Paediatric Drugs

, Volume 3, Issue 4, pp 247–262 | Cite as

Management of Children With Prolonged Fever of Unknown Origin and Difficulties in the Management of Fever of Unknown Origin in Children in Developing Countries

  • George O. AkpedeEmail author
  • Gregory I. Akenzua
Therapy In Practice


This is Part II of a 2-part paper on fever of unknown origin (FUO) in children.It examines the aetiology and management of prolonged FUO in children and the difficulties in the management of FUO in children in developing countries. Part I of this paper discussed acute FUO in children and was published in the March 2001 issue of Paediatric Drugs.

Prolonged FUO is documented fever of more than 7 to 10 days which has no apparent source and no apparent diagnosis after 1 week of clinical investigations. About 34% of cases of prolonged FUO are caused by infections, with bacterial meningitis and urinary tract infection accounting for about 6.5 and 11.4%, respectively, of cases attributable to infections. Chronic infections, particularly tuberculosis and ‘old’ disorders such as Kawasaki disease, cat-scratch disease and Epstein-Barr virus infection presenting with ‘new’ manifestations, collagen-vascular diseases and neoplastic disorders are the other issues of major concern in prolonged FUO. Overall, however, there is a trend towards an increased number of undiagnosed cases. This is due to advancements in diagnostic techniques, such that illnesses which were previously common among the causes of prolonged FUO are now diagnosed earlier, before the presentation becomes that of prolonged FUO.

Clinical examination supplemented with laboratory tests to screen for serious bacterial infections should be the mainstay of initial evaluation of children with prolonged FUO. Use of scanning techniques (such as computerised tomography and ultrasound) as additional supplements to this clinical examination may allow for the earlier diagnosis of causes of prolonged FUO in children such as ‘occult’ abdominal tumours. A common error in management of children with prolonged FUO is the failure to perform a complete history and physical examination; repeated clinical examination and continued observation are of paramount importance in the diagnosis of difficult cases.

Major difficulties in the management of FUO in children in developing countries include constraints in the availability and reliability of laboratory tests, cost, misuse of antibiotics and difficulties encountered in the diagnosis of malaria and typhoid fever. Malaria and typhoid fever are major aetiological considerations in both acute and prolonged FUO in children in developing countries. The newer quinolones may hold great promise for the treatment of serious bacterial infections, including meningitis, which are associated with prolonged FUO in developing countries.


