to be due to the presence of progesterone receptors, which have been demonstrated on both neoplastic and normal equine lymphoid tissues. Progestogens also have glucocorticoid-like activity, which may also account for the response observed in some cases of lymphosarcoma. In one study, progesterone receptors were identified on 67% of the subcutaneous lymphosarcoma tumors that were evaluated (primarily representing T cell-rich, B cell tumors). In the mare diagnosed with simultaneous cutaneous histiolymphocytic lymphosarcoma and a granulosatheca cell ovarian tumor, partial regression of the skin lesions occurred following a ten-day course of the synthetic progestin, altrenogest (0.044 mg/kg q24h PO). A temporary response was also observed after unilateral ovariectomy. The ovarian tumor stained positive for estradiol and led the authors to believe it was estrogen-secreting. The authors speculated that the steroid hormones secreted by the ovarian tumor may have influenced growth of the T cell-rich, B cell tumors by leading to low progesterone concentrations. Anecdotal reports of tumor regression during pregnancy also exist. In one mare with cutaneous T cell lymphosarcoma, regression of nodules was noted after surgical excision, a single intralesional injection of betamethasone (0.04 mg/kg), and an 8-day course of the oral progestogen, megestrol acetate (0.2 mg/kg q24h). Surgical excision may be efficacious in cases in which a single or a small number of cutaneous nodules exists.

The administration of autologous tumor cell vaccines may benefit horses with cutaneous lymphosarcoma. In one report, tumor regression was achieved by using a combination of low-dose cyclophosphamide and autologous tumor cells infected with vaccinia virus. Cyclophosphamide is thought to potentiate the immune response by decreasing suppressor T cell activity. Infection of tumor cells with the vaccinia virus was performed to augment the host antitumor immune response. The treatment protocol included intravenous administration of cyclophosphamide (300 mg/m2) via a jugular catheter over a period of 2 to 3 minutes on days 1 and 36. Immunization with tumor-cell vaccine was performed on days 4 and 21. Response to immunostimulation was confirmed by development of a delayed-type hypersensitivity response to autologous tumor cells injected intradermally in the horse. Potential side effects of cyclophosphamide administration in other species include immunosuppression, enterocolitis, myelosuppression, and hemorrhagic cystitis. No side effects were noted in the horse in this report.

Treatment of epitheliotropic (cutaneous T cell lymphosarcoma) in horses remains speculative because of a paucity of reported cases. Surgical excision of small lesions may be curative. Retinoids and vitamin A analogs inhibit malignant lymphocyte proliferation in human and canine patients with epitheliotropic lymphosarcoma. No reports of the use of retinoids in horses have been published. However, these authors noted no gross or histologic improvement in treating one case of equine epitheliotropic lymphosarcoma with retinoid cream. Side effects included local erythema and signs of irritation after repeated applications.

Investigations as to the effectiveness of radiation therapy and systemic chemotherapy in the management of equine cutaneous lymphosarcoma are needed. Local therapy that consists of intralesional injection of cutaneous nodules with cisplatin has been used successfully in horses with a small number of lesions. Combination chemotherapy that consists of cytosine arabinoside, chlorambucil or cyclophosphamide, prednisone, and vincristine has been reported for use in horses with multicentric lymphosarcoma, as has L-asparaginase.



Cause of Neoplasia

In dogs, tumors of the large intestine are more common than tumors of the stomach and small intestine. The mean age of dogs affected with colonic neoplasia is variably reported between 7 and 11 years of age. Most colonic tumors of dogs are malignant and include the adenocarcinomas, lymphosarcomas, and gastrointestinal stromal tumors (leiomyosarcoma, neurofibrosarcoma, fibrosarcoma, and ganglioneuroma). Leiomyosarcomas are the most common (91 %) of the gastrointestinal stromal tumors. Most colonic neoplasia develop in the descending colon and rectum, although leiomyosarcomas more frequently develop in the cecum. Local tumor invasion apparently occurs at a slower rate with canine colonic neoplasia, and metastasis to distant sites is relatively uncommon. Benign colonic neoplasia (e. g., adenomas, adenomatous polyps, leiomy-oma’s) also occur, although they are less common than malignant tumors. Malignant transformation of adenomatous polyps to carcinoma in situ and invasive adenocarcinoma has been demonstrated in the dog just as it has in humans. Mb Extramedullary plasmacytomas are an uncommon tumor of the gastrointestinal tract but occur in the large intestine and rectum. All of the aforementioned tumors are associated with signs of inflammation and obstruction (i. e., hematochezia, tenesmus, dyschezia). Carcinoids (rare 5-hydroxytryptamine (5-HT]-secreting tumors) are occasionally associated with diarrhea because of the effects of 5-HT on secretion and motility.

In cats, adenocarcinoma (46%) is the most common tumor of the large intestine, followed by lymphosarcoma (41%) and mast cell tumors (9%). The mean age of cats affected with colonic neoplasia is 12.5 years. The descending colon (39%) and the ileocolic sphincter (28%) are the most common sites of colonic neoplasia in the cat. Unlike colonic tumors in the dog, feline colonic tumors have a high rate (63%) of metastasis and, of course, metastasis is associated with decreased survival time. Metastatic sites include colonic lymph nodes, mesenteric lymph nodes, liver, spleen, bladder, urethra, omentum, meso-colon, lungs, duodenum, and peritoneum.

Neoplasia: Pathophysiology

Mechanical obstruction is the most common pathophysiologic consequence of locally invasive colonic tumors. Other non-neoplastic processes such as intussusception, FIP granuloma, fibrosing stricture, linear and nonlinear foreign bodies, hematoma, and phycomycosis lesions also cause intraluminal obstruction. Prolonged obstruction induces smooth muscle hypertrophy proximal to the site of the obstruction. Other pathophysiologic consequences of intestinal obstruction are pronounced fluid secretion and malabsorption of water and solutes; fluid, electrolyte, and acid-base disturbances; proliferation and translocation of luminal bacteria; and inflammation, devitalization, and perhaps even perforation of the colon. Secretory diarrheas have been reported with carcinoids of the rectum, colon, and intestine.

