What's in the Differential Diagnosis of Fever?

Patient Presentation
A 5-year-old male came to clinic for a second opinion of fever referred by his local physician.
Eight weeks previous he had a fever to 40° C and exudative pharyngitis treated with penicillin which was stopped after 2 days because the culture was negative.
The fever continued off and on for the next two weeks up to 39.5° C. Laboratory testing at that time was negative including a complete blood count, differential and monospot.
He was then improved until about 4 weeks previous when he had flu-like symptoms, sore throat, lethargy, and fever to 39° C for 24 hours. He was diagnosed with sinusits and was placed on amoxicillin for 10 days.
He was again improved until 3 weeks ago when he complained of mild right leg pain. Three days later he became febrile and he had a mild limp. He was seen by his local physician again who was concerned about septic arthritis.
Erythrocyte sedimentation rate was 75 mm/hour and the hip ultrasound found a small effusion but no aspiration was done or antibiotics given. A bone scan the following day was negative.
Since that time the leg pain had ceased and he had two fevers to 38.1° C.
The past medical history revealed a healthy child.
The family history was positive for heart disease, thyroid disease, and pyloric stenosis.
The social history revealed traveling to Florida before the first fever. The patient is in childcare where there is a rabbit. Ther is no water exposure.
The review of systems was negative including no joint pain, muscle pain, rashes, weight changes, gastrointestinal or genitourinary complaints.
The pertinent physical exam showed a smiling boy with growth parameters in the 50%. The examination was negative except for bilaterally small axillary nodes and shoddy groin nodes. He had full range of motion in all joints and no pain.
The diagnosis of fever most likely secondary to multiple viral infections (possibly Epstein-Barr virus) and toxic synovitis was made.
The laboratory evaluation that day included a erythrocyte sedimentation rate, C-reactive protein, immunoglobulins, Complement 3, Complement 4, liver function tests, rheumatoid factor, creatinine kinase, and viral titers including Epstein-Barr virus IgG.
These were to screen for viruses, inflammatory bowel disease, rheumatological disease and possible immunodeficiency. These were all found to be negative.
The consulting physician recommended to the private physician to monitor the patient closely and if the fevers returned to possibly evaluate for thyroid disease and tularemia.

Fever is a common concern for parents and for health care providers alike. It is defined as a temperature > 100.5° F or 38.0° C usually determined rectally.
Fever by itself rarely causes a problem for children unless it is extreme, i.e. > 106° F or 41.1° C .
However, fever says that something is not right with the body and that the body is reacting to it, usually as a self-protective mechanism.

The differential diagnosis is extensive but self-limited illnesses predominate. Careful history and physical examination along with judicious use of laboratory testing and careful monitoring of the patient for new or changing symptoms usually elucidates a reason for the fever.

Common definitions:

  • Fever without localizing signs or fever without a source indicate a fever whose cause cannot be found currently after careful history and physical examination and does not meet the criteria for fever of unknown origin. Most occur for < 1 week.
  • Fever of unknown origin is a fever at least twice per week that lasts more than 3 weeks without associated signs of acute toxicity with a basic laboratory evaluation that is negative.
  • Fever in a neonate is a fever without localizing signs in a neonate usually &lt; 28 days but some people extend the timing to < 3 months of age.

Learning Point
The differential diagnosis of fever includes:

  • Allergic
    • Drug reaction – malignant hyperthermia
    • Vaccine reaction
    • Serum sickness
  • Dermatologic
    • Ectodermal dysplasia
  • Immunologic
    • Agammaglobulinemia
    • Hypergammaglobulinemia
  • Infection (by location)
    • Cardiac
      • Endocarditis
      • Myocarditis
      • Pericarditis
    • Dermatologic
      • Cellulitis
      • Exanthems (see also Systemic below)
        • Bacterial
          • Meningococcemia
          • Rocky Mountain spotted fever
          • Scarlet fever
          • Syphilis
          • Others
        • Viral
          • Coxsackie
          • Enterovirus
          • Roseola
          • Rubeola
          • Rubella
          • Varicella
          • Many others
    • Gastrointestinal
      • Abscess, intraabdominal
      • Appendicitis
      • Cholangitis
      • Gastroenteritis, acute
      • Hepatitis
      • Mesenteric adenitis, acute
      • Pancreatitis
      • Peritonitis
    • Genitourinary
      • Abscess, perinephric
      • Epididymitis/orchitis
      • Salpingitis/tubo-ovarian abscess
      • Prostatitis, acute
      • Pyelonephritis
    • Musculoskeletal
      • Septic arthritis
      • Myositis
      • Osteomyelitis
    • Neurologic
      • Abscess
      • Encephalitis
      • Meningitis
    • Ophthalmological
      • Orbital cellulitis/abscess
      • Periorbital/preseptal cellulitis
    • Respiratory tract
        • Upper respiratory tract
          • Abscess – alveolar, peritonsillar, retropharyngeal and lateral pharyngeal wall
          • Adenitis
          • Croup
          • Epiglottitis
          • Otitis media
          • Mastoiditis
          • Parotitis – acute suppurative, mumps
          • Pharyngitis
          • Sinusitis
          • Stomatitis – gingivostomatitis, herpangina
          • Tonsillitis
        • Lower respiratory tract
          • Abscess
          • Bronchitis
          • Bronchiolitis
          • Pneumonia
          • Tuberculosis, pulmonary
      • Systemic (see also Exanthems above)
        • AIDS/HIV
        • Bacterial sepsis
        • Bacteremia, occult
        • Bacteria
          • Brucellosis
          • Cat-scratch disease
          • Leptospirosis
          • Salmonellosis
          • Tuberculosis
          • Tularemia
        • Chlamydia
          • Lymphogranuloma venereum
          • Psittacosis
        • Fungal
          • Blastomycosis
          • Histoplasmosis
        • Parasitic
          • Malaria
          • Toxoplasmosis
          • Visceral larval migrans
        • Rickettsial
          • Q fever
          • Rocky Mountain spotted fever
        • Viruses
          • Cytomegalovirus
          • Epstein-Barr
          • Hepatitis viruses
  • Metabolic
    • Acute intermittent porphyria
    • Diabetes insipidus, central and nephrogenic
    • Etiocholanolone fever
    • Thyrotoxicity
  • Neoplasm
    • Ewing’s sarcoma
    • Hodgkin’s lymphoma
    • Leukemia
    • Lymphoma
    • Neuroblastoma
  • Neurologic
    • CNS lesions of the hypothalamus/brainstem
    • Riley-Day syndrome
    • Seizures, prolonged
    • Subdural effusions
  • Poisoning/toxins
    • Atropine
    • Amphetamine
    • Cocaine
    • LSD
    • Salicylates
    • Other drugs with anticholinergic effects, i.e. anti-depressants
  • Vasculitic
    • Acute rheumatic fever
    • Dermatomyositis/polymyositis
    • Henoch-Schonlein purpura
    • Juvenile rheumatoid arthritis
    • Kawasaki Disease
    • Mixed connective tissue disorder
    • Polyarteritis nodosa
    • Stevens Johnson
    • Systemic lupus erythematosus
  • Other
    • Caffey’s disease
    • Dehydration
    • Crush injuries
    • Factitious/malingering
    • Familiar Mediterranean fever
    • Heat illness and heat stroke
    • Hemolysis, intravascular
    • Hemorrhage into enclosed spaces
    • Inflammatory bowel disease
    • PFAFA syndrome – periodic fever, aphthous ulcers, pharyngitis and adenopathy
    • Sarcoid

Questions for Further Discussion
1. What laboratory testing should be included in the outpatient investigation of fever without a source?
2. What laboratory testing should be done for a fever in a neonate?

Related Cases


      Fever without localizing signs

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at MedlinePlus for this topic: Fever
and at Pediatric Common Questions, Quick Answers for this topic: http://www.virtualpediatrichospital.org/patients/cqqa/feverlevel.shtml

To view current news articles on this topic check Google News.

To view images related to this topic check Google Images.

Fleisher GR, Ludwig S. Synopsis of Pediatric Emergency Medicine. Williams and Wilkins. Baltimore, MD. 1996:90-95.

Illingworth RS. Common Symptoms of Disease in Children. Blackwell Scientific Publications: Oxford. 1998:31-39.

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:893-895.

Woodhead JC. Pediatric Clerkship Guide. Mosby. St. Louis MO, 2003:250-256.

Feigin RD, Cherry JD, Demmler GJ, Kaplan SL. Textbook of Pediatric Infectious Diseases. 5th edit. Volume 1. Saunders, Philadelphia, PA. 2004;825,831.

ACGME Competencies Highlighted by Case

  • Patient Care
    1. When interacting with patients and their families, the health care professional communicates effectively and demonstrates caring and respectful behaviors.
    2. Essential and accurate information about the patients’ is gathered.
    3. Informed decisions about diagnostic and therapeutic interventions based on patient information and preferences, up-to-date scientific evidence, and clinical judgment is made.
    4. Patient management plans are developed and carried out.
    5. Patients and their families are counseled and educated.
    7. All medical and invasive procedures considered essential for the area of practice are competently performed.
    8. Health care services aimed at preventing health problems or maintaining health are provided.
    9. Patient-focused care is provided by working with health care professionals, including those from other disciplines.

  • Medical Knowledge
    10. An investigatory and analytic thinking approach to the clinical situation is demonstrated.
    11. Basic and clinically supportive sciences appropriate to their discipline are known and applied.

  • Interpersonal and Communication Skills

    19. The health professional works effectively with others as a member or leader of a health care team or other professional group.

  • Systems Based Practice
    23. Differing types of medical practice and delivery systems including methods of controlling health care costs and allocating resources are known.
    24. Cost-effective health care and resource allocation that does not compromise quality of care is practiced.

    Donna M. D’Alessandro, MD
    Professor of Pediatrics, Children’s Hospital of Iowa

    August 27, 2007