Malaria Kawasaki Disease Bacterial Meningitis Lyme Disease Brucellosis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Akpede GO, Akenzua GI. Aetiology and management of children with acute fever of unknown origin. Paediatr Drugs 2001; 2(3): 169–93Google Scholar
  2. 2.
    Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Clin Pediatr (Phila) 1977; 16: 768–73CrossRefGoogle Scholar
  3. 3.
    McClung HJ. Prolonged fever of unknown origin in children. Am J Dis Child 1972; 124: 544–50PubMedGoogle Scholar
  4. 4.
    Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975; 55: 468–73PubMedGoogle Scholar
  5. 5.
    Hayani A, Mahoney OH, Ferbach DJ. Role of bone marrow examination in the child with prolonged fever. J Pediatr 1990; 16: 19–20Google Scholar
  6. 6.
    Steele RW, Jones SM, Lowe BA, et al. Usefulness of scanning procedures for diagnosis of fever of unknown origin in children. J Pediatr 1991; 119: 526–30PubMedCrossRefGoogle Scholar
  7. 7.
    Petersdorf RG, Beeson PB. Fever of unexplained origin: report of 100 cases. Medicine 1961; 40: 1–30PubMedCrossRefGoogle Scholar
  8. 8.
    Knockaert DC, Vanneste LJ, Bobbaers HJ. Fever of unknown origin in the 1980s: an update of the diagnostic spectrum. Arch Intern Med 1992; 152: 51–5PubMedCrossRefGoogle Scholar
  9. 9.
    Sharma BK, Kumari S, Varma SC, et al. Prolonged undiagnosed fever in northern India [abstract]. Trop Geogr Med 1992; 44: 32–6PubMedGoogle Scholar
  10. 10.
    Eminson DM, Postlethwaite RJ. Factitious illness: recognition and management. Arch Dis Child 1992; 67: 1510–6PubMedCrossRefGoogle Scholar
  11. 11.
    Bools CN, Neale BA, Meadow SR. Co-morbidity associated with fabricated illness (Munchausen syndrome by proxy). Arch Dis Child 1992; 67: 77–9PubMedCrossRefGoogle Scholar
  12. 12.
    Powell KR. Fever without a focus. In: Behrman RE, Kleigman RM, Arvin AM, editors. Nelson textbook of pediatrics. Philadelphia (PA): Saunders, 1996: 698–704Google Scholar
  13. 13.
    Gartner Jr JC. Fever of unknown origin [abstract]. Adv Pediatr Infect Dis 1992; 7: 1–24PubMedGoogle Scholar
  14. 14.
    Stanfield JP. Fever in children in the tropics. BMJ 1969; I: 761–5CrossRefGoogle Scholar
  15. 15.
    Pececco M, Panizon F. Persistent low-grade fever: a study of 100 cases [abstract]. Ann Nestle 1984; 42: 38Google Scholar
  16. 16.
    Horsburgh Jr CR. Editorial: what it takes to control tuberculosis. Am J Public Health 1998; 88: 1015–6PubMedCrossRefGoogle Scholar
  17. 17.
    Newton RW. Tuberculous meningitis. Arch Dis Child 1994; 70: 364–6PubMedCrossRefGoogle Scholar
  18. 18.
    Citron KM. Tuberculosis in Britain today: notifications are no longer falling. BMJ 1993; 306: 221–3CrossRefGoogle Scholar
  19. 19.
    Snider DE, Roper WL. The new tuberculosis. N Engl J Med 1992; 326: 703–5PubMedCrossRefGoogle Scholar
  20. 20.
    Africa’s tuberculosis burden and chemoprophylaxis [editorial]. Lancet 1990; 335: 1249–50Google Scholar
  21. 21.
    Akpede GO, Adeyemi O, Ambe JP. Trends in the susceptibility to antimicrobial drugs of common pathogens in childhood septicaemia in Nigeria: experience at the University of Maiduguri Teaching Hospital, Nigeria, 1991–1994. Int J Antimicrob Agents 1995; 6: 91–7PubMedCrossRefGoogle Scholar
  22. 22.
    Miller LC, Sisson BA, Tucker LB, et al. Prolonged fevers of unknown origin in children: patterns of presentation and outcome. J Pediatr 1996; 129: 419–23PubMedCrossRefGoogle Scholar
  23. 23.
    Godard C. Fever in childhood: a practising paediatrician’s point of view. Ann Nestle 1984; 42: 11–20Google Scholar
  24. 24.
    Dechovitz AB, Moffet HL. Classification of acute febrile illnesses in childhood. Clin Pediatr (Phila) 1968; 7: 649–53CrossRefGoogle Scholar
  25. 25.
    Petersdorf RG. Chills and fever. In: Petersdorf RG, Adams RD, Braunwald E, et al., editors. Harrison’s principles of internal medicine. Auckland: McGraw-Hill International, 1983: 57–65Google Scholar