Clinical Examination

Most affected dogs have signs of hematochezia, mucoid feces, tenesmus, and dyschezia of varying severity. Importantly, the clinical signs observed with colorectal neoplasia are often indistinguishable from other causes of obstruction or chronic colitis. Hematochezia is infrequently reported with leiomyosarcomas or leiomyomas, presumably because these tumors do not typically involve the mucosa. Other clinical signs depend on the tumor type and location. Vomiting, malabsorption, and cachexia may be observed, for example, when multifocal or diffuse tumors (e. g., lymphosarcoma) involve the proximal portions of the gastrointestinal tract. Gastrointestinal stromal tumors, particularly the leiomyomas, have been associated with hypoglycemia and the resulting clinical signs of muscular weakness and seizure activity. Functional plasmacytomas secrete a single class of immunoglobulin and affected animals may go on to develop hyperviscosity syndrome (e. g., retinal bleeding, epistaxis). If colonic perforation has occurred, animals may be presented moribund with fever, lethargy, anorexia, vomiting, abdominal pain, and collapse.

Vomiting (65%), diarrhea (52%), and weight loss (46%) are common clinical signs in cats with colonic neoplasia. Most cats with colonic (and alimentary) lymphosarcoma are FeLV-negative. These lymphomas are thought to be caused by FeLV, with integrated virus causing neoplastic transformation in the absence of viral replication. Although most lymphomas in cats appear to be comprised of malignant T lymphocytes, most colonic (and alimentary) lymphomas are of B cell origin. Alimentary and colonic lymphomas originate primarily from submucosal lymphocytes, mucosal lymphoid follicles, or both, although one recent study reported an epitheliotropic form of T cell intestinal lymphomas. Epitheliotropic T cell lymphomas have not yet been reported in the feline colon.

Diagnosis of Neoplasia

Canine rectal adenocarcinomas are palpable in 60% to 80% of clinical cases, but colonic and cecal lesions are not as readily apparent on physical examination. More than 50% of cats with colonic masses have a palpable abdominal mass.

Survey and contrast radiographic and ultrasonographic studies have been used with varying levels of success in the diagnosis of canine and feline colonic neoplasia. Annular stenotic lesions associated with adenocarcinoma of the colon may manifest as proximal colonic dilation on survey radiographs.

Radiographic contrast material more precisely outlines the narrowing of the lumen at the site of the tumor. Although still of some clinical utility, contrast studies have been largely superceded by ultrasonography and other imaging modalities. Ultrasonography is presently considered to be the most effective means of diagnosing colonic tumors in dogs and cats and appears to be useful in evaluating mural lesions and associated abdominal changes such as lymphadenopathy. Ultrasonography was reported to be useful 84% of the time in localizing feline colonic neoplasia in one study. Ultrasonographic features of colonic tumors include transmural wall thickening with complete loss of the normal wall layering, fluid accumulation proximal to the lesion, and reduced regional motility. Transabdominal fine needle aspiration, peritoneal fluid cytology, and endoscopic exfoliative cytology may be useful in the diagnosis of lymphoma, but histopathology is generally required for a definitive diagnosis of other colonic neoplasia. CT and magnetic resonance imaging (MRI) scanning have not been sufficiently evaluated at this time for reasonable comparisons to be made with ultrasonography.

Flexible colonoscopy with mucosal biopsy is the preferred method of diagnosis for colonic neoplasia. Endoscopic abnormalities may include mass effect, mucosal bleeding, increased mucosal friability, erosions and ulcers, and circumferential luminal narrowing with submucosal infiltrative lesions. Multiple biopsy specimens should always be taken from diseased tissue, adjacent healthy tissue, and the transition zone between healthy and diseased tissue. With tumor necrosis, the pathologist will have a much better chance of diagnosing and staging the disease by evaluating non-necrotic tissue.

Treatment of Neoplasia

The treatment of colonic neoplasia will depend upon tumor type, anatomic location, and presence and extent of metastases. Complete surgical excision is the recommended therapy for focal adenocarcinomas, cecal leiomyosarcomas, and obstructive lymphomas. Multiagent chemotherapy (prednisone, vincristine, cyclophosphamide) has been used to treat colonic lymphoma, but it does not appear to alter survival time in affected cats. Cyclo-oxygenase II (COX II) up-regulation may contribute to the growth characteristics of some canine colonic neoplasia. Selective COX II inhibitors (e. g., piroxicam, meloxicam) may therefore be useful in the treatment of some canine colonic neoplasia. Plasmacytomas may be managed with adjuvant chemotherapy (e. g., prednisone, melphalan) after surgical excision. Radiation therapy has been used to palliate recurrent adenocarcinomas with varying results and complications; however, postradiation peritonitis and perforation have been reported in some cases.

Prognosis of Neoplasia

The prognosis for adenomatous polyps, leiomy-omas, and fibromas is generally favorable. Adenocarcinomas, lymphosarcomas, and plasmacytomas tend to recur, metasta-size, or both to distant sites. Dogs with annular colorectal adenocarcinomas have a particularly poor prognosis with a median survival time (MST) of only 1.6 months. The prognosis for most malignant tumors is generally guarded. Surgical resection alone results in 22 month (dogs) and 15 month (cats) average survival times in dogs and cats. It should be noted that cats undergoing subtotal colectomy for colonic adenocarcinoma had a longer survival time than those receiving mass resection only (MST of 138 days versus 68 days). Not surprisingly, cats with metastatic lesions had much shorter survival times, 49 days versus 259 days.


Inflammatory Bowel Disease

Inflammatory bowel disease is a collective term that describes a group of disorders characterized by persistent or recurrent gastrointestinal signs and histologic evidence of intestinal inflammation on biopsy material. The disease bears little resemblance to inflammatory bowel disease (Crohn’s disease and ulcerative colitis) of humans, and indiscriminate use of the term “IBD” is no more useful than a dermatologist making a diagnosis of “chronic dermatitis. Although a number of recognized diseases are associated with chronic intestinal inflammation (Box Causes of Chronic Small Bowel Inflammation), the cause of idiopathic inflammatory bowel disease is, by definition, unknown. Variations in the histologic appearance of the inflammation suggest that idiopathic inflammatory bowel disease is not a single disease entity, and the nomenclature reflects the predominant cell type present. Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis) is the most common form reported; eosinophilic (gastro-) enteritis (EGE) is less common; and granulomatous enteritis is rare. Neutrophilic infiltration is a feature of human inflammatory bowel disease but is infrequent in idiopathic inflammatory bowel disease of dogs and cats.

