Fever without Localizing Signs and Symptoms - Infectious Diseases Presenting Non-focally (Table 1)

        A myriad of viral pathogens can cause febrile illnesses. Most present nonspecifically and may be both difficult to diagnosis and self limited in nature lasting days to a week or more. Many are associated with either upper respiratory infection or gastrointestinal symptoms. Patients, although uncomfortable, are non-toxic and do not require extensive diagnostic workups or empiric antibiotics. Other more serious infections can also present nonspecifically with a “flu-like” illness. Diagnosing these illnesses can initially be challenging and a high index of suspicion is needed especially those that do not have the more common upper respiratory infection or gastrointestinal symptoms. Several of the more serious and potentially life threatening infections are briefly reviewed below.

Table 1: Infections That May Present Non-focally 

  • Infectious endocarditis                                                                      

  • Staphylococcus aureus bacteremia                                                      

  • Rocky mountain spotted fever and other rickettsial illnesses  

  • Ehrlichiosis                                                                                                                                     

  • Viral infections: 

    • Hepatitis due to HAV, HBV, HCV, CMV, EBV

    • HIV                                                 

  • Malaria  and travel related infections                                                                                            

  • Infections in the elderly                                                            

HAV= hepatitis A virus, HBV = hepatitis B virus, HCV = hepatitis C virus, CMV = cytomegalovirus,

EBV = Epstein Barr Virus, HIV = human immunodeficiency virus

Infective Endocarditis

        Infective endocarditis usually presents with an ill defined febrile illness. The clinical course can be rapid over days to weeks (Staphylococcus aureus) or more subacute over weeks to months (viridans streptococci). A heart murmur can usually be heard although the classic physical examination finding of a “new” murmur is uncommon. Peripheral stigmata of infective endocarditis such as petechiae, splinter hemorrhage, Osler nodes and Janeway lesions are also uncommon. Blood cultures (two sets) drawn before antibiotic therapy are very sensitive in isolating the pathogen and are key to the diagnosis. Infective endocarditis should be included in the differential diagnosis of a prolonged “influenza”.

Staphylococcus aureus Bacteremia

        Staphylococcus aureus bacteremia is one of the most common and lethal community and hospital acquired bacteremias. Often associated with intravenous catheters or skin infections occurring in those with co-morbid medical illnesses, it can present non-focally in the otherwise healthy patient. Metastatic infection to heart valves, vertebral discs, joints and solid organs is common. Drainage of abscesses and prolonged intravenous antibiotic therapy is required.

Rocky Mountain Spotted Fever and Other Rickettsial Illnesses

        Rocky mountain spotted fever, a tick borne illness caused by Rickettsia rickettsii, is endemic in the south eastern and south central United States. Patients present with fever, myalgia, headache, abdominal pain, nausea and vomiting. The characteristic maculopapular rash with its centripetal distribution begins between the second and fifth day of illness. With time the rash may become petechial or purpuric. 10-15% of patients do not develop a rash. Diagnosis is usually clinically based and confirmed by serology.

        Coxiella burnetii (Q fever) a cause of atypical pneumonia may also present as a self limited febrile illness. Other rickettsial illnesses such as tick, louse borne or scrub typhus are usually associated with overcrowded hygienically poor environments or international travel.


        Ehrlichiosis is a tick borne zoonosis. Human granulocytic anaplasmosis is caused by Anaplasma phagocytophilum while human monocytic ehrlichiosis is caused by Ehrlichia chaffeensis. Both are characterized by fever, headache, myalgias, thrombocytopenia, leukopenia and elevated serum transaminases. A maculopapular rash can occur but is relatively uncommon. Clinical illness can range from a mild flu-like illness to sepsis with renal and respiratory failure and central nervous system involvement. Diagnosis is most often made by polymerase chain reaction (PCR) amplification and serology.

Viral Infections

• Hepatitis from hepatitis A, B or C virus may be asymptomatic or present with fever, myalgia, malaise and arthralgia. Jaundice and right upper quadrant discomfort may be present. Diagnosis is based on elevated transaminases and serologic testing.

• Epstein Barr Virus (EBV) is the causative agent of infectious mononucleosis. Infectious mononucleosis   presents with fever, fatigue, pharyngitis and lymphadenopathy. Laboratory evaluation reveals elevated transaminases and atypical lymphocytosis. Diagnosis is based on detection of heterophile antibodies (mono spot test). Cytomegalovirus, Human Herpes 6 (HHV-6) virus and Toxoplasma gondii can also cause a heterophile negative mono-like illness.

• Primary infection with human immunodeficiency virus (HIV) can also cause a heterophile negative mono-like illness. Patients may present 2-6 weeks after exposure to the virus with fever, fatigue, weight loss, pharyngitis, myalgia, diarrhea, lymphadenopathy and headache. A maculopapular rash is present in 40-80% of patients. Early during acute seroconversion, the HIV antibody titer may be non-detectable. Diagnosis can be confirmed by repeat antibody testing and by detection of HIV RNA by plasma PCR (viral load).

Malaria and Travel Related Illnesses

        A travel history should be obtained in all patients with unexplained fever. Malaria presents non-specifically with fever, headache and myalgia often accompanied with nausea, vomiting and diarrhea. The classic tertian or quartan fever patterns are rarely evident in the returning traveler. There may be anemia, leukocytosis or leukopenia and thrombocytopenia. Diagnosis is confirmed with the use of thick and thin blood smears reviewed by an experienced microbiologist. At least three smears should be performed before the diagnosis is considered ruled out. Other nonlocalizing febrile illnesses that should be considered in the returning international traveler include dengue, typhus, typhoid, leptospirosis and viral hepatitis.

Infections In The Elderly

        The elderly, especially those living in nursing homes, are more prone to infections and those infections are associated with higher mortalities as compared to the young. Classic presentations of routine infections may not occur in the elderly and fever may not be present. Symptoms attributed to the infected organ may not be present; the elderly patient with pneumonia may not experience cough or complain of shortness of breath. Instead the elderly patient may present with change in functional status, worsening cognition, lethargy, falls and incontinence. The elderly patient with change in functional status should be evaluated for an infection even if they are afebrile and do not having localizing symptoms or signs of infection.