Fever of unknown origin in children: Etiology
- Debra L Palazzi, MD, MEd
Debra L Palazzi, MD, MEd
- Associate Professor of Pediatrics, Infectious Diseases Section
- Baylor College of Medicine
- Section Editors
- Morven S Edwards, MD
Morven S Edwards, MD
- Section Editor — Pediatric Infectious Diseases
- Professor of Pediatrics
- Baylor College of Medicine
- Robert Sundel, MD
Robert Sundel, MD
- Section Editor — Pediatric Rheumatology
- Associate Professor of Pediatrics
- Harvard Medical School
- Jan E Drutz, MD
Jan E Drutz, MD
- Section Editor — General Pediatrics
- Professor of Pediatrics
- Baylor College of Medicine
Fever is a common presenting complaint in children, accounting for nearly one-third of pediatric outpatient visits in the United States . The specific entity of "fever of unknown origin" (FUO), as opposed to a "fever without a source" (FWS), has occupied a special place within infectious diseases since the first definition of and series about FUO by Petersdorf and Beeson in 1961 . Although the original definition has been modified, the assessment of broad categories of illness (including infections, connective tissue disease, and malignancy) as a cause of FUO remains useful.
Common etiologies of FUO in children will be discussed below. The approach to the child with FUO, FWS, and fever in unique host groups (eg, newborns, neutropenic children, or those with human immunodeficiency virus [HIV] infection) are discussed separately. (See "Fever of unknown origin in children: Evaluation" and "Fever without a source in children 3 to 36 months of age".)
We apply the term fever of unknown origin (FUO) to children with fever >38.3ºC (101ºF) of at least eight days' duration, in whom no diagnosis is apparent after initial outpatient or hospital evaluation that includes a careful history and physical examination and initial laboratory assessment. (See "Fever of unknown origin in children: Evaluation", section on 'Definitions'.)
The number of infectious and noninfectious etiologies of fever of unknown origin (FUO) in children is extensive (table 1). FUO is usually caused by common disorders, often with an unusual presentation [3-13].
The three most common etiologic categories of FUO in children in order of frequency are infectious diseases, connective tissue diseases, and neoplasms [3-14]. In addition, there are causes of FUO, such as drug fever, factitious fever, central nervous system dysfunction, and others, that do not fit into the above categories. In many cases, a definitive diagnosis is never established and fever resolves.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Finkelstein JA, Christiansen CL, Platt R. Fever in pediatric primary care: occurrence, management, and outcomes. Pediatrics 2000; 105:260.
- PETERSDORF RG, BEESON PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961; 40:1.
- Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Clin Pediatr (Phila) 1977; 16:768.
- McClung HJ. Prolonged fever of unknown origin in children. Am J Dis Child 1972; 124:544.
- Pizzo PA, Lovejoy FH Jr, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975; 55:468.
- Feigin RD, Shearer WT. Fever of unknown origin in children. Curr Probl Pediatr 1976; 6:3.
- Cogulu O, Koturoglu G, Kurugol Z, et al. Evaluation of 80 children with prolonged fever. Pediatr Int 2003; 45:564.
- Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre experience. Acta Paediatr 2006; 95:463.
- Bourrillon A. [Management of prolonged fever in infants]. Arch Pediatr 1999; 6:330.
- Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis 1998; 26:80.
- Chantada G, Casak S, Plata JD, et al. Children with fever of unknown origin in Argentina: an analysis of 113 cases. Pediatr Infect Dis J 1994; 13:260.
- Akpede GO, Akenzua GI. Management of children with prolonged fever of unknown origin and difficulties in the management of fever of unknown origin in children in developing countries. Paediatr Drugs 2001; 3:247.
- Schneider T, Loddenkemper C, Rudwaleit M, et al. [Fever of unknown origin in the 21st century: infectious diseases]. Dtsch Med Wochenschr 2005; 130:2708.
- Cho CY, Lai CC, Lee ML, et al. Clinical analysis of fever of unknown origin in children: A 10-year experience in a northern Taiwan medical center. J Microbiol Immunol Infect 2017; 50:40.
- Arisoy ES, Correa AG, Wagner ML, Kaplan SL. Hepatosplenic cat-scratch disease in children: selected clinical features and treatment. Clin Infect Dis 1999; 28:778.
- Van CT, Thuy NT, San NH, et al. Human leptospirosis in the Mekong delta, Viet Nam. Trans R Soc Trop Med Hyg 1998; 92:625.
- Jackson LA, Kaufmann AF, Adams WG, et al. Outbreak of leptospirosis associated with swimming. Pediatr Infect Dis J 1993; 12:48.
- Centers for Disease Control and Prevention (CDC). Local transmission of Plasmodium vivax malaria--Palm Beach County, Florida, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:908.
- Mace KE, Arguin PM. Malaria Surveillance - United States, 2014. MMWR Surveill Summ 2017; 66:1.
- Tuberculin negative tuberculosis. Am Rev Respir Dis 1973; 107:882.
- Steiner P, Portugaleza C. Tuberculous meningitis in children. A review of 25 cases observed between the years 1965 and 1970 at the Kings County Medical Center of Brooklyn with special reference to the problem of infection with primary drug-resistant strains of M. tuberculosis. Am Rev Respir Dis 1973; 107:22.
