The primary function of red blood cells is to transport oxygen. Abnormal red cell function that results in anemia is dealt with under that heading. Abnormalities of red cell function can included abnormalities in red cell metabolism or the structure or function of hemoglobin. Hemoglobinopathies are not well documented in large animals, with the exception of changes caused by ingestion of oxidants (nitrate, onions, kale, red maple leaves) that cause methemoglobinemia, or the recognition that inhalation of carbon monoxide causes carboxyhemoglobinemia. Both carboxyhemoglobinemia and methemoglobinemia decrease oxygen carriage by hemoglobin.
Reported abnormalities in red cell metabolism include:
• Diminished glucose-6-phosphate activity of red cells caused hemolytic anemia in an American Saddlebred colt1
• Flavine adenine dinucleotide deficiency is reported in a Spanish mustang with mild and variable anemia2
• Glutathione reductase deficiency causing hemolytic anemia in a horse.3 Other abnormalities of glutathione metabolism, with minimal clinical expression, occur in sheep4,5 and horses.6
Disorders of white cells
Leukopenia does not occur as a specific disease entity but is a common manifestation of a number of diseases. Neutropenia, often accompanied by lymphopenia, occurs with a number of acute viral diseases such as hog cholera and equine viral arteritis. It has also been observed in leptospirosis in cattle, although bacterial infections are usually accompanied by a leukocytosis. Acute local inflammation may cause a transient fall in the leukocyte count because of withdrawal of the circulating cells to the septic focus. Neutropenia occurs as part of the response to toxemia, and in particular endotoxemia, because of enhanced migration of neutrophils from blood into tissues. The emigration of neutrophils occurs at a rate faster than their entry into the peripheral blood from bone marrow. Lymphopenia occurs as part of a stress response, and as a result of administration of glucocorticoids.
Leukopenia also occurs as part of a pancytopenia in which all cellular elements of the blood are depressed. Agents that depress the activity of the bone marrow, spleen and lymph nodes and result in pancytopenia occur in poisonings caused by trichloroethylene-extracted soybean meal, toluene, fungal toxins, e.g. fusariotoxicosis, notably that of Stachybotrys alternans, and bracken fern. Pancytopenia occurs also in radiation disease and in calves ascribed to furazolidone poisoning. The disease is discussed under the title of granulocytopenic calf disease. Chronic arsenical poisoning and poisoning by sulfonamides, chlorpromazine and chloramphenicol cause similar blood dyscrasias in humans but do not appear to have this effect in animals. Leukopenia in pigs can occur as a result of iron deficiency.1
Administration of glucocorticoids causes a lymphopenia and eosinopenia in most species. Lymphopenia is present in animals with immune deficiency such as severe combined immunodeficiency in Arabian foals and Fell pony foals with immunodeficiency.
The importance of leukopenia is that it may reduce the resistance of the animal to bacterial infection. Treatment of the condition should focus on the underlying disease, but broad-spectrum antibiotics are often administered because of the presumed greater risk of bacterial infection in leukopenic animals.
Leukocytosis, a white blood cell count in peripheral blood greater than expected in healthy animals, can be an appropriate physiological response to an infectious or inflammatory process, a result of white cell dysfunction or a result of leukoproliferative disease. In this last instance, a particular situation is that in which there is neoplasia of the immune cells with subsequent production of growth factors or interleukins that stimulate inappropriate proliferation of other cells types that are detectable in the peripheral blood. An example is horses with intestinal lymphosarcoma that have peripheral eosinophilia. The leukoproliferative diseases are dealt with under that heading.
Leukocytosis can be a result of an increase in concentration of all white blood cells or a result of increases in count of a particular subset. The changes include lymphocytosis, neutrophilia, eosinophilia, monocytosis and basophilia. Thrombocytosis is dealt with under that heading.
Lymphocytosis not related to infection by bovine leukemia virus is unusual. Chronic viral or bacterial infections can result in mild increases in lymphocyte count in blood but these changes have little diagnostic significance. The ratio of T lymphocytes to B lymphocytes changes in some disease processes, but these subsets are seldom differentiated in routine clinical practice.
Neutrophilia is almost always a response to an inflammatory process, with the exception of the neutrophilia associated with stress (‘stress’ leukogram). Subacute to chronic bacterial disease or inflammation causes marked increases in neutrophil count in peripheral blood. The neutrophilia is variable and can reduce even in the presence of continuing disease, such as R. equi pneumonia. A mature neutrophilia is evident as a high neutrophil count in the absence of immature forms (band cells). A regenerative neutrophilia is characterized by normal to elevated neutrophil counts and the presence of an excessive number of immature neutrophils (so-called ‘left shift’). The presence of a left shift suggests either rebound neutrophilia subsequent to neutropenia, or ongoing severe inflammation. Mature neutrophilia suggests inflammation of longer standing but is not definitive for this time frame. Mature neutrophilia can occur during the recovery stage from anemia, especially hemolytic anemia. Profound neutrophilia occurs in calves with bovine leukocyte adhesion deficiency and in some septicemic foals.
Eosinophilia is usually associated with allergy or parasitism. Examples include milk allergy in cows and intestinal parasitism in horses. Eosinophilia can occur in horses with intestinal lymphosarcoma or multisystemic eosinophilic epitheliotropic disease.
Monocytosis and basophilia are unusual in large animals with the exception of that occurring as part of a rebound bone marrow response to profound neutropenia.
Abnormalities of white cell function can be either congenital or acquired. Congenital defects include Chédiak–Higashi syndrome and bovine leukocyte adhesion deficiency. Acquired defects include those associated with neoplasia of cells of the innate and adaptive immune systems, and dysfunction induced by disease, intoxication or deficiency (such as iron deficiency impairing neutrophil function). A wide variety of infectious diseases can impair function of a white blood cells, including phagocytosis of microorganisms by neutrophils or macrophages. Intoxicants such as some of the mycotoxins impair leukocyte function. Malnutrition, starvation and specific deficiencies (e.g. iron) impair leukocyte function.1
The leukoproliferative diseases are neoplastic diseases of the myeloid (hemapoietic) or lymphoid tissues. The discussion here will be divided into those diseases associated with abnormal lymphoid cells (lymphoproliferative) and those associated with abnormal myeloid cells (myeloproliferative). The most common leukoproliferative diseases of large animals are lymphoma and lymphosarcoma.