  26. 26.
    Feigin RD. Fever of unknown origin. In: Behrman RE, editor. Nelson textbook of pediatrics. Philadelphia (PA): Saunders, 1992: 651–4Google Scholar
  27. 27.
    McCarthy PL, Bachman DT, Shapiro ED, et al. Fever without apparent source on clinical examination, lower respiratory infections in children, bacterial infections, and acute gastroenteritis and diarrhea of infancy and early childhood. Curr Opin Pediatr 1994; 6: 105–25PubMedCrossRefGoogle Scholar
  28. 28.
    Scully RE, Mark EJ, McNelly WF, et al., editors. Case records of the Massachusetts General Hospital: weekly clinicopathological exercises: case 42-1994. N Engl J Med 1994; 331: 1437–44Google Scholar
  29. 29.
    Margileth AM. Cat scratch disease. In: Behrman RE, Kleigman RM, Arvin AM, editors. Nelson textbook of pediatrics. 15th ed. Philadelphia (PA): WB Saunders, 1996; 865–7Google Scholar
  30. 30.
    Colebunders R, Ndumbe P. Priorities for HIV testing in developing countries? Lancet 1993; 342: 601–2PubMedCrossRefGoogle Scholar
  31. 31.
    Wolf SM. Laboratory evaluation of the child with a febrile convulsion. Pediatrics 1978; 62: 1074–6PubMedGoogle Scholar
  32. 32.
    Joint Working Group of the Research Unit of the Royal College of Physicians and the British Paediatric Association. Guidelines for the management of convulsions with fever. BMJ 1991; 303: 634–6CrossRefGoogle Scholar
  33. 33.
    Al-Kassimi FA, Abdullah AK, Al-Orainey IO, et al. The significance of positive Mantoux reactions in BCG-vaccinated children. Tubercle 1991; 72: 101–4PubMedCrossRefGoogle Scholar
  34. 34.
    Warrell DA, Molyneux ME, Beales PF. Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990; 84 Suppl. 2: 1–65Google Scholar
  35. 35.
    Lascari AD. The erythrocyte sedimentation rate. Pediatr Clin North Am 1972; 19: 1113–21PubMedGoogle Scholar
  36. 36.
    Holdstock G, Mithell JRA. Erythrocyte-sedimentation rate before and after in-vitro defibrination: a rapid and simple method for increasing the specificity. Lancet 1977; II: 1314–5CrossRefGoogle Scholar
  37. 37.
    Naber SP. Molecular pathology: diagnosis of infectious diseases. N Engl J Med 1994; 331: 1212–5PubMedCrossRefGoogle Scholar
  38. 38.
    Tompkins LS. The use of molecular methods in infectious diseases. N Engl J Med 1992; 327: 1290–7PubMedCrossRefGoogle Scholar
  39. 39.
    Brook JH, Genese CA, Bloland PB, et al. Brief report: malaria probably acquired in New Jersey. N Engl J Med 1994; 331: 22–3PubMedCrossRefGoogle Scholar
  40. 40.
    Hook EW. Typhoid fever today. N Engl J Med 1984; 310: 116–8PubMedCrossRefGoogle Scholar
  41. 41.
    Taylor DN, Pollard RA, Blake PA. Typhoid fever in the United States and the risk to the international traveler. N Engl J Med 1983; 148: 599–602Google Scholar
  42. 42.
    Hart CA, Kariuki S. Antimicrobial resistance in developing countries. BMJ 1998; 317: 114–7Google Scholar
  43. 43.
    Trape JF, Peelman P, Morault-Peelman B. Criteria for diagnosing clinical malaria among a semi-immune population exposed to intense and perenial transmission. Trans Roy Soc Trop Med Hyg 1985; 79: 435–42PubMedCrossRefGoogle Scholar
  44. 44.
    Ekenna O. Typhoid fever: problems of accurate laboratory diagnosis and antimicrobial therapy. Nig Med J 1992; 23: 93–9Google Scholar
  45. 45.
    Mutabingwa TK, de Geus A, Meuwissen JH, et al. Malaria chemosuppression during pregnancy VI: some epidemiological aspects of malaria in infants. Trop Geogr Med 1994; 46: 1–7PubMedGoogle Scholar
  46. 46.
    Akpede GO, Sykes RM. Malaria with bacteraemia in acutely febrile children without localising signs: coincidence or association/complication? J Trop Med Hyg 1993; 96: 146–50PubMedGoogle Scholar
  47. 47.
    LePage P, Bogaerts J, Van Goethem C, et al. Community-acquired bacteraemia in African children. Lancet 1987; I: 1458–61CrossRefGoogle Scholar
