Etiology

Fever is one of the most common clinical symptoms managed by pediatricians and other healthcare providers.[3][4]​ There are many causes of unexplained fever in children.​ Etiologies include rare diseases, but also include common illnesses presenting unusually. The vast majority of children have underlying bacterial or viral infections.[5] Failure to obtain an adequate history, lack of a thorough examination, delay in obtaining appropriate investigations, and difficulties in interpretation of results often result in missed diagnoses.

Infections

Bacterial, viral, parasitic, and mycobacterial infections can all present as fever of unknown origin, as can tick-borne illness. The duration of symptoms is often shorter and children generally appear more ill with bacterial infections than they do with viral or parasitic infections. Febrile patients with clinically recognizable viral conditions have lower rates of bacteremia than patients with no obvious source of infection.[6]

Although conditions such as cystitis, meningitis, and pneumonia are common causes of fever in children of all age groups, they often have localizing signs and symptoms in older children and rarely present with fever of unknown origin in this age group.

Patients with unusual and nonendemic infections, such as tuberculosis, malaria, dengue fever, and typhoid (enteric fever), often have a history of recent travel abroad or contact with people who have recently traveled to endemic areas.

Infectious causes of fever in children

  • Multisystem infections

    • Bacteremia

    • Malaria

    • Dengue fever

    • Chikungunya

    • Zika virus

    • Typhoid

    • Tuberculosis

    • Cytomegalovirus

    • Toxoplasmosis

    • Viral syndromes

    • Influenza

    • Infectious mononucleosis

    • Tick-borne illnesses such as Lyme disease and Rocky Mountain spotted fever

    • Cat-scratch disease

    • Brucellosis

    • Leptospirosis

    • Tularemia

    • Staphylococcal toxic shock syndrome

    • Streptococcal toxic shock syndrome

    • Scarlet fever

  • Urinary tract infections (UTIs)

    • Cystitis

    • Pyelonephritis

  • Cardiac infections

    • Endocarditis

    • Myocarditis[7][8]

  • Respiratory infections

    • Pneumonia

    • COVID-19

  • ENT infections

    • Sinusitis

    • Tonsillitis

    • Acute otitis media

  • Bone and soft-tissue infections

    • Osteomyelitis

    • Septic arthritis

  • Central nervous system (CNS) infections

    • Meningitis

    • Cerebral abscess

    • Encephalitis

  • Gastrointestinal infections

    • Hepatic abscess

Organic disorders

Inflammatory/vasculitic disorders

  • Causes include systemic lupus erythematosus (SLE), Kawasaki disease, rheumatic fever, juvenile idiopathic arthritis, and sarcoidosis. Patients with fever frequently present with other associated systemic manifestations such as malaise, arthralgias, rash, and multisystem involvement. Patients with Crohn disease and ulcerative colitis may also present with fever of unknown origin, although more commonly patients present with abdominal pain and diarrhea.

  • Patients are often treated with immunosuppressive agents and are at increased risk of developing recurrent infections, which may present with persistent fever.

Malignancies

  • Fever may be a presenting sign of childhood malignancies.[9] Common causes include leukemia, and Hodgkin and non-Hodgkin lymphoma. These patients require urgent evaluation and management.

Endocrine disorders

  • Thyroid storm.

Autonomic disorders

  • Disorders of the sympathetic and/or parasympathetic autonomic nervous system. Temperature dysregulation occurs in patients due to hypo- or anhydrosis, such as in those with hereditary sensory autonomic neuropathy.

Medication-related fever

Many drugs cause drug-related fever. Drugs can cause fever by a variety of mechanisms.

  • Hypersensitivity reactions to drugs such as salicylates, anticonvulsants, sulfonamides, beta-lactam antibiotics, anticholinergics, and drugs of abuse (e.g., amphetamines, cocaine). Serum sickness is a hypersensitivity reaction resulting in the formation of immune complexes that deposit in tissues and can result in fever, rash, and polyarthralgias.

  • Alteration of thermoregulation by medications such as thyroid hormones and antihistamines.

  • Idiosyncratic reactions such as serotonin syndrome manifested by fever, agitation, altered mental status, and muscular rigidity.

Low-grade fevers are also common after childhood vaccinations.

Psychosocial causes

Rarely fever may be factitious or due to factitious disorder imposed on another (formerly known as Munchausen syndrome by proxy). These conditions may be particularly challenging to diagnose; a good psychosocial history and evaluation is required.

Environmental causes

Heat-related illness due to exposure to hot weather.

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