Myeloproliferative disease is rare in large animals but granulocytic, eosinophilic, monocytic and myelomonocytic leukemias are reported:
• Acute (myelogenous) and chronic granulocytic leukemia are reported in horses1,2
• Acute granulocytic leukemia in a goat3
• Systemic mastocytosis in a goat4
• Acute myeloblastic leukemia in cattle5,6 and horses7
• Myelomonocytic leukemia in a calf8 and a horse9
• Malignant histiocytosis in cattle10 and horses11
• Eosinophilic myeloproliferative disease in a horse.12
Cases manifest with nonspecific clinical signs including weight loss, poor performance, episodic ventral and lower limb edema, petechial hemorrhage, splenomegaly, and some with lymph node enlargement or palpable masses in the abdomen in some. Thrombocytopenia and anemia are common because of myelophthisis. Abnormal cells are often apparent on examination of a smear of peripheral blood. Immunohistochemistry and immunostaining of cells for fluorescent cell sorting can identify the abnormal cells.
The diagnosis is often obtained at necropsy examination. Antemortem diagnosis can be facilitated by examination of peripheral blood smears and bone marrow obtained by aspiration or biopsy.
There is no effective treatment, nor are there measures to prevent the disease.
1 Ringger NC, et al. Aust Vet J. 1997;75:329.
2 Searcy GP, et al. Can Vet J. 1981;22:148.
3 Pruette M, et al. J Vet Diagn Invest. 1997;9:318.
4 Khan KN, et al. Vet Pathol. 1995;32:719.
5 Takayama H, et al. J Comp Pathol. 1996;115:95.
6 Takahashi T, et al. J Vet Med Sci. 2000;62:461.
7 Clark P, et al. Equine Vet J. 1999;31:446.
8 Woods PR, et al. J Am Vet Med Assoc. 1993;203:1579.
9 Mori T, et al. Vet Pathol. 1991;28:344.
10 Anjiki T, et al. J Vet Med Sci. 2000;62:1235.
Lymphoproliferative disease occurs in all large animal species but is common only in cattle, where it manifests as lymphoma or lymphosarcoma (bovine viral leukosis). The other lymphoproliferative disease is plasma cell myeloma, which occurs in ruminants and horses. Lymphangiosarcoma is a rare tumor of lymphoid endothelium in horses and cattle.1,2
This is a tumor of plasma cells that sometimes results in production of monoclonal globulins. The disease occurs in cattle,3 sheep4 and horses5-9 and is characterized by proliferation of lymphoid cells that produce an immunoglobulin or immunoglobulin fragment (often referred to as M-protein). The disease characteristically, but not always, involves the bone marrow, in which case it is referred to as multiple myeloma. The tumor cells may or may not secrete abnormal protein.
Clinical signs are often nonspecific and include weight loss, anorexia, limb edema and recurrent infections. There can be signs of excessive bleeding as a result of minor trauma such as needle sticks. The tumor can infiltrate many tissues, accounting for the protean nature of the clinical signs. Involvement of cranial nerves can result in dysphagia8 and infiltration of cervical vertebrae can result in pathological fracture and acute spinal cord compression.9 Involvement of the mediastinal lymph nodes can cause signs of an anterior thoracic mass. The clinical signs can be sufficiently vague that the disease is easily overlooked in its early stages. Radiography reveals the presence of osteolytic bone lesions in some animals.5
Anemia is common and thrombocytopenia occurs in about 20% of affected horses.5 Plasma cells can occasionally be seen in smears of peripheral blood. Hypoalbuminemia and hyperglobulinemia are common findings. Serum protein electrophoresis is useful in demonstrating the presence of a monoclonal proteinopathy in the alpha-2, beta, or gamma regions. Bence–Jones proteinuria occurs in approximately 20% of horses with myeloma.5 Serum concentrations of specific immunoglobulins are often increased – there are two reports of horses with myeloma and elevated concentrations of IgA.6,7 Hypercalcemia occurs in some affected horses5-7 and can be a result of increased concentrations of parathyroid-hormone-related protein.6 Examination of bone marrow obtained by aspiration or biopsy can reveal the presence of an excess number of plasma cells (> 10%).
There is no effective treatment. Most animals present with advanced disease and die within days to weeks, but animals detected earlier in the disease process can live for more than 6 months.6,7
Bovine leukosis virus causes lymphoma in cattle and sheep, but with these exceptions the etiology of lymphoma in large animal species is unknown.
Lymphosarcoma occurs as four distinct clinical entities in cattle:
• Juvenile multicentric lymphosarcoma occurs at birth or in early life. It is multicentric and commonly involves the bone marrow and most lymph nodes
• Thymic lymphosarcoma develops in cattle from 3 months to 2 years of age and involves the thymus, occasionally spreads to other lymph nodes and rarely infiltrates other organs
• Cutaneous lymphosarcoma occurs primarily in cattle at 1–3 years of age
Lymphosarcoma in cattle is discussed in detail under the headings of bovine viral leukosis and sporadic bovine leukosis.
• Lymphoma associated with infection by bovine leukosis virus occurs in sheep.10 The sporadic form of the disease can have a variety of presentations, including involvement of the brain, skin and joints in addition to the expected localization in lymphoid tissue11-13
• Goats develop sporadic lymphoma including a multicentric form14-16
• Pigs develop lymphosarcoma sporadically, with most forms being of B cells, although disease due to T cells is described.17,18 There is also an inherited form of the disease.19,20
The clinical signs of lymphosarcoma are similar to those described for the disease associated with bovine leukosis virus in cattle. Lymphadenopathy and clinical abnormalities arising as a result of lymphadenopathy (dysphagia, bloat, respiratory distress) are common presentations. Radiography or ultrasonography are useful diagnostic aids.15 Biopsy of lymph nodes can yield a diagnosis. Necropsy examination reveals lymphadenopathy and infiltration by neoplastic lymphocytes. There is no documented effective treatment. Administration of glucocorticoids might cause transient improvement because of lympholysis. Radiotherapy is feasible in small ruminants or pigs of sufficient monetary or emotional value, but has not been reported.