- Kaplan SL, Feigin RD. Experience and reason--briefly recorded. Pediatrics 1976; 58:614.
- Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin: a study of 13 patients. Medicine (Baltimore) 1973; 52:1.
- Weinstein L. Bacterial hepatitis: a case report on an unrecognized cause of fever of unknown origin. N Engl J Med 1978; 299:1052.
- Wyllie R, Fitzgerald JF. Bacterial cholangitis in a 10-week-old infant with fever of undetermined origin. Pediatrics 1980; 65:164.
- Steele RW, Jones SM, Lowe BA, Glasier CM. Usefulness of scanning procedures for diagnosis of fever of unknown origin in children. J Pediatr 1991; 119:526.
- Calabro JJ, Marchesano JM. Juvenile rheumatoid arthritis. N Engl J Med 1967; 277:746.
- Lin KL, Wang HS. Reverse Shapiro's syndrome--an unusual cause of fever of unknown origin. Brain Dev 2005; 27:455.
- Hirayama K, Hoshino Y, Kumashiro H, Yamamoto T. Reverse Shapiro's syndrome. A case of agenesis of corpus callosum associated with periodic hyperthermia. Arch Neurol 1994; 51:494.
- Berger H. Fever. An unusual manifestation of epilepsy. Postgrad Med 1966; 40:479.
- Matsuda N, Akanuma J, Shimizu S, et al. [Recurrent episodes of fever of unknown origin as temporal lobe epilepsy]. Rinsho Shinkeigaku 2000; 40:999.
- Chan KM. Epilepsy--another cause of intermittent fever with confusion. Postgrad Med J 1992; 68:119.
- el-Ad B, Neufeld MY. Periodic febrile confusion as a presentation of complex partial status epilepticus. Acta Neurol Scand 1990; 82:350.
- Semel JD. Complex partial status epilepticus presenting as fever of unknown origin. Arch Intern Med 1987; 147:1571.
- WOLFF SM, ADLER RC, BUSKIRK ER, THOMPSON RH. A SYNDROME OF PERIODIC HYPOTHALAMIC DISCHARGE. Am J Med 1964; 36:956.
- Dancis J, Smith AA. Familial dysautonomia. N Engl J Med 1966; 274:207.
- SMITH AA, FARBMAN A, DANCIS J. TONGUE IN FAMILIAL DYSAUTONOMIA, A DIAGNOSTIC SIGN. Am J Dis Child 1965; 110:152.
- Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr 2007; 166:95.
- Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003; 36:306.
- Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia 1996; 10:197.
- Henter JI, Elinder G, Söder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand 1991; 80:428.
- Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007; 48:124.
- Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis. Blood 2011; 118:4041.
- CROHN BB, YARNIS H. Continuous fever of intestinal origin. Ann Intern Med 1947; 26:858.
- LEE FI, DAVIES DM. Crohn's disease presenting as pyrexia of unknown origin. Lancet 1961; 1:1205.
- WALKER SH. Periodic fever in juvenile regional enteritis. J Pediatr 1962; 60:561.
- Scagni P, Peisino MG, Bianchi M, et al. Kikuchi-Fujimoto disease is a rare cause of lymphadenopathy and fever of unknown origin in children: report of two cases and review of the literature. J Pediatr Hematol Oncol 2005; 27:337.
- Lee KY, Yeon YH, Lee BC. Kikuchi-Fujimoto disease with prolonged fever in children. Pediatrics 2004; 114:e752.
- Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy 2005; 4:77.
- Hayem F. [Periodic fevers]. Arch Pediatr 2002; 9:638.
- SHAPIRO TR, EHRENFELD EN. Recurrent polyserositis ("periodic disease," "familial Mediterranean fever") in children. Pediatrics 1962; 30:443.
- Drenth JP, Haagsma CJ, van der Meer JW. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine (Baltimore) 1994; 73:133.
- Grose C, Schnetzer JR, Ferrante A, Vladutiu AO. Children with hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Infect Dis J 1996; 15:72.
- Grose C. Periodic fever in children with hyperimmunoglobulinemia D and mevalonate kinase mutations. Pediatr Infect Dis J 2005; 24:573.
- Klasen IS, Göertz JH, van de Wiel GA, et al. Hyper-immunoglobulin A in the hyperimmunoglobulinemia D syndrome. Clin Diagn Lab Immunol 2001; 8:58.
- REIMANN HA. Periodic disease; periodic fever, periodic abdominalgia, cyclic neutropenia, intermittent arthralgia, angioneurotic edema, anaphylactoid purpura and periodic paralysis. J Am Med Assoc 1949; 141:175.
- GENERALIZED INFECTIONS
- Cat scratch disease
- Viral infections
- LOCALIZED INFECTIONS
- Bone and joint
- Infective endocarditis
- Intraabdominal abscess
- Hepatic infection
- Upper respiratory tract infection
- Urinary tract infection
- RHEUMATOLOGIC DISEASES
- Juvenile idiopathic arthritis
- OTHER CAUSES
- Central nervous system dysfunction
- Diabetes insipidus
- Drug fever
- Factitious fever
- Familial dysautonomia
- Hemophagocytic lymphohistiocytosis
- Infantile cortical hyperostosis
- Inflammatory bowel disease
- Kawasaki disease
- Kikuchi disease
- Periodic fevers
- INFORMATION FOR PATIENTS