Fever vs. Hyperthermia

A large number of dogs and cats presented for veterinary attention develop an increase in core body temperature at some point in the course of their illnesses. This increase can be the result of hyperthermia or pyrexia. Hyperthermia is characterised by a high core temperature without change in the set point of the hypothalamic thermoregulatory centre. It occurs as a result of increased or unregulated heat gain or heat production (e.g., seizure activity, hyperthyroidism), or impaired heat loss (e.g., heat stroke). Fever results from a change in the set point of the hypothalamic thermostat due to the action of endogenous and exogenous pyrogens, leading to increased heat production and conservation. Exogenous pyrogens include bacterial toxins but also products from neoplastic cells or drugs. Endogenous pyrogens are cytokines such as interferons, interleukins 1 and 6 and tumour necrosis factor alpha. Exposure to these pyrogens leads to the production of prostaglandin E2 in the endothelial cells of a vascular plexus lying close to the thermostat. PGE2 causes the thermoregulatory cells to increase their set point through various mediators.

Diagnostic Approach to Pyrexia

Besides the obvious rise in the core temperature (>39.2-39.5°C), a number of clinical signs are usually associated with fever. Febrile animals may be reluctant to move, show a lack of appetite and experience muscle and/or joint stiffness and discomfort. They may be depressed, tachypnoeic and shivering. When confronted with a pyrexic patient, it is important to consider the list of possible differential diagnoses based on information extracted from the history and observed clinical signs (see Figure 1). Ten years ago, a retrospective study performed at the University of Cambridge reported 101 dogs with pyrexia, defined by either recurrent pyrexic episodes (>40°C) or sustained pyrexia (>40°C) for periods of longer than 7 days. The minimal database consisted in most cases of complete blood count (CBC), biochemical screen and thoracic and abdominal radiography; other tests were added at the individual clinician's discretion. 22% of dogs had immune-mediated diseases (most of them immune-mediated polyarthritis), 22% had primary bone marrow diseases such as myelodysplasia, myeloma or various leukaemias, 16% had infectious diseases including discospondylitis, soft tissue abscesses, bronchopneumonia, pulmonary foreign body or osteomyelitis, 9.5% had neoplasia (most of them lymphoma) and 11.5% had miscellaneous conditions (e.g., metaphyseal osteopathy, meningitis, portosystemic shunt). Finally, only 19% had 'pyrexia of unknown origin', as no diagnosis could be made in these dogs based on the information available. It is probable that a repeat study performed today would find more cases of infectious diseases due to the increased mobility of pets to and from the United Kingdom. No comparable studies were performed in cats in recent times. However, 25 years ago a paper from California revealed that the majority of febrile cats suffered from infectious diseases, followed by neoplasia and immune-mediated disorders.

In simple cases, the origin of fever can be detected fairly quickly after history and clinical examination (e.g., bite wound abscesses in cats). In most other cases, a minimal database consisting of CBC, biochemical serum profile, urinalysis, radiographs of one or both body cavities and possibly abdominal ultrasonography is necessary. Additional investigations may include laboratory tests such as bile acids, serological testing for infectious diseases that are prevalent in the area where the animal lives or where it travelled, bacteriological culture and sensitivity testing (urine, blood, joint fluid, exudates), radiological or ultrasound studies of specific locations, cytological evaluations of samples (joint fluid, lymph node aspirates, thoracic or abdominal effusion, bone marrow) and histological evaluation of tissue samples.

Although a systematic, stepwise approach going from the least to the most invasive tests is strongly recommended, the approach must be tailored to the patient. A random series of multiple tests is unlikely to be beneficial to the patient and will be expensive to its owner. It is much better if each abnormal result is assessed for significance and pursued with diligence in order to eventually reach a diagnosis. Pyrexic animals without any localising signs are a special group that will benefit from a systematic and progressive approach.

In young dogs with suspected panosteitis or metaphyseal osteopathy, radiographs of the limbs must be done early in the process. In dogs with neck pain and fever, survey radiographs and cerebrospinal fluid (CSF) collection are usually indicated early in the course of the work-up. In some cats with non-effusive feline infectious peritonitis (FIP), the definitive diagnosis may require a CSF tap (if neurological signs are present) or biopsy of an abdominal organ.