There is no recognized etiology of lymphoma or lymphosarcoma in horses. The disorder is more accurately described as neoplasia of one of many lymphoid cell lines, and with increasing sophistication of immunohistochemical staining it is possible to differentiate lymphoma by the particular cell line that is affected. Both immunohistochemistry of fixed tissue sections and fluorescent cell sorting of cells in body fluids have been used to determine the abnormal cell type.21,22 An additional advantage of advanced testing is that tumors of uncertain origin (lymphoid, myeloid) can sometimes be characterized.22
The tumors in horses are most commonly of T-cell or B-cell lines. Equine B-cell lymphoma accounts for approximately 70% of equine lymphomas.21 B-cell lymphomas that do not contain large numbers of T cells (which are not neoplastic) account for 40% of equine lymphoma and are characteristically tumors of the spleen and thoracic and mediastinal lymph nodes. B-cell tumors that contain large numbers of T cells (T-cell-rich B-cell lymphoma) account for approximately one third of equine lymphoma. These latter are typically tumors of the skin and subcutis.21 T-cell lymphomas account for approximately 20% of equine lymphomas and typically cause disease involving mediastinal lymph nodes. Approximately 50% of equine lymphomas have cells that express progesterone receptors, but none express the estrogen receptor.23
The disease occurs in all ages of horse but there is no information on age-specific incidence. One study has reported cases in horses ranging from 4 months to 22 years of age24 and the mean age of cases in this, and other case reviews, suggests that there is some increase in risk with increasing age. Limited slaughter surveys show a prevalence that varies from 0.7 to 3.2 cases per 100 000 animals.25
The clinical manifestation of lymphosarcoma in horses is probably best described by the statement that the disease can manifest in a protean manner. Lymphosarcoma can exert an influence on the function of any organ system and this is determined by where it occurs in the body. Most cases, certainly over 50% of cases, are multicentric although they may present with signs that are organ-specific and the multicentricity may not be recognized until further, more complete, clinical or postmortem examination.24 External lymphadenopathy is usually a reflection of multicentric disease.26
Common presenting histories for other cases include chronic wasting and chronic diarrhea, upper respiratory distress with stertorous breathing or inspiratory dyspnea, lower respiratory abnormality, subcutaneous edema, anemia and fever of unknown origin.
Lymphosarcoma is the single most common cause of neoplasia in the thorax of the horse.27,28 A common syndrome is that of weight loss, ventral edema of the neck and thorax, sometimes accompanied by pleural or peritoneal effusion, anemia, dyspnea, cough and abdominal masses palpable per rectum.24,25 In cases where the lesions are predominantly in the thorax the syndrome is that produced by a space-occupying lesion,28 manifested by pectoral edema, jugular vein engorgement but an absence of the jugular pulse and dyspnea. The heart may be displaced and there may be cardiac murmurs. If there is compression of the esophagus, dysphagia is present.
Another relatively common syndrome is chronic weight loss, with or without diarrhea, associated with infiltration of the intestine.29,30 A case review of chronic diarrhea in horses found alimentary lymphosarcoma to be the cause in five of 51 cases.31 Oral glucose tolerance tests are adversely affected by the intestinal infiltration of lymphosarcoma but an abnormal test is not pathognomonic for this disease.32 Lymphosarcoma is also a cause of recurrent colic in horses.33
Cutaneous lymphosarcoma is a common disease in horses and might be the most common form of lymphoma in horses. The tumors can be solitary or multiple and are usually discrete, firm, nonpainful swellings. The swellings are often haired, but in the more severe disease there is loss of hair. The lesions tend to be on the head, neck and dorsal trunk, but can be anywhere on the body. The tumors sometimes metastasize but horses affected with a mild or waxing and waning disease can live for years. The tumor is usually a T-cell-rich B-cell lymphoma. Diagnosis is by excisional biopsy. Another variation is mycosis-fungoides, a T-cell lymphoma of the skin that appears to have a more aggressive course.34 Pruritus with alopecia can occur as part of a paraneoplastic syndrome in horses with diffuse lymphoma.35
Lymphosarcoma is the final diagnosis in a significant proportion of horses with fever of unknown origin36 and also should be considered in the differential diagnosis of horses with signs of ataxia or other signs of neurological disease.37,38 The organ systems affected by lymphosarcoma in the horse are not restricted to those mentioned above and individual horses may show involvement of virtually any body system.
Ultrasound can aid in the location of tumor masses or accumulation of pleural or peritoneal fluid, and in aspiration of material from these sites. Radiography is useful for detecting mediastinal disease. Rhinolaryngoscopy permits detection and assessment of disease of the pharynx.
A specific diagnosis can be obtained by cytology and needle aspirates or biopsy with cytological examination of affected lymph nodes is diagnostic. Samples can be obtained from enlarged lymph nodes or from bone marrow. Cytological examination of fluid obtained by thoracocentesis or abdominocentesis where there is thoracic or abdominal involvement is also frequently diagnostic.
Anemia is a consistent finding in horses with advanced lymphosarcoma. The anemia can be due to tumor cells occupying bone marrow,39 but this is not a usual manifestation of the disease. More commonly, anemia is probably due to increased destruction of red cells or anemia of chronic disease. Only a small proportion of horses with lymphadenopathy due to lymphosarcoma have concurrent leukemic blood changes. Sézary-like cells have been detected in the blood of a horse with B-cell lymphoma.40 Thrombocytopenia occurs in approximately 30% of cases.24
Immunophenotyping cells obtained at necropsy examination, by biopsy of affected organs or lymph nodes, or from peripheral blood can aid in determining the cell type involved.21,22
Hypergammaglobulinemia and hypoalbuminemia occur in some horses. Hypergammaglobulinemia in horses with lymphosarcoma is almost always due to a polyclonal globulinopathy – in contrast to horses with plasma cell myeloma – and is probably attributable to the inflammatory response to the tumor. Plasma fibrinogen concentrations can be elevated in horses with lymphosarcoma for the same reason.
Low serum immunoglobulin concentrations have been reported in horses with lymphosarcoma41 but this finding is not specific for lymphosarcoma. Detection of low serum IgM concentration has poor sensitivity and specificity for diagnosis of lymphosarcoma.42 The sensitivity and specificity of serum IgM below 60 mg/dL for diagnosis of lymphosarcoma in horses are 50% and 35%, respectively. This is not a good screening or diagnostic test for lymphosarcoma in horses.
