A New Medical Mystery from our Internal Medicine Specialist

Dr Susana Silva DVM CertSAM DipECVIM-CA MRCVS

You are presented with “Evie”, a 5 year old female neutered Pointer who has been lethargic and anorexic for 2 days. However, her owners are concerned because she is significantly more lethargic in last 12 hours.

Her routine vaccinations and worming are up to date and she received regular flea and tick treatment. The owners had noticed a tick a few months before which they removed promptly. She normally enjoys long walks in the countryside with frequent swims in the river; she’s fed a balanced commercial dry dog food, and her owners report no other problems.

On examination, Evie is extremely lethargic, pyrexic (38.4C), tachycardic (140/min) and tachypnoeic (48/min). Her mucous membranes are jaundiced and pale; CRT was < 2 seconds. Peripheral pulses were of good quality and the femoral pulses were strong, unusually so. Auscultation revealed the presence of a grade I/VI systolic murmur with PMI at the left heart base. Abdominal palpation was not painful however the spleen felt enlarged. Grabbing the Doppler, you confirm that her systolic blood pressure is 160 mmHg.

 

What problems have you identified? And what are the differential diagnoses?

 

Problem List and Broad Differential Diagnoses

 

  • Pyrexia
    – Infection
    – Inflammation
    – Immune-mediated
    – Neoplasia
  • Jaundice
    – Pre-hepatic – haemolysis
    – Hepatic – hepatobiliary disease (inflammatory, infectious, neoplastic, toxic)
    – Post-hepatic – biliary obstruction (pancreatitis, neoplasia, cholelithiasis, bile duct rupture)
    – Sepsis
  • Anaemia (pale mucous membranes and normal CRT)
    – Blood loss
    – Haemolysis
    – Reduced production RBC’s
  • Hyperdynamic femoral pulses (those “strong” or “bounding” pulses)
    – Anaemia
    – Aortic insufficiency (no audible diastolic murmur)
    – Patent ductus arteriosus (type of murmur not consistent)
  • Splenomegaly
    – Infiltration (neoplasia, inflammation)
    – Extramedullary haematopoiesis
    – Congestion (congestive heart failure, thrombosis)
    – Infection
  • Grade I/VI systolic heart murmur
    – This is a low grade murmur. In the presence of anaemia and the absence of other cardiac signs, it’s likely to represent a haemic murmur
  • Tachycardia and tachypnoea
    – Possibly secondary to the presumed anaemia (compensated hypoxia) and pyrexia but other causes possible.
  • Lethargy and anorexia
    – These are very, very non-specific findings – all this shows us is that Evie is feeling rubbish! In this case, they’re probably secondary to the underlying pathology.

 

What tests would you like to perform next?

 

We’ve hung a lot of our differentials on the presence of anaemia – however, there are other possible explanations for pale mucous membranes. Therefore, it would be sensible to start with haematology to confirm that the patient is in fact anaemic! If so, we can also ascertain the degree of anaemia and also investigate if it is regenerative or not. Of course, a smear assessment should always be considered as part of the normal haematology.

Since we’re drawing bloods from Evie, it would be worth taking a serum or lith-hep tube for biochemistry to confirm and assess the degree of hyperbilirubinemia, help assess the liver enzymes, the renal parameters and also electrolytes amongst others.

This is a very sick patient with no immediately apparent cause, so urinalysis is worth doing to generate an MDB.

Results

 

Haematology  results
Patient Result Reference Range Units
HgB 3.81* 12.0-18.0 g/dl
Hct 12.20* 35.0-45.0 %
RBC 1.35* 5.4-8.0 X1012/l
MCV 90.0* 65.0-75.0 fl
MCH 28.20* 22.0-25.0 pg
MCHC 31.40* 34.0-37.0 g/dl
Platelets 120* 170-500 X109/l
WBC corrected 60.9* 5.5-17.0 X109/l
nRBC’s 9.25* X109/l
Neutrophils 41.41* 3.0-11.5 X109/l
Lymphocytes 1.71 0.7-3.6 X109/l
Monocytes 7.92 0.1-1.5 X109/l
Eosinophils 0.61 0.2-1.4 X109/l
Basophils 0.0 0.0-0.1 X109/l
Reticulocytes 510 X109/l
* – abnormal result.

Smear comment: polychromasia +++, anisocytosis +++, spherocytes ++, agglutination, macrothrombocytes

 

Biochemistry  results
Patient Result Reference Range Units
Urea 6.1 2.0-7.0 mmol/l
Creatinine 102 100-133 mmol/l
Total protein 70.5 63.0-71.0 g/l
Albumin 32.2 32.0-38.0 g/l
Globulins 38.3* 20.0-35.0 g/l
Glucose 4.3 mmol/l
ALT 870* 20-60 IU/l
ALKP 1198* 0-110 IU/l
Bilirubin 212.3* 0-10 mmol/l
Sodium 148 135-150 mmol/l
Potassium 3.6 3.5-4.5 mmol/l
Chloride 109 102-112 mmol/l
Calcium 2.45 2.3-2.6 mmol/l
Phosphate Not measurable 0.75-1.25 mmol/l
* – abnormal result.

 

Urinalysis  results
Patient Result
SG 1.017
pH 6.2
Blood/ Hb +++
Protein +++
Glucose rather Negative
Ketones Negative
Bilirubin +++
Sediment

RBC < 5 phpf

WBC < 5 phpf

No casts, no crystals

 

Given the results above, what is your interpretation? Have you updated or refined your differential diagnosis?