Causes of Chronic Small Bowel Inflammation

Chronic infection

  • Giardia sp.
  • Histoplasma sp.
  • Toxoplasma sp.
  • Mycobacteria sp.
  • Protothecosis
  • Pythiosis
  • Pathogenic bacteria (Campylobacter, Salmonella spp., pathogenic Escherichia coli)

Food allergy

Small bowel inflammation associated with other primary gastrointestinal diseases

  • Lymphoma
  • Lymphangiectasia

Idiopathic causes

  • Lymphocytic-plasmacytic enteritis (lymphocytic-plasmacytic enteritis)
  • Eosinophilic gastroenterocolitis (EGE)
  • Granulomatous enteritis (same as regional enteritis?)

Clinical Presentation

Idiopathic inflammatory bowel disease is a common cause of chronic vomiting and diarrhea in dogs and cats, but its true incidence is unknown. In reality it is often overdiagnosed because of difficulties in interpretation of histopathologic specimens and failure to eliminate adequately other causes of mucosal inflammation. No apparent gender predisposition occurs in dogs and cats, but in both species inflammatory bowel disease is most common in middle-aged animals. gastrointestinal signs, which may have been variably controlled by dietary manipulation, are sometimes seen from an earlier age. Although inflammatory bowel disease can potentially occur in any dog or cat breed, certain predispositions are recognized, such as lymphocytic-plasmacytic enteritis in German shepherds and Siamese cats, lymphoproliferative enteropathy in basenjis, and protein-losing enteropathy / protein-losing nephropathy (protein-losing enteropathy / PLN) in soft-coated wheaten terriers. Shar Peis often have a severe lymphocytic-plasmacytic enteritis with hypoproteinemia and extremely low serum cobalamin concentrations. In cats an association, called triaditis, has been reported for inflammatory bowel disease, lymphocytic cholangitis, and chronic pancreatitis.

Clinical Signs Associated with Inflammatory Bowel Disease

Vomiting of bile with or without hair in cats and grass in dogs


Small intestinal — type diarrhea

  • Large volume
  • Watery
  • Melena

Thickened bowel loops

Large intestinal — type diarrhea

  • Hematochezia
  • Mucoid stool
  • Frequency and tenesmus

Abdominal discomfort / pain

Excessive borborygmi and flatus

Weight loss

Altered appetite

  • Polyphagia
  • Decreased appetite / anorexia
  • Eating grass

Hypoproteinemia / ascites

Vomiting and diarrhea are the most common clinical signs, but an individual case may show some or all of the signs in Box Clinical Signs Associated with Inflammatory Bowel Disease.Sometimes an obvious precipitating event (e. g., stress, dietary change) is present in the history, but clinical signs may wax and wane. The nature of signs crudely correlates with the region of the gastrointestinal tract affected: gastric signs are more common if gastric or upper small intestine inflammation is present; in cats, vomiting is often the predominant sign of small intestinal IBD; and Li-type diarrhea may be the result of colonic inflammation or may result from prolonged small intestine diarrhea. The presence of blood in the vomit or diarrhea is associated with more severe disease, especially eosinophilic inflammatory infiltrates. Severe disease is associated with weight loss and protein-losing enteropathy, with consequent hypoproteinemia and ascites. Appetite is variable; polyphagia may be present in the face of significant weight loss, whereas anorexia occurs with severe inflammation. Milder inflammation may not affect appetite, although postprandial pain can be significant even without other signs. Systemic consequences of inflammatory bowel disease can occur, although reports are sparse.

Etiology and Pathogenesis

The underlying etiology of small animal inflammatory bowel disease is unknown, and comparisons have been made with similar human conditions. In this regard, the breakdown of immunologic tolerance to luminal antigens (bacteria and dietary components) is thought to be critical, perhaps resulting from disruption of the mucosal barrier, dysregulation of the immune system, or disturbances in the intestinal microflora. Therefore antigens derived from the endogenous microflora are likely to be important in disease pathogenesis, and a potential role for diet-related factors is suggested by the clinical benefit of dietary therapy in some cases of canine inflammatory bowel disease.

Genetic factors are likely to contribute to the pathogenesis of inflammatory bowel disease, and in humans the strongest associations are with genes of the human MHC (human leukocyte antigen [HLA]). Furthermore, some human patients with Crohn’s disease have a mutation in the NOD2 gene on chromosome 16. This gene’s product detects bacterial lipopolysac-charide and can activate the proinflammatory transcription factor NF-kB. Such a link may explain the development of aberrant immune responses to bacteria in certain individuals. Genetic factors are also likely in dogs, given the recognized breed predispositions, although studies are lacking


Intestinal biopsy is necessary for a definitive diagnosis of inflammatory bowel disease, although the clinical signs and physical findings may be suggestive (see Box Clinical Signs Associated with Inflammatory Bowel Disease). The term idiopathic inflammatory bowel disease is limited to cases in which histologic evidence of inflammation is found without an obvious underlying cause. All other etiologies, including infectious, diet-responsive, and antibacterial-responsive conditions, should be excluded. Therefore before intestinal biopsy is undertaken, laboratory evaluation and diagnostic imaging are performed. Such tests cannot provide a definitive diagnosis of inflammatory bowel disease, but they can help eliminate the possibility of anatomic intestinal disease (e. g., tumor, intussusception), extraintestinal disease (e. g., pancreatitis), and known causes of intestinal inflammation. Furthermore, by determining whether focal or diffuse intestinal disease is present, the clinician can choose the most appropriate method of intestinal biopsy.

Hematology Occasionally neutrophilia, with or without a left shift, is noted. Eosinophilia may suggest EGE, but it is neither pathognomonic nor invariably present. Anemia may reflect chronic inflammation or chronic blood loss.

