V88

Fever of Unknown Origin L. Ari Jutkowitz, VMD, DACVECC Michigan State University East Lansing, MI, USA
OBJECTIVES OF THE PRESENTATION

To familiarize the clinician with the pathophysiology and etiologies of fever and provide a stepwise approach to diagnosis and treatment when the cause of the fever is not apparent.
KEY CLINICAL DIAGNOSTIC POINTS

As with most clinical entities, history and physical examination is the key to localizing and diagnosing causes of fever. When no localizing symptoms are present, a stepwise approach to diagnosis is offered below. Because infectious diseases are by far the most common causes of fever, these should be ruled out first. The abdomen, thorax, and urogenital tract are the most common sources of bacterial infections in small animals. Concurrent search for neoplasia, autoimmune disease, and a variety of inflammatory diseases should be considered prior to the institution of therapy.
KEY ETIOLOGIC AND PATHOPHYSIOLOGIC POINTS

Fever is a beneficial physiologic response to a variety of endogenous and exogenous stimuli. Causes of fever, in order of frequency, include infectious disease, autoimmune disease, paraneoplastic processes, and inflammatory disorders.
KEY THERAPEUTIC POINTS

Samples for bacterial culture should be obtained prior to initiation of antibiotic therapy. Infectious disease and lymphoma should be ruled out prior to administration of immunosuppressive agents. Tetracyclines may be considered if vector-borne illness is likely. Antipyretics and mechanical cooling are not recommended unless severe (>106 F) fever is present, or symptoms related to fever are unacceptable (e.g.,. prolonged anorexia)
KEY PROGNOSTIC POINTS

Survival is dependent upon the cause of fever. Dogs with infectious, inflammatory, auto-immune, or undiagnosed causes typically have a good prognosis. Neoplastic or myeloproliferative disorders carry a more guarded prognosis.
OVERVIEW OF THE ISSUE

Fever of Unknown Origin (FUO) is defined in human medicine as an illness of more than 3 weeks duration, with a fever 1.5 F above normal body temperature on multiple occasions, the cause of which remains uncertain after 1 week of in-hospital investigation.1 In veterinary medicine, the term is much more loosely applied to any patient with a sustained or episodic fever without a readily apparent cause after routine laboratory testing. Fever of unknown origin tends to be a challenging clinical entity in veterinary medicine, frequently necessitating diagnostic testing that is labor intensive, expensive, invasive, and time consuming. Despite this, causes of fever may still go undiagnosed. Understanding the pathophysiology and varied causes of fever is critical to successful management of these frustrating cases.
ADDITIONAL DETAIL

The febrile response is a complex physiologic reaction to disease, involving a cytokine mediated rise in core temperature, generation of acute phase reactants, and activation of numerous physiologic,

endocrinologic, and immunologic systems. 2 Fever develops when exogenous or endogenous stimuli such as endotoxin, viral, bacterial rickettsial, or fungal agents, tumor antigens, tissue necrosis, or immune-mediated diseases induce mononuclear cells to release endogenous pyrogens. The pyrogens most commonly associated with febrile responses include interleukins (IL-1 and IL-6), tumor necrosis factor (TNF), and interferon. Exogenous antigens taken up by Kupffer cells in the liver, or endogenous pyrogens entering the central nervous system at the anterior hypothalamus elevate the thermoregulatory setpoint through upregulation of prostaglandin E2.3 Alteration of the hypothalamic thermostat in this way triggers physiologic mechanisms such as shivering and vasoconstriction that increase heat production and conservation within the body. Animal experimental models evaluating the effect of fever on survival during infection suggest that mild to moderate fevers benefit the host, and may improve survival during sepsis.4 Increased temperature is known to induce change in phagocytic cells and lymphocytes, stimulate release of interferon, and induce the heat shock response. This heat shock response leads to the production of heat shock proteins (HSPs) that serve to protect against cell death from a variety of stressors, including endotoxemia.5 Additionally, increasing temperature may lower minimum inhibitory concentrations of antibiotics, progressively increasing their antimicrobial activity.6 Severe fever (>106 F) may become dangerous however, as a result of altered cellular metabolism and direct thermal damage to a variety of tissues (i.e.,. Heatstroke). Causes of fever may be divided into 4 major categories; infectious, inflammatory, paraneoplastic, and immune-mediated (see table 1). By far, infection is the most common cause of fever in veterinary patients, though many of these cases may be diagnosed and/or treated successfully without the need for intensive diagnostics and care. Immune-mediated disease is the second most common cause of fever, accounting for over one-quarter of cases presenting with persistent fevers. Of the immune-mediated diseases, polyarthritis and vasculitis are the ones most commonly associated with fevers. Neoplastic processes are the third most common cause, accounting for approximately 1520% of cases. In older patients presenting with fevers, neoplasia rises to the top of the list of differential diagnoses. A variety of miscellaneous or inflammatory conditions account for the remainder of the fevers of unknown origin. A definitive cause may not be determined in 1020% of cases.7-9
Table 1. Causes of fever, grouped according to category
Infectious Inflammatory Paraneoplastic Autoimmune