 

Haematology revealed severe regenerative anaemia with spherocytes and auto-agglutination.

It also revealed a marked leukocytosis with severe neutrophilia and monocytosis. When faced with these changes the broad differential diagnoses to consider are inflammatory, infectious, immune-mediated or neoplastic disease. Additionally, both neutrophilia and monocytosis are seen as part of a stress leukogram.

In cases where the leukocytosis is so marked in response to inflammation, it is called a leukaemoid reaction (> 50 x10’9/l). If a typical cause for a leukaemoid reaction (e.g. IMHA, pyometra, pyothorax or other infection where the pus is unable to drain out) is not identified, leukaemia might need to be considered a differential diagnosis.

Biochemistry showed mild hyperglobulinemia, which could be due to infectious, inflammatory, immune-mediated or neoplastic disease. ALT and ALP are markedly elevated being consistent with, respectively, hepatocellular damage and cholestasis.

Serum bilirubin is markedly elevated as anticipated in an icteric patient.

The anaemia is severe is almost certainly the cause of the heart murmur.

Unsurprisingly, but supporting our suspicions, the urine contains blood/haemoglobin; no red blood cells were seen which would be consistent with the presence of haemoglobin due to intravascular haemolysis. There was protein 2+ on the dipstick, which is again not unexpected given the amount of haemoglobin present.

Overall the clinicopathological findings are consistent with IMHA. The elevation of the liver enzymes could be secondary to the haemolysis and hypoxia but could also be secondary to a potential inciting cause for the IMHA.

In this particular case, with IMHA being identified, the leukaemoid response was thought to be secondary to it. Some of the suggested mechanisms by which IMHA can lead to a leukaemoid reaction include centrilobular hepatocyte degeneration/necrosis as a consequence of the anaemia, marked production of inflammatory cytokines by activated macrophages and also non-specific bone marrow stimulation. If WBC changes did not improve or resolve with treatment for the IMHA, other differentials (especially chronic myelogenous leukaemia) would have to be considered.

 

How would you like to manage the patient?

 

The patient is severely anaemic and is persistently tachycardic suggesting the need for a blood transfusion. In this case, only red blood cells are lacking therefore transfusion with packed red blood cells would be the preferred approach.

The patient was blood typed (D.E.A. 1.1 positive) to help decrease the risk of transfusion reactions and also help best manage the often scarcely available blood products. If you don’t have donors on hand, the Pet Blood Bank is a resource worth having on your speed dial!

As the patient was not eating, fluid therapy with crystalloids via a different IV catheter to the transfusion was also initiated.

IMHA can be primary or secondary to another disease process, – prognosis and response to treatment can be vastly different between the two types. What further tests would you like to perform?

Thoracic radiographs and abdominal ultrasound should be considered with a view to try to identify a potential inflammatory, infectious or neoplastic cause.

A negative urine culture does not rule out pyelonephritis, so it would be sensible to try to exclude urinary tract infection.

Despite the vaccination status of the patient, it would be worthwhile considering testing for leptospirosis given the recent reported increase in prevalence and the very outdoor environment that the patient is exposed to.

 

Results

 

Thoracic radiographs were unremarkable. Abdominal ultrasound confirmed splenomegaly with homogenous echogenicity of the parenchyma likely secondary to the IMHA; post-hepatic causes of jaundice were discarded. The splenomegaly was suspected to represent extra-medullary haematopoiesis; cytology of the spleen could be considered to help try to rule out neoplasia.

 

So, our working diagnosis is…

 

Immune-mediated haemolytic anaemia, possibly primary, but results still pending.

 

Treatment:

 

The patient was administered a unit of DEA 1.1 positive packed red blood cells and fluid therapy was continued. The PCV post-transfusion was 22% and the patient had a normal heart rate and pulses were normal.

Immunosuppression was initiated with dexamethasone 0.3mg/kg slow IV once which was followed by prednisolone 1mg/kg PO BID the following day. As a precaution, omeprazole was provided as a gastroprotectant. Low-dose acetyl salicylic acid was added for its anti-thrombotic properties.

Given the potential for an infectious disease such as Borrelia or Leptospira to be inciting causes for the IMHA, a course of doxycycline was also started.

The following day the PCV had decreased to 18% but the dog remained haemodynamically stable. Over the following 48 hours, the PCV continued to decrease, reaching a nadir of 15% – this is not uncommon, and does not necessarily reflect a failure of therapy. Thereafter, she progressively improved, with the agglutination disappearing and was discharged 5 days after admission with a PCV of 22%.

 

Results

 

Serology for Borrelia and PCR for Anaplasma were negative, ruling out those tick-borne diseases which are native to the UK, as the cause of the haemolytic anaemia.
Babesia infection in dogs that have not travelled outside the UK has now been documented in the south east of England but was not tested for in this case as the patient has never travelled abroad and had always lived in the south west of England.

Leptospira serology was negative for all serovars, urine PCR and blood PCR were negative.

The course of doxycycline was stopped after the results were received.

 

Final Diagnosis

 

Primary immune-mediated haemolytic anaemia

 

Going forward, how would you monitor and manage the patient?

 

It would be sensible to maintain the same dose of immunosuppressants for 3 to 4 weeks and afterwards consider slowing weaning off the medication over the subsequent 4 to 6 months. Before each dose decrease, haematology should be assessed and it would be wise to assess biochemistry and urinalysis at the same time.

If the patient developed significant side-effects of the corticosteroids we could consider adding another drugs such as ciclosporin or azathioprine in order to be able to decrease the dose of prednisolone sooner than initially planned.

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