  48. 48.
    Akpede GO, Abiodun PO, Sykes RM. Acute fevers of unknown origin in young children in the tropics. J Pediatr 1993; 122: 79–81PubMedCrossRefGoogle Scholar
  49. 49.
    Walsh AL, Phiri AJ, Graham SM, et al. Bacteraemia in febrile Malawian children: clinical and microbiologic features. Pediatr Infect Dis J 2000; 19: 312–8PubMedCrossRefGoogle Scholar
  50. 50.
    Hendrickse RG, Hasan AH, Olumide LO, et al. Malaria in early childhood: an investigation of five hundred seriously ill children in whom a “clinical” diagnosis of malaria was made on admission to the children’s emergency room at University College Hospital, Ibadan. Ann Trop Med Parasitol 1971; 65: 1–20PubMedGoogle Scholar
  51. 51.
    Guerra-Caceres JG, Gotuzzo-Herencia E, Crosby-Dagnino E, et al. Diagnostic value of bone marrow culture in typhoid fever. Trans R Soc Trop Med Hyg 1979; 73: 680–3PubMedCrossRefGoogle Scholar
  52. 52.
    Levine MM, Grados O, Gilman RH, et al. Diagnostic value of the Widal test in areas endemic for typhoid fever. Am J Trop Med Hyg 1978; 27: 795–800PubMedGoogle Scholar
  53. 53.
    Dugan MB, Beyer L. Enteric fever in young Yoruba children. Arch Dis Child 1975; 50: 67–71CrossRefGoogle Scholar
  54. 54.
    Abraham G, Teklu B, Gedebu M, et al. Diagnostic value of the Widal test. Trop Geogr Med 1981; 33: 329–33PubMedGoogle Scholar
  55. 55.
    Choo KE, Razif A, Ariffin WA, et al. Typhoid fever in hospitalized children in Kelantan, Malaysia. Ann Trop Paediatr 1988; 8: 207–12PubMedGoogle Scholar
  56. 56.
    Mohammed I, Chikwem JO, Gashau W. Determination by Widal agglutination of the baseline titre for the diagnosis of typhoid fever in two Nigerian states. Scand J Immunol 1992; 36 (Suppl.): 153–6CrossRefGoogle Scholar
  57. 57.
    Gilman RH, Terminel M, Levine MM, et al. Relative efficacy of blood, urine, rectal swab, bone marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever. Lancet 1975; I: 1211–3CrossRefGoogle Scholar
  58. 58.
    Carme B. “Pseudo-resistant” malaria in tropical countries. Lancet 1992; 340: 896–7PubMedCrossRefGoogle Scholar
  59. 59.
    Onuigbo NAC. Typhoid fever epidemic in Nigeria? The abuse of the Widal test and the antibiotic chloramphenicol. Nig Med Pract 1989; 18: 23–5Google Scholar
  60. 60.
    Animashaun T, Odugbemi T. Widal test: its use and abuse in Nigeria. Nig Med Pract 1990; 19: 96–8Google Scholar
  61. 61.
    Singhi S, Kohli V, Ayyargiri A. Bacteremia and bacterial infections in highly febrile children without apparent focus. Indian Pediatr 1992; 29: 1285–9PubMedGoogle Scholar
  62. 62.
    Kohli V, Singhi S, Sharma P, et al. Value of serum C-reactive protein concentrations in febrile children without apparent focus. Ann Trop Paediatr 1993; 13: 373–8PubMedGoogle Scholar
  63. 63.
    Alausa KO, Montefiore D, Sogbetun AO. Septicaemia in the tropics: a prospective epidemiological study of 146 patients with a high case fatality rate. Scand J Infect Dis 1977; 9: 181–5PubMedGoogle Scholar
  64. 64.
    Maher D, Kumwenda J. Bacteraemia in Blantyre. Trop Doctor 1994; 24: 82–3Google Scholar
  65. 65.
    Njokanma OF, Olanrewaju DM, Akesode FA. Antibiotic resistance among bacterial isolates in neonatal septicaemia. Nig J Paediatr 1994; 21: 47–51Google Scholar
  66. 66.
    Antibiotic therapy in neonatal septicaemia [editorial]. Nig J Paediatr 1996; 23: 1–3Google Scholar
  67. 67.
    Omokhodion SI. The use of ofloxacin in infants with rapidly deteriorating septicaemia and multiple antibiotic resistance [abstract]. Nig J Paediatr 1994; 21: 83–4Google Scholar
  68. 68.
    Tefuarani N, Vince JD. Purulent meningitis in children: outcome using a standard management regimen with chloramphenicol. Ann Trop Paediatr 1992; 12: 375–83PubMedGoogle Scholar
  69. 69.
