Fever of unknown origin (Proceedings)

Definition

Fever is defined as a higher than normal body temperature (>102.5) due to altered thermoregulatory mechanisms in the hypothalamus. Fever of unknown origin (FUO) is a fever that does not resolve spontaneously and for which no obvious cause is identified. Infectious disease, immune-mediated conditions and neoplasia account for over 75% of FUO cases.

With aggressive diagnostics usually only 10% of FUO cases are considered idiopathic. Prior to beginning a diagnostic investigation for FUO, one must rule out non-pyrogenic causes of an elevated body temperature (i.e. heatstroke, over-exertion).

Pathophysiology

The hypothalamus is responsible for thermoregulation. Fever occurs when the hypothalamic setpoint is reset to higher than normal. Inflammation and bacterial endotoxins increase the hypothalamic set point by causing the release of endogenous pyrogens such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha.

Differential diagnoses

Infectious, neoplastic and immune-mediated diseases account for over 75% of FUO cases. Below is a list of possible causes of FUO. C=Canine, F=Feline.

     o Infectious

          • Localized or Systemic Bacterial Infections (C /F)

               - Discospondylitis, osteomyelitis, bacterial endocarditis, septic arthritis, prostatitis, pyelonephritis, septic meningitis, cholangiohepatitis, abscesses, pyothorax, peritonitis, pneumonia, pyometra, catheter site infections

          • Specific Bacterial Infections

               - Leptospirosis (C), Lyme disease (C), brucellosis (C), mycobacterium (C/ F), bartonellosis (C/ F), hemotrophic Mycoplasma (Haemobartonella) (C /F), tularaemia (C/F), salmonellosis (C/F)

          • Viral

               - Canine distemper virus (C), parvovirus (C/F), FeLV(F), FIV(F), FIP(F)

          • Rickettsial

               - Ehrlichiosis/anaplasmosis (C/F), Rocky Mountain Spotted Fever (Rickettsia rickettsii)(C)

          • Fungal (C/F)

               - Histoplasmosis, blastomycosis, coccidiomycosis, cryptococcosis, aspergillosis

          • Protozoal

               - Babesiosis (C), leishmaniasis (C), trypanosomiasis (C), hepatozoonosis (C), toxoplasmosis (C/F), cytauxzoonosis (F)

     o Immune- mediated

          • Immune-mediated polyarthritis (C/F), SLE (C/F), rheumatoid arthritis (C), vasculitis (C), meningitis (C), pemphigus, immune-mediated hemolytic anemia (IMHA) (C/F), immune-mediated thrombocytopenia (IMT) (C/F), transfusion reaction (C/F)

     o Neoplastic (C/F)

          • Lymphoma, leukemia, multiple myeloma, solid necrotic tumors

     o Other (C/F)

          • Pancreatitis

          • Drug induced (tetracyclines, penicillins, sulfas), toxins, metabolic bone disorders, hyperthyroidism, tissue necrosis

Diagnostic plan

The diagnostic goal is directed towards identifying a specific underlying cause of fever and instituting specific therapy. When a specific organ system is obviously affected, diagnostics should target that system. The following tests should be performed on all FUO cases.

     o CBC, chemistry profile, and urinalysis

     o Urine bacterial culture and sensitivity should be performed in all cases of FUO even if urine sediment is inactive. Helpful with detection of pyelonephritis or prostatitis.

     o FeLV antigen and FIV antibody tests for all felines

The following tests should be considered in cases without an obvious source of fever:

     o Serial blood cultures: to detect bacteremia associated with discospondylitis, endocarditis or other foci of infection. A negative culture does not rule out bacteremia

     o Cytology of enlarged lymphnodes or affected organs – neoplasia or identification of infectious agents

     o Specific serologic tests for infectious agents: antibody titers or antigen tests are obtained for evidence of infectious disease. If infectious disease is suspected and initial titers are negative repeat in 2-4 weeks

     o Polymerase chain reaction testing for specific infectious agents

     o Fungal cultures and/or serology

     o Cytology and Cultures of CSF and/or synovial fluid

     o Immune-mediated polyarthritis will frequently NOT be associated with detectable joint swelling, therefore arthrocentesis is indicated in all FUO cases where no underlying cause has been identified

     o CT/MRI often indicated before CSF tap to rule out an intracranial mass and decrease risk of herniation

     o Tests to support immune-mediated diseases: ANA test if suspected systemic lupus erythematosus (SLE), Coombs test if suspicion of immune mediated hemolytic anemia (IMHA) or thrombocytopenia (ITP), serum protein electrophoresis

     o Thoracic radiographs: to evaluate for evidence of neoplasia, effusions or pulmonary infiltrates

     o Abdominal radiographs: evaluate for abdominal masses, effusions, free gas

     o Spinal and longbone radiographs: examine for evidence of discospondylitis, osteomyelitis, periosteal proliferation

     o Nuclear scintigraphy: to find "hotspots" which are often associated with infection

     o Abdominal ultrasound: rule out pyelonephritis, prostatitis or pyometra as well as identifying and aspirating any enlarged abdominal organs or masses

     o Echocardiogram: evaluate for vegatative valvular lesions

     o Bone marrow aspirates and/or biopsy: If CBC changes are reflective of bone marrow involvement or neoplasia is suspected

     o Muscle biopsy – hepatozoonosis

     o Abdominocentesis – peritonitis and pancreatitis

     o Transtracheal wash or bronchoalveolar lavage if respiratory involvement

Treatment

The goal in all cases of FUO is to obtain a specific diagnosis and treat accordingly. Therapeutic trials should only be initiated when a specific diagnosis cannot be ascertained. Patients with persistent fevers that are < 105F should be treated symptomatically with IV fluids and mechanical cooling. Anti-pyretic drugs should only be reserved for patients with fevers > 105F and those that have failed to respond to fluids and mechanical cooling, as they can mask the effects of other therapies and can be associated with adverse effects such as GI ulceration, hepatic and or renal toxicity.

     o Antibiotic trials:

          • Broad spectrum antibiotic therapy may be initiated after all culture specimens have been collected. Therapy should be based on the agents most likely present and their known antibiotic sensitivity

     o Glucocorticoid trials

          • Used when immune-mediated disease is suspected or confirmed

          • Should only be used when infectious disease has been ruled out

          • A dramatic response (fever reduction) should be seen within 24-48 hours

Drug therapy trials without a definitive diagnosis may interfere with future diagnosis and may exacerbate an undiagnosed condition that may be life threatening.

References available upon request