Serum biochemistry No pathognomonic changes are seen in 1BD, but diseases of other organ systems should be recognized and excluded. Hypoalbuminemia and hypoglobulinemia” are characteristic of protein-losing enteropathy, whereas hypocholesterolemia may suggest malabsorption. Intestinal inflammation in dogs may cause a “reactive hepatopathy, ” with mild elevations in liver enzymes (alanine aminotransferase (ALT] and alkaline phosphatase [ALP]). In contrast, because of the shorter half-lives of liver enzymes in cats, increases are more likely to be the result of hepatocellular or cholestatic disease.

Fecal examination Fecal examination is most important for eliminating other causes of mucosal inflammation, such as nematodes (e. g., Trichuris, Uncinaria, Ancylostoma, and Strongyloides spp.), Giardia infection, and bacterial infection (e. g., Salmonella or Campylobacter spp. or clostridia). Given that fecal parasitology may not always detect Giardia organisms, empirical treatment with fenbendazole is recommended in all cases.

Increased fecal alphap1-PI concentrations would be expected in dogs with inflammatory bowel disease, as well as significant intestinal protein loss even before hypoproteinemia develops (see above).

Folate and cobalamin Serum concentrations of both these vitamins are affected by intestinal absorption, therefore proximal, distal, or diffuse inflammation can result in subnormal folate concentrations (proximal inflammation) or cobalamin concentrations (distal inflammation) or both (diffuse inflammation). Although such alterations are not pathognomonic for inflammatory bowel disease, deficiencies may require therapeutic correction. Measurement of serum folate and cobalamin is now commercially available for cats, and cobalamin deficiency associated with inflammatory bowel disease has been documented. Cobalamin deficiency has systemic metabolic consequences, and anecdotal evidence suggests that deficient cats with inflammatory bowel disease require parenteral supplementation to respond optimally to immunosuppression.

Diagnostic imaging Imaging studies document whether focal or diffuse disease is present and whether other abdominal organs are affected. Such information, in conjunction with specific clinical signs, allows the clinician to choose the most appropriate method of biopsy. Plain radiographs may be useful for detecting anatomic intestinal disease; contrast studies rarely add further information. Ultrasonographic examination is superior to radiography for documenting focal anatomic intestinal disease and is particularly useful in cats with inflammatory bowel disease. Ultrasonography permits evaluation of intestinal wall thickness and can document mesenteric lymphadenopathy. Ultrasound-guided fine needle aspiration (FNA) can provide samples for cytologic analysis, which may aid in diagnosis.

Intestinal biopsy Intestinal biopsy is necessary to document intestinal inflammation. Endoscopy is the easiest method of biopsy, but it has limitations, because samples are superficial and in m6st cases can be collected only from the proximal small intestine. In some cases exploratory laparotomy and full-thickness biopsy are necessary, although the procedures are more invasive and can be problematic if severe hypoproteinemia is present. These techniques may be more suitable for cats, given the tendency in this species for multiorgan involvement.

Histopathologic assessment of biopsy material remains the gold standard for inflammatory bowel disease diagnosis, and the pattern of histopathologic change depends on the type of inflammatory bowel disease present. However, the limitations of histopathologic interpretation of intestinal biopsies are recognized. The quality of specimens can vary, agreement between pathologists is poor, and differentiation between normal specimens and those showing inflammatory bowel disease and even lymphoma can be difficult. Grading schemes for the histopathologic diagnosis of inflammatory bowel disease have been suggested, but these have not yet been widely adopted.

IBD activity index In humans, activity indices are used to quantify the severity of inflammatory bowel disease; this helps practitioners to assess the response to treatment and to make a prognosis by allowing comparisons between published studies in the literature. Recently an activity index was suggested for canine inflammatory bowel disease, and this may aid disease classification in the future.

Other diagnostic investigations Given the limitations of histopathology, other modalities are required. One approach would be the use of immunohistochemistry or flow cytometry to analyze immune cell subsets. However, such techniques are labor intensive and poorly standardized and are unlikely to be generally available in the foreseeable future.


Whatever the type of inflammatory bowel disease, treatment usually involves a combination of dietary modification and antibacterial and immunosuppressive therapy. Unfortunately, objective information on efficacy is lacking, and most recommendations are based on individual experience. The authors usually recommend a staged approach to therapy whenever possible; initial treatment involves antiparasiticides to eliminate the possibility of occult endoparasite infestation. Thereafter, sequential treatment trials with an exclusion diet and anlibacterials are pursued; immunosuppressive medication is used only as a last resort. However, in some cases, clinical signs or mucosal inflammation is so severe that early intervention with immunosuppressive medication is essential. If clinical signs are intermittent, the owners should keep a diary to provide objective information as to whether treatments produce genuine improvement.

Dietary modification The diets recommended for patients with inflammatory bowel disease are antigen limited, based on a highly digestible, single-source protein preparation. An exclusion diet trial should be undertaken to eliminate the possibility of an adverse food reaction, and most clients are happy to try this, given concerns over the side effects of immunosuppressive drugs. An easily digestible diet decreases the intestinal antigenic load and thus reduces mucosal inflammation. Such diets may also help resolve any secondary sensitivities to dietary components that may have arisen from disruption of the mucosal barrier. After the inflammation has resolved, the usual diet often can be reintroduced without fear of an acquired sensitivity.

Well-cooked rice is the preferred carbohydrate source because of its high digestibility, but potato, corn starch, and tapioca are also gluten free. Fat restriction reduces clinical signs associated with fat malabsorption. Modification of the n3 to n6 fatty acid ratio may also modulate the inflammatory response and may have some benefit both in treatment and in maintenance of remission, as in human inflammatory bowel disease. However, no direct studies have been done to prove a benefit in canine inflammatory bowel disease. Supplementation with oral folate and parenteral cobal-amin is indicated if serum concentrations are subnormal.

Antibacterial therapy Treatment with antimicrobials can be justified in inflammatory bowel disease, partly to treat secondary small intestinal bacterial overgrowth and partly because of the importance of bacterial antigens in the pathogenesis of inflammatory bowel disease. Ciprofloxacin and metronidazole are often used in human inflammatory bowel disease, and metronidazole is the preferred drug for small animals. The efficacy of metronidazole may not be related just to its antibacterial activity, because it may exert immunomodulatory effects on cell-mediated » immunity. Furthermore, other antibacterials (e. g., tylosin) may also have immunomodulatory effects and have efficacy in canine inflammatory bowel disease.

