Aetiology

Fever is one of the most common clinical symptoms managed by paediatricians and other healthcare providers.[3][4]​​ There are many causes of unexplained fever in children.​ Aetiologies include rare diseases, but also include common illnesses presenting unusually. The 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

Most children who present acutely with fever without source (or fever of unclear source) have an underlying self-limiting viral infection, but occasionally these children (especially young infants) have more serious infections requiring urgent evaluation and empirical treatment. Febrile patients with clinically recognisable viral conditions have lower rates of bacteraemia than patients with no obvious source of infection.[6]

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.

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

Patients with unusual and non-endemic 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 travelled to endemic areas.

Infectious causes of fever in children include:

  • Multisystem infections

    • Bacteraemia

    • 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

    • Tularaemia

    • 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

    • Viral upper respiratory tract infections

  • ENT infections

    • Rhinosinusitis

    • 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's disease and ulcerative colitis may also present with fever of unknown origin, although more commonly patients present with abdominal pain and diarrhoea.

  • 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 leukaemia, and Hodgkin's and non-Hodgkin's 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, sulphonamides, beta-lactam antibiotics, anticholinergics, and illicit drugs (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 illness occurs when thermal loads overwhelm the body's thermoregulatory responses and homeostasis is altered. Extremes of temperature and humidity make heat dissipation less efficient and can lead to heat illness. Heat illness comprises a spectrum of diseases from minor to severe, including heat oedema, heat cramps, heat syncope, heat exhaustion, and life-threatening heat stroke. Physical effort generates intrinsic heat, and can rapidly lead to heat illness when combined with environmental factors.[10]

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