Idiopathic Neutropenia Case Studies

WHAT IS YOUR DIAGNOSIS? A 6 year old, neutered female crossbreed presented to the R(D)SVS Small Animal Medicine Service with a 2 week history of reduced appetite, lethargy and pyrexia which was unresponsive to amoxicillin. On physical examination, the dog was in good body condition (score 5/9), quiet, responsive, and normally hydrated. The mucus membranes were pink with capillary refill time of < 2 seconds. The heart rate was 110 beats per minute with matched pulse of good quality. The rectal temperature was 40.2oC. The rest of the examination was unremarkable. The biochemistry and haematology results are shown below. Haematology Parameter Day 0 Reference Range Packed Cell Volume 0.41 0.39-0.55l/l Red Blood cells 6.29 5.5-8.5 x 1012/l Haemoglobin 13.5 12-18g/l Mean Cell Volume 66 60-77fl MCHC 32.4 32-36% Total WBC 4.8 6-15 x109/l Neutrophils 0.24 3.6-12 x109/l Lymphocytes 2.01 0.7-4.8 x109/l Monocytes 2.44 0-1.5 x109/l Eosinophils 0.1 0-1 x109/l Basophils 0 0-0.2 x109/l Platelets 277 200-500 x109/l page 1 of 6 Biochemistry Total Protein 70.6 58-73 g/l Albumin 26.5 26-35g/l Globulin 44 18-37g/l Bile Acids 6.6 0-7 umol/l Bilirubin 1.6 0-6.8umol/l Chloride 110 99-115 mmol/l Creatinine 104 40-132umol/l Glucose 3.7 3-5mmol/l Urea 4.1 1.7-7.4mmol/l AlKP 62 20-60IU/l ALT 16 21-102IU/l Calcium 2.35 2.3-3.0mmol/l Phosphate 1.25 0.9-2.0mmol/l Sodium 143 139-154mmol/l Potassium 4.9 3.6 -5.6mmol/l 1) What are your differential diagnoses for the case? 2) What further investigations would you like to perform? page 2 of 6 1) What are your differential diagnoses for the case? The main problems in this case were the hyperthermia and neutropenia. Hyperthermia may be due to fever related to pyrogens from infection, inflammation, necrosis, drugs or immunemediated disease. Alternatively increased body temperature may be due to a high environmental temperature, increased muscle activity (strenuous exercise, muscle tremors, seizures) or increased metabolic rate (e.g. hyperthyroidism). In this case, the elevated temperature was thought to be true pyrexia as there was no history of exposure to high temperatures, increased muscle activity or prior drug administration. This pyrexia may be due to a severe infection which is resulting in the neutropenia (overwhelming demand for tissue neutrophils), or the neutropenia may have predisposed to infection producing the pyrexia. Neutropenia may be due to decreased or ineffective production (myelodysplasia, myelofibrosis, infiltrative bone marrow disease, cytotoxic or idiosyncratic drug reaction), decreased survival (due to sepsis/endotoxaemia, extreme hyperthermia/pyrexia or immune mediated destruction), temporary shift to marginating pool or overwhelming demand and sequestration into the tissue pool. As the neutropenia was persistent, decreased production or increased destruction was thought more likely as tissue sequestration or margination would be expected to cause only a transient neutropenia until a compensatory increase in marrow production occurred. Decreased production may be due to bone marrow disease although it would be expected that other cell lines would also be affected. Increased destruction may be due to immune-mediated process which may be idiopathic (i.e. primary) or secondary (drug associated, paraneoplastic, infectious). Additional abnormalities were the monocytosis which may be due to an inflammatory response, as part of a stress leucogram or seen with monocytic leukaemia (although the total count would have been expected to be higher). Hyperglobulinaemia may be monoclonal due to; neoplasia (multiple myeloma, lymphoma, chronic or acute lymphocytic leukaemia), certain infectious diseases (Ehrlichia, Leishmania, Dirofilaria; uncommon in the UK and the dog had no prior travel history) or monoclonal gammopathy of unknown significance (MGUS), or polyclonal due to; inflammation, infection or immune-mediated disease. The increase in alkaline phosphate was mild and considered clinically insignificant. page 3 of 6 2) What further investigations would you like to perform? Although the dog was currently receiving antibiotics, making a positive culture less likely, blood and urine culture and urinalysis were performed as sepsis or urinary tract infection was a possible cause of the pyrexia and neutropenia. Both cultures were negative. Thoracic ultrasonography and abdominal ultrasound were performed as a hidden septic focus could not be completely excluded and also to investigate for underlying neoplasia. No abnormalities were detected on diagnostic imaging. Serum protein electrophoresis was carried out to define the hyperglobulinaemia which