Immunosuppressive drugs The most important treatment modality in idiopathic inflammatory bowel disease is immunosuppression, although this should be used only as a last resort. In human inflammatory bowel disease, glucocorticoids and thiopurines (e. g., azathioprine, 6-mercaptopurine) are used most widely. In dogs, glucocorticoids are used most frequendy, and prednisone and prednisolone are the drugs of choice. Dexamethasone should be avoided, because it may have deleterious effects on enterocytes. In severe inflammatory bowel disease, prednisolone can be administered parenterally, because oral absorption may be poor. The initial dosage of 1 to 2 mg / kg given orally every 12 hours is given for 2 to 4 weeks and then tapered slowly over the subsequent weeks to months. In some cases therapy can be either completely withdrawn or at least reduced to a low maintenance dose given every 48 hours.

Signs of iatrogenic hyperadrenocorticism are common when the highest glucocorticoid dose is administered. However, signs are transient and resolve as the dosage is reduced. If clinical signs of inflammatory bowel disease consistently recur when the dosage is reduced, other drugs can be added to provide a steroid-sparing effect. Budesonide, an enteric-coated, locally active steroid that is destroyed 90% first-pass through the liver, has been successful in maintaining remission in human inflammatory bowel disease with minimal hypothalamic-pituitary-adrenal suppression. A preliminary study showed apparent efficacy in dogs and cats, but limited information is available on the use of this drug.

In dogs, azathioprine (2 mg / kg given orally every 24 hours) is commonly used in combination with prednisone / prednisolone when the initial response to therapy is poor or when glucocorticoid side effects are marked. However, azathioprine may have a delayed onset of activity (up to 3 weeks) and, given its myelosuppressive potential, regular monitoring of the hemogram is necessary. Azathioprine is not recommended for cats; chlorambucil (2 to 6 rag / m given orally every 24 hours until remission, followed by drug tapering) is a suitable alternative. Other immunosuppressive drugs are methotrexate, cyclophosphamide, and cyclosporine. Methotrexate is effective in the treatment of human Crohn’s disease, but it is not widely used in companion animals; it often causes diarrhea in dogs. Cyclophosphamide has few advantages over azathioprine and is rarely used. However, cyclosporine may show promise for the future, given its T lymphocyte-specific effects and efficacy in canine anal furunculosis. Unfortunately, it is expensive, and studies in human inflammatory bowel disease have shown variable efficacy and toxicity.

Novel therapies for inflammatory bowel disease Novel therapies are increasingly used for human inflammatory bowel disease in an attempt to target more accurately the underlying pathogenetic mechanisms. These therapies include new immunosuppressive drugs, monoclonal antibody therapy, cytokines and transcription factors, and dietary manipulation (Table Novel Therapies for Human Inflammatory Bowel Disease). In the future, such therapies may be adopted for small animal inflammatory bowel disease.

Novel Therapies for Human Inflammatory Bowel Disease

Therapy Mechanism Of Action
Drug Therapy
Tacrolimus Immunosuppressant macrolide
Mycophenolate Inhibits lymphocyte proliferation; reduces IFN-gamma production
Leukotriene antagonists (zileuton, verapamil) Inhibit arachidonic acid cascade
Prostaglandin (PG) targeting agents Mucosal protection from PC analogs; anti-inflammatory effects from PC antagonists
Thromboxane synthesis inhibitors Anti-inflammatory effects
Oxpentifylline Inhibits TNF-αlpha expression
Thalidomide Inhibits TNF-αlpha and IL-12 expression; reduces leukocyte migration; impairs angiogenesis
Bone Marrow and Stem Cell Transplantation
Bone marrow grafts Unknown; immunomodulation (?)
Dietary Manipulation
Protein hydrolysate diets “Hypoallergenic”
Fish oil therapy Diverts eicosanoid metabolism to LTB5 and PGE3
Short chain fatty acid therapy
Butyrate Provides nutrition for enterocytes
Probiotics and prebiotics Antagonize pathogenic bacteria; immunomodulatory effects
Cytokine Manipulation
Systemic IL-10 Down-modulatory cytokine
Anti-IL-2 monoclonal antibody (MAb) Counteracts proinflammatory effects
Anti-IL-2R (CD25) MAb Inhibits IL-2 effects
Anti-IL-12 MAb Counteracts proinflammatory effects
Anti-IL-11 MAb Downregulates TNF-alpha and IL-1beta
Recombinant IFN-alpha Anti-inflammatory; antiviral (?)
Anti-IFN-gamma MAb Immunomodulatory effect on Th 1 cells
Anti-TNF-αlpha MAb Counteracts proinflammatory effects; induces inflammatory cell apoptosis
Endothelial Cell Adhesion Molecules and Their Manipulation
ICAM-1 (antisense oligonucleotide) Reduces immune cell trafficking
Anti-alpha4 / beta7 MAb Reduces immune cell trafficking
Other Immune System Modulations
Intravenous immunoglobulin Saturates Fc receptors; other (?)
T-cell apheresis Immunomodulation
Anti-CD4 antibodies Immunomodulation
Transcription Factors
NF-kB antisense oligonucleotide Inhibits proinflammatory cytokine expression
ICAM-1 antisense oligonucleotide Reduces immune cell trafficking

IFN, interferon; IL, interleukin; ICAM, intercellular adhesion molecule; LTB, leukotriene B; MAb, monoclonal antibody; PG, prostaglandin; PGE, prostaglandin E; Th 1, T helper 1; TNF, tumor necrosis factor

Mycophenolate mofetil recently has been used to treat human inflammatory bowel disease, although its efficacy is variable. Drugs that target TNF-α (e. g., thalidomide and oxpentifylline) may be suitable for the treatment of canine inflammatory bowel disease because of the importance of this cytokine in disease pathogenesis. Human open-label trials have demonstrated a beneficial effect for thalidomide in refractory Crohn’s disease. Oxpentifylline has shown efficacy in studies in vitro, but clinical results have been less rewarding. Anti-TNF-alpha monoclonal antibody therapy, which has also undergone trials in human inflammatory bowel disease, has the additional beneficial effect of inducing apoptosis in inflammatory cells. Species-specific monoclonal antibodies will be needed for canine and feline inflammatory bowel disease.