Abnormalities in serum calcium concentration are uncommon and variable, with both hypocalcemia and hypercalcemia being reported. Hypercalcemia can be associated with elevated serum concentrations of parathyroid hormone related peptide.
Treatment of lymphoma in horses is scarcely reported. Immunotherapy with cyclophosphamide and vaccinia-virus-infected autologous tumor cells resulted in some remission of disease in a stallion with cutaneous lymphosarcoma and the animal remained clinically stable for 19 months without tumor progression.43 Removal of an ovarian granulosa theca cell tumor in a mare with waxing and waning cutaneous lymphosarcoma was associated with regression of the tumor.44 Radiotherapy of localized disease of the head and pharynx might be effective in treatment of the lymphoma in horses,45 as lymphoma in other species is radiosensitive. Surgical removal of isolated masses in the skin is appropriate in some cases of cutaneous lymphosarcoma.
Administration of oncolytic agents has resulted in remission of disease in some horses. Drugs used include prednisolone, vincristine, cyclophosphamide and cytarabine. The glucocorticoids cause lysis of abnormal lymphocytes and can result in some improvement in clinical signs. A protocol that has met with some success involves administration of cyclophosphamide (2 mg/kg, intravenously) once weekly for 4–6 weeks, and then once every 2–3 weeks, combined with oral administration of prednisolone (0.5–1.5 mg/kg every 24–48 h). Another protocol involves administration of vincristine (0.008 mg/kg intravenously) and cyclophosphamide (2 mg/kg intravenously) once every 2 weeks for four to six treatments, combined with daily administration of prednisolone. The aim of all these treatments is to induce remission or to reduce clinical signs of the disease when these signs are due to lymphadenopathy (such as dysphagia, dyspnea). An example could be the treatment of a pregnant mare with retropharyngeal tumor that causes dysphagia, with a view to prolonging the mare’s life until parturition.
1 Ijzer J, van den Ingh TSGAM. J Comp Pathol. 2000;122:312.
2 Ruggles RG, et al. J Am Vet Med Assoc. 1992;200:1987.
3 Kameyama M, et al. J Vet Diagn Invest. 2003;15:166.
4 Perez J, et al. Vet Pathol. 2000;37:479.
5 Edwards DF, et al. J Vet Intern Med. 1993;7:169.
6 Barton MH, et al. J Am Vet Med Assoc. 2004;225:409.
7 Pusterla N, et al. Vet Rec. 2004;155:19.
8 McConkey S, et al. J Vet Diagn Invest. 2000;12:282.
9 Drew RA, et al. Equine Vet J. 1974;6:131.
10 Dimmock CK, et al. Immunol Cell Biol. 1990;68:45.
11 Da Silva DL. J S Afr Vet Assoc. 2002;73:90.
12 Roels S, Vanopdenbosch E. Vet Rec. 2001;149:392.
13 Pearson GR, et al. J Comp Pathol. 1999;120:295.
14 Guedes RM, et al. Vet Rec. 1998;143:51.
15 Rozear L, et al. Vet Radiol Ultrasound. 1998;39:528.
16 DiGrassie WA, et al. Can Vet J. 1997;38:383.
17 Vo TD, et al. J Vet Med A. 2004;51:348.
18 Hejazi R, Danyluk AJ. Aust Vet J. 2005;46:179.
19 Head KW, et al. Vet Rec. 1974;95:523.
20 McTaggart HS, et al. Vet Rec. 1979;105:36.
21 Kelley LC, Mahaffey EA. Vet Pathol. 1998;35:241.
22 McClure JT, et al. J Vet Intern Med. 2001;15:144.
23 Henson KL, et al. Vet Pathol. 2000;29:40.
24 Rebhun WC, Bertone A. J Am Vet Med Assoc. 1984;184:720.
25 Van der Hoven R, Franken P. Equine Vet J. 1983;15:49.
26 Kofler J, et al. J Vet Med A. 1998;45:11.
27 Sweeney CR, Gillette DM. J Am Vet Med Assoc. 1989;195:374.
28 Mair TS, et al. Equine Vet J. 1985;17:428.
29 Wilson RG, et al. Equine Vet J. 1985;17:148.
30 Platt H. J Comp Pathol. 1987;97:1.
31 Love S, et al. Vet Rec. 1992;130:217.
32 Mair TS, et al. Equine Vet J. 1991;23:344.
33 Mair TS, Hillyer MH. Equine Vet J. 1997;29:415.
34 Potter K, Anez D. J Am Vet Med Assoc. 1998;212:550.
35 Finley MR, et al. J Am Vet Med Assoc. 1998;213:102.
36 Mair TS, et al. Equine Vet J. 1989;21:260.
37 Zeman DH, et al. J Vet Diagn Invest. 1989;1:187.
38 Williams MA, et al. Prog Vet Neurol. 1992;3:51.
39 Lester GD, et al. J Vet Intern Med. 1993;7:360.
40 Polk AC, et al. J Vet Intern Med. 1999;13:620.
41 Furr MO, et al. J Am Vet Med Assoc. 1992;201:307.
42 Perkins GA, et al. J Vet Intern Med. 2003;17:337.
43 Gollagher RD, et al. Can Vet J. 1993;34:371.
Lymphadenopathy (lymphadenitis)
Lymph nodes can be enlarged because of inflammation (lymphadenitis) or infiltration with neoplastic cells. Enlargement of peripheral nodes causes visible and palpable swellings and in some cases obstruction to lymphatic drainage and subsequent local edema, as in sporadic lymphangitis of horses. Enlargement of internal nodes may cause obstruction of the esophagus or pharynx, trachea or bronchi. Enlargement of the lymph nodes can occur as a result of infection or of neoplastic invasion. Lymphadenopathy as part of lymphoma and lymphosarcoma are discussed under ‘Leukoproliferative diseases’.
Lymphadenitis occurs most commonly in response to infection or inflammation in the region of the body distal to, and drained by, the lymph node. Lymphadenitis also accompanies other signs in many other diseases, including bovine malignant catarrh, sporadic bovine encephalomyelitis, the porcine reproductive and respiratory syndrome, East Coast fever, Ondiri disease and ephemeral fever.