revealed a polyclonal gammopathy. Bone marrow aspiration was performed to evaluate maturation of neutrophilic lineage and to detect bone marrow disease. Although tick-borne disease is uncommon in the UK, whole blood and bone marrow were submitted for Ehrlichia, Borrelia and Bartonella PCR. The infectious disease screens were negative. Bone marrow analysis was consistent with myeloid hypoplasia and maturation arrest at the neutrophilic promyelocyte stage. Although this could have been consistent with an early marrow response to increased consumption, the fact that no underlying septic focus was identified on imaging and the neutropenia was persistent, made this unlikely. Immunemediated destruction was thought most likely at this stage. As no underlying cause had been identified, an idiopathic possibly primary immune-mediated neutropenia was the presumptive diagnosis. The profound neutropenia meant that the dog was at risk of sepsis. As a result, antibiotic cover was increased with 12.5mg/kg potentiated amoxicillin every 8 hours and 2mg/kg marbofloxacin every 24 hours administered. As the dog appeared stable, these medications were given orally to avoid the risk of introducing infection with intravenous catheter placement. Although the highest risk of sepsis is via translocation from the gastro-intestinal tract, reverse barrier nursing was instituted to reduce the risk of noscomial infection. Twenty-four hours after increasing antibiotic cover the dog appeared brighter, ate small amounts of food and the rectal temperature reduced to 39.5oC. Antibiotic cover was continued and oral prednisolone was administered at a dose of 1mg/kg twice daily. Forty-eight hours after starting immunosupression (Day 4), the dog appeared bright, alert responsive and had a good appetite. Rectal temperature was within reference range. Routine haematology was repeated which demonstrated that the neutrophil count was within the reference range. page 4 of 6 The dog was discharged on oral medication. Twelve days after discharge, the dog was reported behaving normally aside from polyuria/polydipsia (PUPD) which was thought to be most likely due to steroid administration. Clinical examination was unremarkable and the dog was normothermic. Haematology revealed a normal neutrophil count, the monocytosis was less pronounced. Antibiotic cover was withdrawn after 5 days. Twenty-three days after discharge the owners only concern was PUPD. Prednisolone was slowly tapered over the following 4 months. Discussion: The diagnosis was steroid-responsive idiopathic neutropenia as no underlying cause could be found and a prompt response was seen to prednisolone. It is suspected that immunemediated destruction was the cause of the neutropenia. Immune-mediated neutropenia is well described in humans and anti-neutrophil antibody tests are recommended to reach a diagnosis. Although direct and indirect testing for anti-neutrophil antibodies have been described in dogs, these are not commercially available and not available for this case. It has been suggested that until these tests are available, the diagnosis of immune-mediated neutropenia be based on fulfilment of three of four criteria; 1) Exclusion of other known causes of neutropenia, 2) Presence of concurrent immune-mediated disease, 3) Bone marrow cytology supportive of immune-mediated destruction of neutrophils and 4) Prompt response to corticosteroid administration. Although this case had no other concurrent immune-mediated disease, it did fulfil the other 3 criteria and, as a result on this basis could be classified as immune-mediated neutropenia. In dogs, immune-mediated attack has been reported the level of mature neutrophils, in which case the myeloid series may appear normal or increased on bone marrow examination. Alternatively, destruction of neutrophil precursors may occur and an absence of neutrophil precursors may be seen. This case demonstrated apparent maturation arrest at the level of neutrophilic promyelocyte, suggesting that immune-mediated attack was at the precursor stage. Monocytosis and hyperglobulinaemia as seen in this case, are reported in human and canine IMN, and suspected canine IMN cases. These increases are assumed to be a compensatory response to the neutropenia. page 5 of 6 Consistent with previously reported cases of canine IMN and suspected IMN, this case showed a rapid response to immunosuppressive medication. Spontaneous remission is reported in human cases and canine cases have been reported to have good prognoses. The University of Edinburgh is a charitable body, registered in Scotland, with registration number SC005336. www.ed.ac.uk/vet/hfsa-int-med page 6 of 6