Finally, modulation of the enteric flora with probiotics or prebiotics may have benefits in targeting the pathogenesis of inflammatory bowel disease. A probiotic is an orally administered living organism that exerts health benefits beyond those of basic nutrition. In addition to having direct antagonistic properties against pathogenic bacteria, they modulate mucosal immune responses by stimulating either innate (e. g., phagocytic activity) or specific ( e. g., secretory IgA) immune responses. However, care should be taken to select the most appropriate organisms, which are likely to vary between host species.

Prebiotics are selective substrates used by a limited number of “beneficial” species, which therefore cause alterations in the luminal microflora. The most frequently used prebiotics are nondigestible carbohydrates, such as lactulose, inulin, and FOS. Both probiotics and prebiotics can reduce intestinal inflammation in mouse models of inflammatory bowel disease. Preliminary placebo-controlled trials with probiotics and prebiotics in human inflammatory bowel disease patients have shown promising results, although similar trials in canine and feline inflammatory bowel disease are still awaited.

Lymphocytic-Plasmacytic Enteritis

Basenji Enteropathy

A severe, hereditary form of lymphocytic-plasmacytic enteritis has been well characterized in basenjis, although the mode of inheritance is unclear. It has been likened to immunoproliferative small intestinal disease (IPSID) in humans, because both conditions involve intense intestinal inflammation. However, IPSID is characterized by an associated gammopathy (alpha heavy chain disease) and a predisposition to lymphoma. Affected basenjis often have hyper-globulinemia but not alpha heavy chain disease and may be predisposed to lymphoma. The intestinal lesions in basenjis are characterized by increases in CD4+ and CD8+T cells.

Clinical Signs

Signs of chronic intractable diarrhea and emaciation are most rommon Lymphocytic-plasmacytic paslritis, with hypergasirmemia and mucosal hyperplasia, may be seen in addition to the enteropathy. Protein-losing enteropathy often occurs, with consequent hypoalbuminemia, although edema and ascites are not common. Clinical signs are usually progressive, and spontaneous intestinal perforation may occur.


The approach to diagnosis is the same as before, and ultimately depends on histopathological examination of biopsy specimens.


Treatment generally is unsuccessful, with dogs dying within months of diagnosis. However, early, aggressive combination treatment with prednisolone, antibiotics, and dietary modification may achieve remission in some cases.

Familial Protein-Losing Enteropathy and Protein-Losing Nephropathy in Soft-Coated Wheaten Terriers

Recendy a clinical syndrome unique to soft-coated wheaten terriers was characterized. Affected dogs present with signs of protein-losing enteropathy or PLN or both. A genetic basis is likely, and although the mode of inheritance is not yet clear, pedigree analysis of 188 dogs has demonstrated a common male ancestor. The disease is probably immune mediated, given the presence of inflammatory cell infiltration. A potential role for food hypersensitivity has been suggested, because affected dogs have demonstrated adverse reactions during provocative food trials and alterations in antigen-specific fecal IgE concentrations.

Clinical Signs

Signs of protein-losing enteropathy tend to develop at a younger age than PLN. Clinical signs of the protein-losing enteropathy include vomiting, diarrhea, weight loss, and pleural and peritoneal effusions. Occasionally, thromboembolic disease may occur.


Preliminary laboratory investigations, as in most dogs with protein-losing enteropathy, demonstrate panhypoproteinemia and hypocholesterolemia. In contrast, hypoalbuminemia, hypercholesterolemia, proteinuria, and ultimately azotemia are seen with PLN, Histopathologic examination of intestinal biopsy material reveals evidence of intestinal inflammation, villus blunting, and epithelial erosions, as well as dilated lymphatics and lipogranulomatous lymphangitis.

Treatment and Prognosis

The treatment for protein-losing enteropathy is similar to that described for general inflammatory bowel disease, but the prognosis is usually poor.

Eosinophilic Enteritis

Other Forms of Inflammatory Bowel Disease

Granulomatous Enteritis

Granulomatous enteritis is a rare form of inflammatory bowel disease characterized by mucosai infiltration with macrophages, resulting in the formation of granulomas. The distribution of inflammation can be patchy. This condition is probably the same as “regional enteritis,” in which ileal granulomas have been reported. Granulomatous enteritis has some histologic features in common with human Crohn’s disease, but obstruction, abscessation, and fistula formation are not noted. Conventional therapy is not usually effective, and the prognosis is guarded, although a combination of surgical resection and anti-inflammatory treatment was reported to be successful in one case. In cats, a pyogranulomatous transmurai inflammation has been associated with FIPV infection.

Proliferative Enteritis

Proliferative enteritis is characterized by segmental mucosal hypertrophy of the intestine. Although many species can be affected, the condition is most common in pigs. A similar but rare condition has been reported in dogs. There have been suggestions of an underlying infectious etiology, and Lawsonia intracellularis has been implicated, although this has not yet been proved. Other infectious agents with a proposed link are Campylobacter spp. and Chlamydia organisms

Complementary Medicine


Mange (Demodectic / Sarcoptic)

Definition and cause

Demodex is a localized or generalized parasitic disease caused by Demodex spp. mites. The underlying cause is believed to be genetic or related to immune deficiency or imbalance. In cats it is most often associated with other systemic disease such as FIV. Sarcoptic mange is a highly pruritic parasitic disease caused by the mite Sarcoptes scabiei.

Medical therapy rationale, drug(s) of choice, and nutritional recommendations

For demodex the medical therapies of choice are Amitraz, Ivermectin, or Milbemycin, all of which have potential side effects and are potentially toxic. Amitraz is particularly toxic to humans, and proper precautions should be taken to protect humans from exposure to its active ingredient. None of these treatments address the underlying immune imbalance. Therapy for sarcoptic mange involves mitocidal shampoos or dips along with the medications used in demodex, and / or the use of Selamectin. In addition, antipruritic medications such as antihistamines and corticosteroids are often recommended.