Infection and enlargement of lymph nodes is the major presenting sign in a small number of diseases, which include:
• Caseous lymphadenitis of sheep and ulcerative lymphangitis in horses and cattle due to infection with Corynebacterium pseudotuberculosis
• Internal abscessation associated with C. pseudotuberculosis in horses1
• Anthrax, especially in the pig but also in the horse, which may initially manifest as cervical lymphadenopathy with considerable inflammation and swelling in the pharyngeal region and neck
• Strangles in horses associated with S. equi and lymphadenitis produced by Streptococcus zooepidemicus. Lymphadenopathy that causes enlargement of abdominal lymph nodes is a characteristic of infection with S. equi in the burro
• Anorectal lymphadenopathy in young horses, causing extraluminal rectal obstruction with colic and sometimes urinary dysfunction2
• Cervical adenitis (jowl abscess) of pigs, caused principally by group E type IV Streptococcus sp. but also by Actinomyces pyogenes and Pasteurella multocida
• Granulomatous cervical adenitis, which also occurs in pigs and is a common finding at slaughter. The lesions rarely cause clinical illness but are a public health concern because they may be tuberculosis. Most commonly they are associated with R. equi or atypical mycobacteria but Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium bovis are also causes
• Tularemia, infection with Francisella tularensis, in tick-infested sheep
• Melioidosis associated with infection with Pseudomonas (Malleomyces) pseudomallei
• Tick pyemia associated with Staphylococcus aureus in sheep infested with the tick Ixodes ricinus
• Retropharyngeal lymph node enlargement up to three or four times normal, and colored bright green, have been identified in cattle as resulting from infection with the algae Prototheca spp.3
• Lymphadenitis in lambs associated with P. multocida, and in some cases of actinobacillosis
• Morel’s disease of sheep associated with a micrococcus
• Bovine farcy and atypical skin tuberculosis, the latter involving the lymphatics but not associated with lymph node enlargement.
In acute lymphadenitis there may be pain and heat on palpation but the nodes are for the most part painless. Obstructions produced by enlarged lymph nodes can result in secondary signs such as respiratory difficulty with enlargement of the retropharyngeal lymph nodes and esophageal obstruction by enlarged mediastinal lymph nodes. Needle biopsy for cytology and culture can aid in the determination of the cause of lymphadenitis and can allow the differentiation between lymphadenitis and neoplastic enlargement. Ultrasound may also aid in diagnosis.4 The diseases above are discussed in more detail under their specific headings.
Absence of lymphoid tissue occurs as a congenital defect in Arabian foals with severe combined immunodeficiency and is recorded in an Angus calf.
Diseases of the spleen and thymus
The spleen serves a number of functions – it is a storage organ for blood, a source of extramedullary erythropoiesis in some species, a major component of the reticuloendothelial system, and an important component of the immune system. Its function is most evident in the horse, in which an intact and functioning spleen is necessary for normal work capacity. Blood in the spleen of horses has a hematocrit much higher than that of blood (70–80%) and when relaxed the spleen contains many liters of blood. Excitement or exercise cause splenic contraction through an alpha-1-mediated event and ejection of the red-cell-rich blood into the peripheral circulation, with subsequent marked increases in hematocrit.1,2 The spleen of an adult horse can eject 5–10 L of blood into the circulation and, together with declines in plasma volume during exercise, increase hematocrit to 55–60% (0.55–0.60 L/L).1
Splenectomy is performed as part of treatment of idiopathic refractory thrombocytopenia, or as a consequence of splenic infarction. Removal of the spleen (splenectomy) impairs the oxygen-carrying capacity of blood during exercise, by preventing the normal increase in hematocrit, and prevents the normal cardiovascular responses to exercise, including increases in right atrial pressure.3,4
Diffuse diseases of the spleen that result in enlargement are usually secondary to diseases in other organs. Splenomegaly with complete destruction of splenic function is virtually symptomless, especially if the involvement occurs gradually, and in most cases clinical signs are restricted to those caused by involvement of other organs. An enlarged spleen may be palpable on rectal examination in the horse and careful percussion may detect enlargement of the spleen in cattle, but in most instances involvement of the organ is not diagnosed at antemortem examination unless laparotomy is performed.
Left dorsal displacement of the colon in the horse is a colic in which the spleen is displaced medially and this may give the impression that the organ is enlarged. Rupture of a grossly enlarged spleen may cause sudden death due to internal hemorrhage. This is sometimes the cause of death in bovine viral leukosis or equine amyloidosis.5 Moderate degrees of splenomegaly occur in many infectious diseases, especially salmonellosis, anthrax, babesiosis, equine infectious anemia and diplococcus septicemias in calves, and in some noninfectious diseases such as copper toxicity in sheep. Animals that die suddenly because of lightning stroke, electrocution and euthanasia may also show a moderate degree of splenomegaly but the enlargement is minor compared to that observed in congestive heart failure, portal obstruction or neoplastic change.
Neoplasms of the spleen are not common in large animals but may include lymphosarcoma, hemangiosarcoma, myelocytic leukemia or malignant melanoma in horses.6-8 Metastasis of hepatic carcinoma to the spleen of a dairy cow is reported.9 The abnormality is usually readily detected by ultrasonographic examination of the spleen. They may be discovered incidentally during rectal examination or because of colic resulting from displacement of the bowel by the enlarged spleen.
Splenic abscess may result when a septic embolus lodges in the spleen, but is more commonly caused by extension of infection from a neighboring organ. Perforation by a foreign body in the reticulum of cattle is the commonest cause of the disease in large animals and gastric penetration by sharp metal have caused splenitis in the horse. Perforation of a gastric ulcer or an erosion of the gastric wall caused by Gasterophilus intestinalis10 or extension of a granuloma caused by larvae of Habronema sp. in horses may lead, by extension, to development of a suppurative lesion in the spleen. In those occasional cases of strangles in horses in which systemic spread occurs, splenic abscess occasionally occurs.
Splenic abscesses associated with C. pseudotuberculosis infection are diagnosed in horses in those parts of the world where the infection is endemic. The most common clinical signs are concurrent external abscesses, anorexia, fever, lethargy, weight loss and signs of respiratory tract disease or abdominal pain. Clinicopathological abnormalities included serum synergistic hemolysin inhibition titer of 512 or more, and leukocytosis with neutrophilia, hyperglobulinemia, hyperfibrinogenemia and anemia. Diagnosis is based on the presence of appropriate clinical signs and ultrasonographic examination of the spleen. Prolonged treatment with antimicrobials is successful in most cases.11
If the abscess is extensive and acute there are systemic signs of fever, anorexia and increased heart rate. Pain is evidenced on palpation over the area of the spleen and hematological examination reveals a marked increase in the total white cell count and a distinct shift to the left in the differential count.