Bacterial Abscess Pneumonia Urinary/Pyelonephritis - Peritonitis - Endocarditis - Pyothorax - Cholangiohepatitis - Pyometra - Prostatitis - Discospondylitis - Osteomyelitis - Septic arthritis - Leptospirosis

HOD Panosteitis Pancreatitis Hepatitis Trauma Surgery Intervertebral Disc

Lymphoma Hemangiosarcoma Metastatic Leukemias, various Myeloproliferative

Polyarthritis Vasculitis Panniculitis Meningitis Systemic Immune Dz

Viral - FeLV, FIV, FIP - Other Fungal - Histoplasmosis - Blastomycosis - Coccidiomycosis - Cryptococcosis - Opportunistic Vector-Borne - Lyme, RMSF, - Ehrlichia, Bartonella, - Brucella, Other Protozoal - Toxoplasma The diagnostic workup for animals presenting with pyrexia should begin with a complete history and physical examination. Historical information solicited should include travel history, possible tick exposure, contact with other animals, recent vaccinations, medications, and response to therapy. Close attention should also be given to systemic manifestations of disease such as respiratory, gastrointestinal, or urinary signs as these may help to localize the source of the fever. Physical examination should proceed from head to tail. Eyes should be examined for the presence of uveitis or fundic lesions that may suggest systemic illness. The oral cavity should be assessed for mucocutaneous lesions or ulcers (see Figure 1), petechiation, or discoloration of mucous membranes. Lymph nodes should be palpated and size noted. The presence or absence of a thyroid nodule should be noted in cats. The thorax should be ausculted and the presence of murmurs, arrhythmias, or crackles noted. Abdominal palpation should be performed to identify mass lesions, organomegaly, or pain. All joints should be flexed and extended and pain, heat, or effusion noted. A complete neurological examination should be performed to identify intracranial disease. Spinal palpation should be performed to assess for pain. Rectal palpation should be performed to assess for masses, lymphadenopathy, prostatic enlargement, or urethral thickening. Diagnostic testing typically proceeds in 3 stages. The first tier generally focuses on abnormalities identified on history and physical examination, as well as the collection of a minimum database, including a complete blood count, chemistry panel, and urinalysis. Because the most common sources of infection (and neoplasia) in dogs and cats arise from the abdominal cavity, respiratory, and urinary systems, radiographs of chest and abdomen are generally indicated as well. In cats, testing for feline leukemia and FIV should not be overlooked.

