Evidence-based management of IMHA (Proceedings)
Immune-mediated hemolytic anemia is one of the most common reasons for referral to veterinary internists. The most common presenting complaint is that the patient is inadequately responding to appropriate immunosuppression. In all cases referral is welcome (we appreciate your trust and your business!); however many times this reflects an unfamiliarity with some of the treatment options beyond glucocorticoids, or a difficult-to-diagnose causative underlying disease. This presentation will briefly review the more common causes of secondary immune-mediated hemolytic anemia (IMHA) and the diagnostic tests which I routinely consider prior to instituting immunosuppresive therapy, and then discuss in depth treatment options for dogs with this disease.
IMHA: DIAGNOSTIC WORK-UP
Primary versus Secondary causes of IMHADevelopment of anti-erythrocyte antibodies can occur idiopathically (primary IMHA), or secondary to a number of infectious or neoplastic diseases, toxins and envenomations, and commonly used drugs. Other diseases (i.e. neoplasia, zinc, heartworms) can cause hemolytic anemia without the presence of anti-erythrocyte antibodies. Differentiation can be difficult, as dogs with IMHA are not reliably autoagglutinating or Coomb's positive. For this reason intense history-taking and physical examination are required in every case, as well as screening tests to ensure that there are no concurrent diseases. Diseases which are definitely associated with hemolytic anemia and secondary IMHA include:
• Non-immune mediated hemolytic anemia:
• Caval syndrome (secondary to heartworm disease)
• Zinc toxicity (especially after ingestion of pennies)
• Any cause of Heinz bodies
Secondary IMHA (more common causes, not a complete list)
• Drugs: sulfonamides, cephalosporins, anti-thyroidal drugs
• Recent vaccination?
• Neoplasia: Lymphoma, malignant histiocytosis; solid tumors (carcinomas, sarcomas), particularly when metastatic
• Infectious diseases: Babesia sp.; Ehrlichia sp.; Mycoplasma haemominutum (aka Hemobartonella felis); FeLV
• Immune-mediated diseases: SLE
• Other: bee stings; rattlesnake envenomations
The majority of patients with IMHA that present to first-line practitioners are relatively stable. Although immunosuppression in most cases is appropriate and will rapidly lead to resolution of clinical signs, internists (including myself) always recommend some diagnostic testing to ensure that there is no secondary cause of disease. If the history or physical examination reveal any clinical signs or findings that do not fit with a 'classic' case of IMHA then these should be pursued. The more difficult cases are those dogs that present slightly depressed and have normal physical examinations, but are obviously anemic and autoagglutinating. In these cases I definitely balance my diagnostic testing with the owner's budget; I always make sure to not result in the euthanasia of my patient just because the owner cannot afford the 'just in case' work-up. At a minimum I always insist on a full minimum database—complete blood count, full serum chemistry panel, and urinalysis. I only recommend a urine culture if the urinalysis suggests an infection may be present; however other internists have reported anecdotal cases of IMHA secondary to UTIs. I always perform some form of imaging studies. Thoracic and abdominal radiographs and abdominal ultrasound are ideal; however the abdominal ultrasound is only really required on my part if I detect an abnormality on physical examination, or if the patient's signalment is not typical for IMHA (fpr example, if the dog is greater than 8 years old or so). High quality radiographs are usually sufficient screening tests for mass lesions and heavy metal densities. I consider a fundic examination to be part of a normal physical examination; vasculitis (suggesting rickettsial disease or hematologic malignancies), granulomas (fungal lesions), or neoplastic cells (particularly lymphoma) may be detected using this test. Careful palpation of lymph nodes is done multiple times, and if there is any hint of lymphadenopathy, I aspirate and at a minimum look at the slide myself. Lymphoma is the most common cause of secondary IMHA!
The final diagnostic test I consider in every case of IMHA is a bone marrow aspirate. If any other cell line is decreased in addition to the erythrocyte lineage, or if there is no evidence of regeneration, I will always collect bone marrow. Period. Either of these CBC findings requires that primary bone marrow disease be ruled out, particularly infiltrative neoplasia. For other cases I still offer it to owners, discussing it as a gold standard diagnostic test. As mentioned above, lymphoma is the most common cause of secondary IMHA, and this disease must be diagnosed prior to instituting immunosuppression. All the drugs used to treat IMHA, particularly glucocorticoids, result in lysis of lymphocytes; therefore treatment may put these dogs into remission. Although this may be an apparent advantage, prednisone alone is not the optimal therapy for lymphoma—dogs with lymphoma treated with prednisone alone have a median survival of only 3 months, as opposed to longer survival rates with combination chemotherapy. Additionally administration of prednisone prior to the diagnosis of lymphoma worsens long-term prognosis, as glucocorticoids induce multi-drug resistance against many other chemotherapeutic agents.