Anticipated prognosis

Localized demodectic mange usually carries a good prognosis. Generalized demodecosis in immune-compromised animals often has a more guarded prognosis. Sarcoptic mange has a good prognosis.

Integrative veterinary therapies

Mange is a nondescript term meaning infestation with one of several mite ectoparasites. These ectoparasites cause irritation through their waste products and physical injury to the host (burrowing), and by their physical presence on the host, which triggers various responses directed at elimination of the mites (pruritus, grooming, self destructive behavior). Damage directly from the mite’s activities and or from the host response leads to a worsening condition.

The integrative approach expands the medical therapy to include the immune system. The integrative approach is cellular protective for the potential toxic effects of medication and mitacidal dips, and helps improve immune function and its ability to rid the body or prevent re-infestation of the mites and lessens inflammation, pruritus, and discomfort.


General considerations / rationale

While medical therapy is focused locally upon destruction of the mite and the skin (inflammation and / or pruritus), the nutritional approach adds gland support for the organs of the immune system as well as nutrients to help decrease local inflammation and improve waste elimination. Because mange, especially demodex, can range in severity from local to generalized and can affect other organs, it is recommended that blood be analyzed both medically and physiologically to determine associated organ involvement and disease. This gives clinicians the ability to formulate therapeutic nutritional protocols to address the skin and organ involvement such as liver inflammation secondary to medication or chemical dips (see site, Nutritional Blood Testing, for more information).

Appropriate nutrients

Nutritional / gland therapy: Glandular adrenal, thymus and lymph provide intrinsic nutrients and help neutralize cellular immune organ damage and protect organs from ongoing inflammation and eventual degeneration (See site, Gland Therapy, for more information).

Sterols: Plant-derived sterols such as betasitosterol show antiinflammatory properties, which appear to be similar to corticosteriods. A cortisone-like effect without the associated immune suppressing effects is beneficial in inflammatory skin conditions. Bouic (1996) reports on the immune-enhancing and balancing effect that plant sterols have on the body.

Quercetin: Quercetin functions like an antihistamine and an antioxidant, and is beneficial for the skin. In its antihistamine role, quercetin has been shown to inhibit cells from releasing histamines, which makes it helpful in treating inflammatory dermatitis.

Lecithin / phosphatidyl choline: Phosphatidyl choline is a phospholipid that is integral for cellular membranes. It is an essential nutrient required by the skin, which is the body’s largest cellular organ.

Essential fatty acids: Much research has been conducted on the importance of essential fatty acids on the clinical management of allergic dermatitis. In addition, the importance of the ratio between omega-6 and omega-3 fatty acids has been substantiated. Research on the use of poly-unsaturated fatty acids has shown their beneficial and antipruritic effects on skin.

Vitamin C: De la Fuente (1998) and Penn (1991) showed that vitamin C in combination with other vitamins significantly improved immune function as compared with a placebo.

Chinese herbal medicine / acupuncture

General considerations / rationale

Mange is a result of parasites in both Western and traditional Chinese medicine theory. Both modalities have the same treatment objectives: kill the parasite, decrease discomfort, and prevent secondary infections. It may also be prudent in some patients to improve immune function to allow the patient to clear the parasite.

Appropriate Chinese herbs

For topical application:

Alumen (Ming fan): Has been shown to inhibit bacterial growth, which may help to prevent secondary bacterial infections in lesions caused by scratching.

Cnidium (She chuang zi): Has antibiotic properties. It also decreases itching. In a study involving 607 patients with severe pruritis, it stopped itching in 84% of the participants.

Prickly ash (Hua jiao): Possesses antibacterial and antidermatophyte properties. This may help prevent secondary infections.

Realgar (Xiong huang): Has traditionally been used to kill internal and external parasites by traditional Chinese medicine practitioners. It has been shown to treat pinworms and malaria, which are internal parasites. The efficacy shown against internal parasites suggests that it would also be effective topically against external parasites.

Sulfur (Liu huang): Is commonly used topically in Western medicine for mange, often as a lime sulfur dip. It has been used as a component for the treatment of psoriasis. For immunosuppression:

Angelica root (Dang gui): Increases the phagocytic activity of macrophages.

Astragalus (Huang qi): Stimulates the cellular and humoral immune systems. It contains astragalan, which enhances phagocytic activity of macrophages and antibody synthesis.

Codonopsis (Dang shen): Enhances the immune system by increasing the weight of the spleen and thymus and the total number of white blood cells and lymphocytes.

Dioscorea (Shan yao): Enhances both the cellular and humoral immune systems.

Fleece flower root (He shou wu): Increases the total white cell count, especially the T-cells, and increases the phagocytic activity of macrophages.

Licorice (Gan cao): Can enhance the phagocytic activity of macrophages.

Lotus seed (Lian zi): Was shown to increase the number of T cells in the thymuses in mice, which implies that it may be useful in treating immunosuppression.

Poria (Fu ling): Contains pachman, which increases the phagocytic function of macrophage.

Psoralea (Bu gu zhi): Stimulates the phagocytic actions of macrophages.

Rehmannia (Shu di huang): Increases the phagocytic activity of macrophages.

Schizandra (Wu wei zi): Can prevent cyclophosphamide-induced decrease in the white blood count.

White atractylodes (Bai zhu): Increases the TH cell count and the TH / TS ratio. It increases the phagocytic function of macrophages.

Wolfberry (Gou qi zi): Increases the phagocytic activity of macrophage phagocytic and raises the total T cell count.

Zizyphus (Suan zao ren): Enhances cellular and humoral immunity.


General considerations / rationale

A genetic predisposition (Degeneration Phase) is involved with demodectic mange, and affected individuals should not be used for breeding.

Palmquist relies on conventional therapy to treat most of these (lyme dip and Ivermectin in breeds which can tolerate the drug), but in certain cases it may prove helpful to support immune function, detoxification, and repair of tissues injured by homotoxins. Antihomotoxic agents may have a place in therapy in such cases. The authors are unaware of any work reporting single use of homo-toxicology in the management of veterinary mange cases.

Appropriate homotoxicology formulas

BHI-Hair and -Skin: May help repair skin and hair in recovery phase and detoxification, provide support in cases of damage from vaccines, and promote vicariation of chronic diseases.