Figure 1. Mucocutaneous lesions associated with a Systemic Lupus-like Disease

If the source of the fever has not been identified during the first stage of testing, the next tier of testing may include urine culture, abdominal ultrasound, blood cultures, vector-borne disease screening, fungal serology, antinuclear antibody titers, echocardiography, lymph node aspirates, orthopedic and spinal radiographs, joint taps, liver or other organ aspirates, skin biopsies of erythematous areas, diagnostic peritoneal lavage. Testing generally proceeds stepwise in this fashion based upon physical exam findings and clinical index of suspicion. If a diagnosis has still not been reached, a third tier of testing consisting of the more invasive diagnostics should be pursued. Bone marrow aspiration to identify immune-mediated, neoplastic disease, or myeloproliferative diseases, CT scan or MRI to identify tumors or inflammatory brain lesions, CSF tap, bronchoscopy, and bronchoalveolar lavage may be performed during this time if not already done. Once samples have been obtained for bacterial culture and sensitivity, empirical antibiotic therapy may be initiated if dictated by severity of the patients clinical picture, clinical index of suspicion, or financial constraints of the owner. Broad-spectrum antibiotic therapy combinations directed against gram positives (a penicillin or cephalosporin), gram negatives (quinolone or aminoglycoside) and anaerobes (a penicillin or metronidazole) are typically used. If vecor-borne disease is a strong possibility based upon clinical signs or geographic location, tetracyclines may also be considered. Administration of corticosteroids or other immunosuppressive drugs is typically reserved for patients in whom infectious disease and neoplasia have been convincingly ruled out. Much debate exists as to whether patients with fever should be treated pharmacologically or with active cooling techniques such as iced fluids, cool water blankets, or baths. There is little evidence to support these practices, which are frequently driven by family members or nursing staff because of mistaken perceptions about the detrimental effects of fever. It becomes easy, under these conditions, to simply treat the fever rather than the underlying cause. However, as discussed previously, mild to moderate fevers are believed to exert beneficial effects in critical patients. Pharmacologic intervention using non-steroidal anti-inflammatories may exacerbate renal injury in patients with hypovolemia or underlying renal disease. Mechanical cooling tends to be ineffective and is not recommended as it increases resting energy requirements by inducing shivering and vasoconstriction as the patient attempt to bring its temperature back up to the new setpoint. Finally, fever tends to be a useful sentinel of

response to therapy. For these reasons, it is recommended that fever only be treated if it approaches temperatures at which adverse effects are considered likely (>106 F). The prognosis for small animals presenting with fevers of unknown origin is ultimately dependent upon the cause.8 Fevers attributed to infectious, inflammatory, or immune-mediated causes have been reported to carry a favorable prognosis, with over 70% of animals still alive at one year in retrospective studies. Fevers related to neoplasia or myeloproliferative disorders carry a more guarded prognosis, with less than 10% of animals still alive at one year. In cases where the cause of fever remains indeterminate despite testing, prognosis is reported to be favorable, with a mean survival of 82 weeks in the above study.
KEY DRUGS, DOSAGES AND INDICATIONS Key Drug Ampicillin sodium Cefazolin Enrofloxacin Amikacin Prednisone Azathioprine Drug Class penicillin cephalosporin quinolone aminoglycoside glucocorticoid Purine analogue Dose Range 22 mg/kg 22 mg/kg 5 mg/kg 15 mg/kg 24 mg/kg/day 2 mg/kg Frequency Q68h Q8h Q1224 h Q24h Divided BID Q2448h Route IV IV IV diluted* IV PO PO Indications Susceptible infections Susceptible infections Susceptible infections Susceptible infections Immunosuppression Immunosuppression

* extralabel usage SUMMARY

Fever is a beneficial physiologic response to a variety of antigenic stimuli. Causes of fever include infection, inflammation, immune-mediated disease, and neoplasia By taking a stepwise approach to diagnosis and therapy as described above, the majority of cases may have a good outcome.
REFERENCES 1. Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med 2003;253:263-275. 2. Plaisance KI, Mackowiak PA. Antipyretic therapy: physiologic rationale, diagnostic implications, and clinical consequences. Arch Intern Med 2000;160:449-456. 3. Blatteis CM, Li S, Li Z, et al. Cytokines, PGE2, and endotoxic fever: a reassessment. Prostaglandins & other Lipid Mediators 2005;76:1-18. 4. Kluger MJ, Kozak W, Conn CA, et al. The adaptive value of fever. Infect Dis Clin North Am 1996;10:1-20. 5. Ryan AJ, Flanagan SW, Moseley PL, et al. Acute heat stress protects rats against endotoxin shock. J Appl Physiol 1992;73:1517-1522. 6. Mackowiak PA, Marling-Cason S, Cohen RL. Effects of temperature on antimicrobial susceptibility of bacteria. J Infect Dis 1982;145:550-553. 7. Lunn KF. Fever of unknown origin: A systematic approach to diagnosis. Compend Cont Ed Prac Vet 2001;23:976-992. 8. Dunn KJ, Dunn JK. Diagnostic investigation in 101 dogs with pyrexia of unknown origin. J Small Anim Prac 1998;39:574-580. 9. Bennett D. Diagnosis of pyrexia of unknown origin. In Practice 1995;17:470-481.