Abdominocentesis usually provides evidence of chronic peritonitis by the presence of a large amount of inflammatory exudate. Peritonitis is often coexistent and produces signs of mild abdominal pain with arching of the back and disinclination to move. Mild recurrent colic may also occur. Anemia, with marked pallor of mucosae, and terminal ventral edema are also recorded. The spleen may be sufficiently enlarged to be palpable per rectum.12
Treatment of splenic abscess is often unrewarding because of the extensive nature of the lesion before clinical signs appear. The systemic signs can usually be brought under control by treatment with sulfonamides or antibiotics over a period of about 7 days but relapses are common and death is the almost certain outcome. Splenectomy is recommended if adhesions and associated peritonitis are absent.
Formation of a hematoma in the spleen or, in the more severe instance, splenic rupture usually occurs as a result of trauma. The syndrome is best described in horses, occurring as a result of falling on to a stirrup or blunt trauma to the left side of the rib cage.7,13,14 The clinical signs include colic, tachycardia, cold extremities and pallor of the mucous membranes– all of which are suggestive of hemorrhagic shock. If a hematoma is present ultrasonographic examination of the abdomen will reveal an abnormally shaped spleen containing a hypoechoic mass. Rupture of the spleen with be apparent as accumulation of a large quantity of fluid within the abdomen. The fluid will have the ultrasonographic characteristics of blood (a swirling echodensity). Laparoscopy can be used to confirm the diagnosis. Hematology can reveal leukocytosis and low hematocrit. Peritoneal fluid can be serosanguinous if the hematoma has not ruptured, or bloody if the spleen is ruptured.
Infarction of the spleen is reported rarely in horses and so predisposing factors are not identified.15 In other species splenomegaly predisposes to infarction. The clinical signs are mild to moderate colic, tachycardia and signs of hemorrhagic shock. Ultrasonography and exploratory laparotomy are diagnostic. The spleen is enlarged and has numerous zones of varying echogenicity, which is in marked contrast to the usual homogenous echogenicity of normal spleen. There can be excessive, echogenic fluid in the abdomen consistent with blood. Treatment is surgical, although technically challenging because of the splenomegaly and risk of rupture of the spleen.
Treatment of a splenic hematoma is conservative, with enforced rest for a period of up to 3 months. Resolution of the hematoma can be monitored by periodic ultrasonographic examination. Horses with a ruptured spleen usually die within a short period of time. Theoretically, emergency splenectomy might be useful, but timely diagnosis and surgery is difficult to achieve because of the short time course of the disease.
1 McKeever KH, et al. Am J Physiol. 1993;265:R404.
2 Hardy J, et al. Am J Vet Res. 1994;55:1570.
3 McKeever KH, et al. Am J Physiol. 1993;265:R409.
4 Kunugiyama I, et al. J Vet Med Sci. 1997;59:733.
5 Pusterla N, et al. J Vet Intern Med. 2005;19:344.
6 Chaffin MK, et al. J Am Vet Med Assoc. 1992;201:743.
7 Geelen SNJ, et al. Tijdschr Diergeneeskd. 1996;121:544.
8 MacGillivray KC, et al. J Vet Intern Med. 2002;16:452.
9 Jeong WI, et al. Vet Pathol. 2005;42:230.
10 Dart AJ, et al. Aust Vet J. 1987;64:155.
11 Pratt SM, et al. J Am Vet Med Assoc. 2005;227:441.
12 Spier S, et al. J Am Vet Med Assoc. 1986;189:557.
13 Dyke TM, Friend SCE. Equine Vet J. 1998;20:138.
Abdominal situs inversus is reported in a calf.1 The calf had a rumen that was on the right side of its abdomen, and two spleens, among other abnormalities. The clinical presentation was chronic bloat.
The thymus is the source of T cells in animals and is essential for development of normal immune responses. These functions occur during late gestation and in the neonate. Primary diseases of the thymus are rare in farm animals. The thymus is largest, relative to body size, in neonates and atrophies in adults to the extent that it can be difficult to identify. Aplasia or thymic hypoplasia occurs as part of severe combined immunodeficiency in Arabian foals. Aplasia of the thymus is reported in a Holstein calf.1 The congenital condition results in increased susceptibility to infection. Extrathoracic thymus tissue occurs in lambs and can be mistaken for enlargement of the thyroid glands.2 Neoplasia of the thymus occurs in most species. Thymic lymphomas are reported in horses,3 pigs4 and calves.5 Thymoma and thymic carcinoma are reported in horses and cattle.6-8 The clinical syndrome is that of a cranial thoracic mass. There can be compression of the cranial vena cava with obstructed blood flow and signs of congestive heart failure. The jugular veins are distended and there can be submandibular edema. There can be accumulation of excessive pleural fluid. Esophageal obstruction evident as bloat in cattle or dysphagia in cattle and horses occurs. Radiography or ultrasonography of the chest demonstrate the mass, and histological diagnosis can be achieved at necropsy or in samples obtained by fine-needle biopsy.
1 Yeruham I, et al. J Vet Med B. 2000;47:315.
2 Kock ND, et al. Vet Rec. 1989;124:635.
3 Van den Hoven R, Franken P. Equine Vet J. 1983;15:49.
4 Kadota K, et al. Zentralbl Veterinärmed A. 1990;37:592.
5 Angel KL, et al. J Am Vet Med Assoc. 1991;198:1771.
6 Whitely LO, et al. Vet Pathol. 1986;23:627.
Immune deficiency disorders (lowered resistance to infection)
Increasingly, animals are encountered that are much more susceptible to infection than their cohorts. These animals may be suffering because of a reduction in their immune function and need to be identified as such. The history and signs that should suggest the possible presence of compromised immune function are:
• Infections developing in the first 6 weeks of life
• Repeated or continuous infections that respond poorly to treatment
• Increased susceptibility to low-grade pathogens and organisms not usually encountered in immunocompetent animals
• Administration of attenuated vaccines leading to systemic illness
• Low leukocyte counts, either generally or as lymphopenia or neutropenia, perhaps within an associated low platelet count.