    Pecoul B, Varaine F, Keita M, et al. Long-acting chloramphenicol versus intravenous ampicillin for treatment of bacterial meningitis. Lancet 1991; 338: 862–6PubMedCrossRefGoogle Scholar
  70. 70.
    Akpede GO, Dawodu SO, Umoffia ME. Response to antimicrobial therapy in childhood bacterial meningitis in tropical Africa: report of a bi-centre experience in Nigeria, 1993–1998. Ann Trop Paediatr 1999; 19: 237–43PubMedCrossRefGoogle Scholar
  71. 71.
    Campagne G, Schuchat A, Djibo S, et al. Epidemiology of bacterial meningitis in Niamey, Niger, 1981–96. Bull World Health Organ 1999; 77: 499–508PubMedGoogle Scholar
  72. 72.
    Andriole VT. The future of the quinolones. Drugs 1999; 58 (Suppl. 2): 1–5PubMedCrossRefGoogle Scholar
  73. 73.
    Jafri HS, McCracken Jr GH. Fluoroquinolones in paediatrics. Drugs 1999; 58 Suppl. 2: 43–8PubMedCrossRefGoogle Scholar
  74. 74.
    Schaad UB. Use of the quinolones in paediatrics. Drugs 1993; 45 Suppl. 3: 37–41PubMedCrossRefGoogle Scholar
  75. 75.
    Karstaedt AS, Khoosal M, Crewe-Brown HH. Pneumococcal bacteraemia during a decade in children in Soweto, South Africa. Pediatr Infect Dis J 2000; 19: 454–7PubMedCrossRefGoogle Scholar
  76. 76.
    Daley CL. Tuberculosis recurrence in Africa: true relapse or re-infection? Lancet 1993; 342: 756–7PubMedCrossRefGoogle Scholar
  77. 77.
    Iseman MD. Treatment of multi-drug-resistant tuberculosis. N Engl J Med 1993; 329: 784–91PubMedCrossRefGoogle Scholar
  78. 78.
    Randal G, Seidel JS. Malaria. Pediatr Clin North Am 1985; 32; 893–916Google Scholar
  79. 79.
    Consultation in Geneva tackles malaria diagnostics. Geneva: UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). 2000 Feb. TDR news no. 61Google Scholar
  80. 80.
    Spielman A, Perrone JB, Teklehaimanot A, et al. Malaria diagnosis by direct observation of centrifuged samples of blood. Am J Trop Med Hyg 1988; 39: 337–42PubMedGoogle Scholar
  81. 81.
    Rickman LS, Long GW, Oberst R, et al. Rapid diagnosis of malaria by acridine orange staining of centrifuged parasites. Lancet 1989; I: 68–71CrossRefGoogle Scholar
  82. 82.
    Rougemont A, Breslow N, Brenner E, et al. Epidemiological basis for clinical diagnosis of childhood malaria in endemic zone in West Africa. Lancet 1991; 338: 1292–5PubMedCrossRefGoogle Scholar
  83. 83.
    Redd SC, Kazembe PN, Luby SP, et al. Clinical algorithm for treatment of Plasmodium falciparum malaria in children. Lancet 1996; 347: 223–7PubMedCrossRefGoogle Scholar
  84. 84.
    Patel CC. Acute febrile encephalopathy in Ugandan children. Afr J Med Sci 1971; 2: 127–34PubMedGoogle Scholar
  85. 85.
    Malarial diagnosis in semi-immunes [editorial]. Med Digest 1986; 12: 46Google Scholar
  86. 86.
    Akpede GO, Abiodun PO. The micro-erythrocyte sedimentation rate as a screening test for bacteraemia in young children with non-focal infections. W Afr J Med 1995; 14: 147–51Google Scholar
  87. 87.
    Johnson AOK, Aderele WI. Enteric fever in childhood. J Trop Med Hyg 1981; 84: 29–35PubMedGoogle Scholar
  88. 88.
    Singhi S, Singhi P. Extra abdominal manifestations of enteric fever: a review. Indian J Paediatr 1978; 45: 229–38CrossRefGoogle Scholar
  89. 89.
    Sack RB. Serologic tests for the diagnosis of enterobacterial infections. In: Rose NR, Friedman H, Fahey JL, editors. Manual of clinical laboratory immunology. 3rd ed. Washington, DC: American Society for Microbiology, 1986; 359–62Google Scholar
  90. 90.
    Agbonlahor DE, Aghahowa MO, Idukpaye O, et al. Baseline typhoidal antibody levels in apparently healthy Nigerians. Q J Hosp Med 1997; 7: 242–6Google Scholar

Copyright information

© Adis International Limited 2001

Authors and Affiliations

  1. 1.Department of Paediatrics, College of MedicineAmbrose Alli UniversityEkpomaNigeria
  2. 2.Department of Child Health, College of Medical SciencesUniversity of BeninBenin CityNigeria

Personalised recommendations