BHI-Skin: Treats eczema on elbows, scaly scratchy dermatitis, ulcerations, and urticarial reactions.

Coenzytne compositum: Contains cis-Aconitum acidum for pruritus, skin diseases, and psoriasis. Several of the active skin catalysts in Coenzytne compositum are common to Cutis compositum.

Cutis compositum: Provides support of all skin conditions. This is a critical skin remedy, named primarily for Cutis suis, and indicated in allergic reactions, dermatoses, eczema, seborrheic conditions, pemphigus, psoriasis, dermatomycoses, neurodermatitis, and other skin conditions, as well as disturbances of renal excretion. Contains Ichthyolum, which has pustular acne and violent pruritus (facial) as its main indications. Ichthyol ointment serves to soften and clear out abscesses and is a stimulative treatment in inflammations. Sulphur is also a critical component (See Sulphur-Heel). The remedy contains Cortisone in homeopathic dilution, which is indicated for diseases manifested in the connective tissue, such as disorders of the skin, blood, and vascular systems. Fumaricum acidum, Alpha ketoglutaricum, and Natrum oxalaceticum included are for pruritus, skin diseases, and psoriasis. These catalysts are also found in Coenzytne compositum. Funiculus umbicalis suis is indicated for rehabilitation of tissue. This is a connective tissue remedy indicated in almost all chronic diseases. It repairs damage to connective tissue, and is used for psoriasis, skin eruptions, and dermatitis.

Echinacea compositum: Used for secondary infections. Arsenicum is indicated for skin eruptions and other symptoms of a stubborn nature that may border on the phase of Degeneration. It also contains Sulphur (see Sulphur Heel) and Cortisonum acidum (see Cutis compositum).

Engystol N: Is immune supportive in allergic and viral cases, and contains sulfur, which is indicated in chronic issues.

Graphites homaccord: Treats pigmented, greasy lesions without hair.

Hepar compositum: Improves detoxification status by its action on the liver.

Psorinoheel: A phase remedy in Excretion and Impregnation cases. Psorinum is an extract of scabies mange excretions and has been used in classical homeopathy for many years. This also contains Sulfur, which is indicated in chronic conditions (see Sulphur-Heel). May be helpful in so-called constitutional cases.

Schwef-Heel: Works through its higher potency of Sulfur.

Solidago compositum: Used in Deposition phases, this remedy assists the skin by its support of the kidney.

Sulphur-Heel: Primarily named for the contained remedy, Sulphur, known for its use in various skin diseases, especially those of chronic nature, and pruritic eczema and suppurative skin diseases. Sulphur is one of the most important components of tissue in the body. Therefore, Sulphur is the major remedy in practically all cellular phases, particularly in the Impregnation Phase, which still displays a tendency to turn regressive. This also contains Mezereum, which is useful for pruritic skin irritations and skin suppuration, and has several other skin-active remedies as components.

Traumeel S: Treats inflammatory lesions with much inflammation.

Authors’ suggested protocols


Skin and immune support formula: 1 tablet for every 25 pounds of body weight BID.

Lymph support formula: One-half tablet for every 25 pounds of body weight BID.

Betathyme: 1 capsule for every 35 pounds of body weight BID. (maximum 2 capsules BID.)

Lecithin / phosphatidyl choline: One-fourth teaspoon for every 25 pounds of body weight BID.

Eskimo fish oil: One-fourth to 1 teaspoon per meal for cats. 1 teaspoon for every 35 pounds of body weight per meal for dogs.

Oil of evening primrose: 1 capsule for every 25 pounds of body weight SID.

Additional vitamin C: 100 mg for every 25 pounds of body weight BID.

Quercetin: 50 mg for every 10 pounds of body weight SID.

Chinese herbal medicine

To kill the mites, the authors use a combination of sulfur (Liu huang), 30g; realgar (Xiong huang), 15g; Alumen dehydratum (Ming fan), 45g; prickly-ash (Hua jiao), 25g; and Cnidium seed (She chuang zi), 25g. Mix well and apply topically daily for 2 to 3 weeks.

The authors also recommended H7 Immune Stimulator for 6 months in conjunction with Mitaban dips, daily Interceptor, Ivermectin, or herbal parasite dips to counteract immunosuppression. The H7 ImmuneStimulator is dosed at 1 capsule for every 10 to 20 pounds twice daily. In addition to the herbs mentioned above, Immune Stimulator contains euryale (Qian shi), longan fruit (Long yan rou), saussurea (Mu xiang), and white peony (Bai shao). These herbs increase the efficacy of the formula.


(Dose: 10 drops PO for 50-pound dog; 5 drops PO small dog or cat)

Psorinoheel and Schwef-Heel: Mixed and given twice daily orally.

Cutis compositum: Given initially, and then as needed.

Autosanguis Therapy:

1. Traumeel

2. Hepar compositum

3. Galium-Heel

4. Cutis Heel

5. Ubichinon compositum

Oral cocktail: Schwef homaccord, Psorinoheel, and Lymphomyosot, plus the remains of autosanguis in a syringe, taken orally BID to TID.

Echinacea compositum forte tabs: Use if needed.

Ivermectin: Give PO daily in breeds that can tolerate the drug.

Nutraceuticals: AFA Algae, GlutaDMG, vitamin E, fatty acids.

Product sources


Skin, immune and lymph support formula: Animal Nutrition Technologies. Alternatives: Immune System Support — Standard Process Veterinary Formulas; Immuno Support — Rx Vitamins for Pets; Immugen — Thorne Veterinary Products; Canine Dermal System Support — Standard Process Veterinary Formulas; Derma Strength — Vetri Science Laboratories.

Betathyme: Best for Your Pet. Alternative: Moducare — Thorne Veterinary Products.

Oil of evening primrose: Jarrow Formulas.

Eskimo fish oil: Tyler Encapsulations.

Lecithin / phosphatidyl choline: Designs for Health.

Quercetin: Source Naturals; Quercetone — Thorne Veterinary Products.

Chinese herbal medicine

Formula: H7 Immune Stimulator Natural Solutions, Inc.


BHI / Heel Corporation