It is not proposed to detail the mechanisms of humoral and cellular immunity here because there is a large literature based on the subject in immunology. However, it is necessary to remember that the normal immune response is a very complicated process, including many sequential steps, and there are various sites at which defective development or function can occur.
The disorders of immunity may be primary, in which the animal is born with a congenital defect of one of the immune processes, or secondary, in which the animal has a normal complement of immunological processes at birth but suffers a dysfunction of one of them, often temporarily, during later life. Toxicological and microbiological agents can have this effect.
Immunosuppression is a state of temporary or permanent dysfunction of the immune response resulting from damage to the immune system and leading to increased susceptibility to disease agents.1 In immunosuppression there is decreased immune responsiveness to all foreign antigens, whereas in immune tolerance there is a state of decreased or nonresponsiveness to one particular antigen. Immunosuppression may be associated with infectious and noninfectious agents. A review of the general aspects of immunosuppression and the various agents responsible is available.1 Infectious agents include bacteria, viruses, protozoa and helminths; noninfectious causes include chemicals, hormones and some antimicrobials such as chlortetracyclines and toxins. Environmental factors such as extremes of temperature, humidity, high population density and mixing animals from different origins, and prolonged transportation have also been implicated as causes of immunosuppression but the pathogenesis of these has not been well explained.
Various laboratory methods can be used to evaluate immunosuppression. The criteria which can be used to evaluate immune functions include:
• Gross and microscopic changes in the morphology of central or peripheral lymphoid tissues
• Changes in the concentration or ratios of different classes of immunoglobulin
• Changes in serum complement concentration
• Changes in the functional activity of immunoglobulins
• Changes in functional activity of the immune response
• Interference with the results of vaccination
• Exacerbation in the course of disease associated with other agents
• Changes in the number and viability of cells from lymphoid organs.1
The development of monoclonal antibody reagents has allowed new approaches to veterinary immunopathology, particularly the identification and analysis of leukocyte subpopulations in health and disease.2
Most of the diseases associated with immunological deficiency states are dealt with in systems or other categories of disease throughout this book and only a checklist is provided here.
The primary immunodeficiencies can be in either innate immunity or adaptive immunity. Deficiencies of innate immunity include:
• Chédiak–Higashi syndrome, an inherited defect of many animal species, including cattle. This is a defect of phagocytic capacity via the neutrophils and monocytes
• Bovine leukocyte adhesion deficiency of Holstein calves, which results from a deficiency in CD18 and accumulation of profound numbers of neutrophils in circulation but not in tissue.
Deficiencies of adaptive immunity include:
• Combined immunodeficiency (CID) of Arabian horses due to an inherited failure to produce and differentiate lymphoid precursor cells into B and T lymphocytes. See Table 34.2 for a listing of immunodeficiencies of horses. A similar disease is reported in an Angus calf
• Agammaglobulinemia of Standardbred and Thoroughbred horses, a probably inherited failure to produce B lymphocytes. These horses live much longer than those affected with CID
• Selective deficiencies of one or more globulins. A deficiency of IgM in Arabian horses and Quarter horses is listed.3 IgM and IgA combined deficiencies with diminished but discernible levels of IgG are observed occasionally in horses. A transient hypogammaglobulinemia (absence of IgG) has been reported in one Arabian foal, which was immunodeficient until it was 3 months old and then became normal
• Selective IgG2 deficiency in Red Danish cattle
• A syndrome of immunodeficiency in Fell ponies
• Common variable immunodeficiency is described in adult horses4,5
• Lethal trait A46 (inherited parakeratosis) of cattle is a primary immunodeficiency influencing T lymphocytes, with impairment of cellular immunity
• Selective IgG2 deficiency of cattle causes increased susceptibility to gangrenous mastitis and other infections. It is a primary deficiency of IgG2 synthesis, and is recorded in the Red Danish milk breed
• Sheep and pigs – there are as yet no recognized primary immunodeficiencies in these species.
• Failure of transfer of passive immunity, i.e. of antibodies from colostrum to the offspring, is well known as the commonest cause of deficient immunity in the newborn and is discussed in Chapter 3
• Atrophy of lymphoid tissue and resulting lymphopenia associated with:
• General suppression of immune system responsiveness, e.g.:
1 Muneer MA, et al. Br Vet J. 1988;144:288.
2 MacKay CR, MacKay IR. Aust Vet J. 1989;145:185.
3 Perryman LE, et al. J Am Vet Med Assoc. 1977;170:212.
4 Flaminio J, et al. J Am Vet Med Assoc. 2002;221:1296.
5 Pellegrini-Masini A, et al. J Am Vet Med Assoc. 2005;227:114.
6 Shibahara T, et al. J Vet Med Sci. 2000;62:1125.
Amyloidoses
The amyloidoses are a group of diseases characterized by the deposition of an extracellular proteinaceous substance, amyloid, in the tissues with subsequent disruption of normal tissue architecture leading eventually to organ dysfunction. Amyloidosis in farm animals usually occurs in association with a chronic suppurative process elsewhere in the body and is due to accumulation of AA amyloid. Another form of the disease involves accumulation of AL amyloid, especially as localized disease in horses.
Amyloidosis occurs rarely and when it does occur it is most common in animals exposed systemically and repeatedly to antigenic substances. Examples include repeated injections of antigenic material for commercial production of hyperimmune serum and long-standing suppurative diseases or recurrent infection as in Chédiak–Higashi syndrome. Severe strongylid parasitism in the horse has been reported as a cause. Holstein calves with bovine leukocyte adhesion deficiency have accumulation of amyloid in tissue, although this is not the primary disease. Many cases of amyloidosis in large animals are without apparent cause.