Figure 1. Practical list of differential diagnoses for the febrile patient.

This list is not comprehensive. (FCV: feline calicivirus; FeLV: feline leukaemia virus; FIV: feline immunodeficiency virus; GME: granulomatous meningoencephalitis; IBD: inflammatory bowel disease; NME: necrotic meningoencephalitis; SRMA: steroid-responsive meningitis-arteritis; SLE: systemic lupus erythematosus)

When and How to Treat?

Ideally, treatment is best directed against the underlying disease at the origin of fever. However, the causative disease process cannot always be identified and a practical compromise must be found. If the clinical condition of the animal allows it, it is better to delay therapeutic interventions directly aimed at reducing fever before a diagnosis can be reached. Frequent rechecks should be performed in order to detect possible new clinical signs and follow the course of fever. This intensive follow-up also allows taking necessary emergency measures as needed.

When is the fever so detrimental that antipyretic therapy must be initiated? In hyperthermic patients, physical methods of cooling are applied, such as spraying the hair coat with water and using a fan, cool water baths, use of cool intravenous fluids etc., to prevent central nervous system damage, disseminated intravascular coagulation and metabolic disorders that can occur if the body temperature is above 41-41.5°C. These measures are less likely to contribute to significant cooling of the core temperature in pyrexic patients because the increased body temperature results directly from the higher set point of the thermoregulatory centre. Fortunately, most febrile patients have body temperatures between 39.5°C and 41°C. However, in some instances, pyrexia may significantly compromise quality of life and the use of antipyretics may be considered. Proper hydration is an essential prerequisite, as catastrophic side effects may occur in patients with inadequate hepatic or renal perfusion or pre-existing liver or kidney diseases. Paracetamol is strictly contraindicated in cats and may cause severe liver damage in dogs. Most antipyretics belong to the non-steroidal anti-inflammatory drug (NSAID) family and can exert side effects on the gastrointestinal mucosa as well as on renal perfusion. Moreover, NSAIDs should always be used cautiously in cats. Those licensed for use in dogs and cats in the UK include meloxicam, carprofen, ketoprofen and tolfenamic acid.

It is not possible to pursue advanced diagnostics in all febrile patients. In some cases, coexisting medical problems restrict the use of sedation or anaesthesia and prevent completion of more invasive procedures. In other cases, the financial situation of the owner may dictate that only few diagnostic procedures can be performed, if any. Considering the important part infectious diseases have in the aetiology of pyrexia, trial therapy with antibiotics should definitely be considered. However, the clients must have a clear understanding of the limitations and risks of such empirical therapy. The choice of antibiotics should be guided by the sensitivity spectrum of suspected bacteria and the localisation of the infectious process. Moreover, general rules of antibiotic therapy must be respected: full dose, minimal duration of therapy of 5 days (in case of success, continue treatment for at least 10-14 days). Finally, veterinary surgeons should refrain from using the newest and most powerful antibiotic as the first line of empirical treatment. This inevitably leads to the appearance of resistance against that antibiotic and can cause problems for the treatment of complicated infections.

Patients refractory to antibiotic treatment may suffer from immune-mediated diseases. In such cases, glucocorticoids, often used at immunosuppressive doses, may be helpful. This approach can be dangerous, even life threatening in dogs and cats with cryptic infections. Excellent communication between veterinary surgeon and the pet's owners must exist at all times during the treatment trial. Additionally, both parties should be aware that the use of glucocorticoids might render any future diagnostic efforts to identify the cause of pyrexia fruitless.

References

1.  Dunn KJ, Dunn JK. Diagnostic investigations in 101 dogs with pyrexia of unknown origin. Journal of Small Animal Practice 1998; 39: 574-580.

2.  Lunn KF. Fever. In Greene, CE. ed. Infectious disease of the dog and cat (third edition). St. Louis: Saunders Elsevier, 2006; 1028-1037.