ACVIM consensus statement on the diagnosis of immune-mediated hemolytic anemia in dogs and cats

Abstract

Immune-mediated hemolytic anemia (IMHA) is an important cause of morbidity and mortality in dogs. IMHA also occurs in cats, although less commonly. IMHA is considered secondary when it can be attributed to an underlying disease, and as primary (idiopathic) if no cause is found. Eliminating diseases that cause IMHA may attenuate or stop immune-mediated erythrocyte destruction, and adverse consequences of long-term immunosuppressive treatment can be avoided. Infections, cancer, drugs, vaccines, and inflammatory processes may be underlying causes of IMHA. Evidence for these comorbidities has not been systematically evaluated, rendering evidence-based decisions difficult. We identified and extracted data from studies published in the veterinary literature and developed a novel tool for evaluation of evidence quality, using it to assess study design, diagnostic criteria for IMHA, comorbidities, and causality. Succinct evidence summary statements were written, along with screening recommendations. Statements were refined by conducting 3 iterations of Delphi review with panel and task force members. Commentary was solicited from several professional bodies to maximize clinical applicability before the recommendations were submitted. The resulting document is intended to provide clinical guidelines for diagnosis of, and underlying disease screening for, IMHA in dogs and cats. These should be implemented with consideration of animal, owner, and geographical factors.

Keywords: Delphi survey; comorbidity; direct antiglobulin test; erythrocyte; evidence; flow cytometry; hemolysis; iceberg model; spherocyte; veterinary and comparative clinical immunology society.

Figure 1

Curation of records. Papers captured by a search algorithm for anemia that met inclusion criteria (n = 248) were manually curated to remove duplicates (n = 67), after which remaining papers were screened to assess whether they mentioned comorbidities, yielding 63 papers; an additional 6 were added in March 2018. An independent search for infectious agents yielded an additional 11 papers of relevance. One additional paper was identified by examining reference lists of the captured papers. IMHA, immune‐mediated hemolytic anemia

Figure 2

Diagnostic algorithm for immune‐mediated hemolytic anemia (IMHA). Having identified anemia in a patient, biomarkers of immune‐mediated destruction should next be assessed, including the saline agglutination test (SAT), direct antiglobulin test (DAT), and/or flow cytometry (FC); at least 2 should be present, or a positive SAT that persists with washing, to make a firm diagnosis of IMHA. Signs of hemolysis should then be assessed, at least 1 of which should be present for a firm diagnosis. Variations on this theme would yield a supportive or suspicious diagnosis, provided another cause of anemia is not identified. Additional abbreviations: ≥, at least; dz, disease

Figure 3

Integrated metric of evidence (IME) summary for all comorbidity categories. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. Most IME values fell within the negligible and low zones of evidence, while a small number were 0, indicating evidence against that comorbidity inducing immune‐mediated hemolytic anemia (IMHA). No studies of relevance to vaccination as a potential trigger for IMHA in cats could be found

Figure 4

Integrated metric of evidence (IME) values for infectious agents and diseases in dogs. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. spp, species (plural term)

Figure 5

Integrated metric of evidence (IME) values for infectious agents and diseases in cats. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. Ca., Candidatus; FeLV, feline leukemia virus; FIP, feline infectious peritonitis; FIV, feline immunodeficiency virus; Hem., hemotropic; M., Mycoplasma

Figure 6

Integrated metric of evidence (IME) values for cancer types in dogs. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. Miscellaneous cancer types included pheochromocytoma, unspecified abdominal, adrenal, bladder, cardiac, mediastinal, and splenic masses, other hematopoietic tumors, and unspecified neoplasia. Lym., lymphoid; Myeloid, myeloid leukemia or myeloproliferative disease

Figure 7

Integrated metric of evidence (IME) values for cancer types in cats. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. Miscellaneous cancer types included gastrointestinal and uncharacterized neoplasia. Lym., lymphoid; Myeloid, myeloid leukemia or myeloproliferative disease

Figure 8

Integrated metric of evidence (IME) values for inflammatory diseases. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. infl'n, inflammation; SLE, systemic lupus erythematosus

Figure 9

Integrated metric of evidence (IME) values for drugs. Horizontal dotted lines indicate the threshold IME values between negligible and low (2.95), low and intermediate (4.37), and intermediate and high (5.78) levels of evidence. The single antimicrobial drug yielding high‐level evidence in dogs was cefazedone. NSAID, non‐steroidal anti‐inflammatory drug

Figure 10

Iceberg model and proposed new nomenclature for immune‐mediated hemolytic anemia (IMHA). A, The iceberg model posits that pathomechanisms underlying IMHA fall on a spectrum, both recognized (above the water level) and currently unrecognized or occult (concealed), the latter postulated to be the majority. Hypothetical occult pathomechanisms are listed. B, We propose a new nomenclature for IMHA to better reflect the heterogeneity in pathomechanisms underlying IMHA