The incidence of visceral AA amyloidosis in slaughtered cattle in a group of 302 cattle older than 4 years of age in Japan was 5.0% compared with those previously reported from Japan and other countries ranging from 0.4–2.7%.1 Systemic AA-amyloidosis associated with tuberculosis has been described in a European wild boar.2 Systemic amyloidosis in goat kids with chronic arthritis associated with seroconversion to Erysipelothrix rhusiopathiae has been described.3
Out of 16000 horses referred for clinical examination into a veterinary teaching hospital over a period of 13 years, nine horses were identified with amyloidosis.4 Cutaneous amyloidosis has been associated with malignant histiocytic lymphoma in the horse.5
A case of cardiac amyloidosis causing heart failure in a 16-year-old Thoroughbred gelding has been described.6 The disease was due to accumulation of AL amyloid.6
The AL form of amyloidosis is characteristically associated with unstable monoclonal immunoglobulin light chains produced by plasma cell dyscrasia and resulting in deposition of AL fibrils.6
How amyloid is formed is uncertain but a hyperglobulinemia is commonly present and this, together with the circumstances under which it occurs, suggest an abnormality of the antigen–antibody reaction. Amyloidoses are classified by the types of amyloid protein deposited. AA amyloid is derived from serum amyloid-A protein (SAA), which is an acute-phase reactant produced by hepatocytes.7 However, increased concentrations of SAA alone are not sufficient to cause amyloidosis. AA (secondary) amyloidosis is associated with recurrent acute or chronic infections, inflammatory disease or neoplasia.
Extensive amyloid deposits may occur in the spleen, liver or kidneys and cause major enlargement of these organs and serious depression of their functions. The commonest form that is clinically recognizable in animals is renal amyloidosis. This presents as a nephrotic syndrome with massive proteinuria and a consequent hypoproteinemia and edema. Terminally, the animal is uremic, becoming comatose and recumbent. The edema of the gut wall and its infiltration with amyloid create the conditions necessary for the development of diarrhea. In horses, cases of multiple cutaneous lesions are recorded. The amyloid is present in 5–25 mm diameter nodes in the skin of the head, neck and pectoral regions.
Rare cases of involvement of the upper respiratory tract (nasal cavities, pharynx, larynx, guttural pouch and lymph nodes of the head and neck, and conjunctiva) are also recorded in horses. The amyloid material deposited in the tissues is usually of the AL form, whereas systemic disease is almost always the AA form.
AL amyloidosis is also reported in an adult cow with bovine leukocyte adhesion deficiency.8
Many cases of amyloidosis are detected incidentally at necropsy. The cutaneous form in horses is characterized by the presence of hard, nonpainful, chronic plaques in the skin.5 Most of the lesions, which can be widespread and severe, are on the sides of the neck, shoulders and head. Respiratory tract involvement in the horse is usually limited to the nasal cavities, and this may cause dyspnea.4
Chronic heart failure due to cardiac amyloidosis secondary to systemic amyloidosis in a 16-year-old gelding was characterized clinically by weight loss, dysphagia, recurrent episodes of esophageal obstruction and anorexia of a few weeks duration.1 Ventral edema, tachycardia and irregular heart rate associated with atrial fibrillation were present. The clinical findings were consistent with biventricular heart failure from ventricular dysfunction, atrial fibrillation and pulmonary hypertension. The amyloid was of the AL form.
A case of systemic AL amyloidosis associated with multiple myeloma in a horse was characterized clinically by rapid weight loss, muscle atrophy, soft unformed feces and ventral edema.9
Hemoperitoneum and acute death secondary to splenic or hepatic rupture in horses with systemic amyloidosis is reported.10
Clinical cases in cattle are characterized by emaciation and enlargement of the spleen, liver or kidneys; involvement of the kidney causes proteinuria and is often accompanied by profuse, chronic diarrhea, polydipsia and anasarca. In cattle the grossly enlarged left kidney is usually palpable per rectum. Cases may occur within 2 weeks of calving. They are characterized by anorexia, watery diarrhea, anasarca, rapid emaciation and death in 2–5 weeks.
Corpora amylacea are small, round concretions of amyloid material found in mammary tissue of cows. They are usually inert but may cause blockage of the teat canal.
An extreme, persistent proteinuria should suggest the presence of renal amyloidosis. Electrophoretic studies of serum may be of value in determining the presence of hyperglobulinemia. Alpha-globulin levels are usually elevated and albumin levels depressed. Horses with hepatic amyloidosis have elevated activities of gamma-glutamyltransferase and, to a lesser extent, bile acids.11 In cattle there is hypocalcemia, hyperfibrinogenemia, hypomagnesemia, high serum urea and creatinine concentration, low-specific-gravity urine and prolongation of the bromsulfalein clearance time. Biopsy of cutaneous plaques is an accurate diagnostic technique.
Affected organs are grossly enlarged and have a pale, waxy appearance. In the spleen, the deposits are circumscribed; in the liver and kidneys they are diffuse. In a horse with systemic AL amyloidosis associated with multiple myeloma, diffuse gastrointestinal hemorrhage, thickened jejunal mucosa and splenomegaly were present.9
The pathology of AA amyloidosis in domestic sheep and goats has been described.12 Most sheep had pneumonia and other sites of chronic inflammation. Amyloid was detected in all grossly affected kidneys using Congo red staining.
Deposits of amyloid in tissues may be made visible by staining with aqueous iodine. Amyloid is detected as green birefringence of Congo-Red-stained tissues viewed under polarized light. AA and AL amyloidosis can be differentiated by treatment of tissue sections with potassium permanganate. Tissue containing AA will lose its green birefringence after treatment with potassium permanganate whereas tissue containing AL will continue to appear green after Congo Red staining and viewing under polarized light.
The Shtrasburg method is now available for the identification of AA amyloid and to distinguish it from amyloid types in a large number of domestic and wild animals.13
1 Tojo K, et al. Amyloid. 2005;12:103.
2 Segales J, et al. J Vet Med A Physiol Pathol Clin Med. 2005;52:135.
3 Wessels M. Vet Rec. 2003;152:302.
4 Van Andel ACJ, et al. Equine Vet J. 1988;20:277.
5 Gliatto JM, Alroy J. Vet Rec. 1995;137:68.
6 Nout YS, et al. J Vet Intern Med. 2005;17:588.
7 Vanhooser SL, et al. Equine Vet J. 1988;20:274.
8 Taniyama H, et al. Vet Pathol. 2000;37:98.
9 Kim DY, et al. Vet Pathol. 2005;42:81.
10 Pusterla N, et al. J Vet Intern Med. 2005;19:344.
11 Abdelkader SV, et al. J Comp Pathol. 1991;105:203.
Porphyrias
Porphyria is not common in farm animals.1 The congential disease in cattle is discussed in Chapter 34.