The classical Petersdorf and Beeson criteria for PUO defined it as a well-documented fever above 38.3°C for atleast 3 weeks without an apparent source after 3 weeks of outpatient evaluation or 1 week of in-hospital evaluation.
1 Currently, PUO in a child may be defined as a temperature above 38.3°C, atleast once a day, for atleast 8 days with an inconclusive history, physical examination and preliminary investigations, evaluated by a paediatrician out patiently.
PUO understandably poses a diagnostic dilemma for clinicians with a wide spectrum of causes including infectious, autoimmune, malignancy, factitious, and iatrogenic
3. Chien et al.
4 proposed a four-level approach to childhood PUO. The first level involves a detailed history and physical examination, followed by simple screening tests such as complete blood counts, routine biochemistry tests, urinalysis, urine or blood or stool culture, and chest radiographs. The second level involves more specific screening tests including viral cultures, bacterial and viral serology, abdominal or lymph node ultrasonography, and basic autoimmune panels. The third level entails targeted and invasive investigations such as computerized tomography/magnetic resonance imaging, bone marrow sampling, lumbar puncture, lymph node biopsy, echocardiography, and polymerase chain reaction testing for viruses. The final level, if the cause of PUO is still unknown, advocates for a treat-and-assess approach involving the use of antimicrobial agents, steroids and so forth based on clinical judgement and response to therapy.
4
Most recent studies of PUO in children have found infectious diseases to be the most common cause, followed closely by autoimmune and malignant diseases.
4,5,6,7 While several bacterial, viral, fungal, and parasitological infections may cause PUO in children, in an Indian context it is essential to work-up for bacterial pneumonia, respiratory viral infections, urinary tract infections, vector-borne diseases, scrub typhus, enteric fever, tuberculosis, and brucella.
5,6,7 Autoimmune causes in childhood PUO include systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), inflammatory bowel disease, sarcoidosis, vasculitis, Kawasaki disease, and Behcet disease.
3 Indian studies have found SLE, JIA, and Kawasaki disease as common causes of childhood PUO.
5,7 Malignancy as a cause of childhood PUO has a somewhat similar prevalence as autoimmune disorders. Common malignant causes include leukemias, lymphomas, neuroblastoma, hemophagocytic lymphohistiocytosis, and Langerhans cell histiocytosis.
3 In Indian children, the common malignancies implicated as etiologies in PUO include acute myeloid leukemia, acute lymphoblastic leukemia, and neuroblastoma.
5,6,7
Additional important causes to keep in mind while evaluating a patient with PUO include pseudo-PUO and iatrogenic fevers. Pseudo-PUO refers to successive episodes of self-limited febrile infections that are perceived by the caregivers as a single prolonged febrile episode. This occurs when a well-defined infection that resolves is followed by other febrile illnesses that are poorly-defined. Ruling out pseudo-PUO required careful history taking, including maintaining a fever diary, in order to avoid an expensive and unneeded workup.
3 Iatrogenic or drug-induced PUO can be caused by any medication including antibiotics, anticonvulsants, chemotherapeutic drugs, non-steroidal anti-inflammatory drugs, and antipyretics, and can manifest at any point after starting the drug. Drug-induced fever can be confirmed by the resolution of fever usually within two half-lives of stopping the offending drug.
The first step in the management of PUO is to discontinue all the non-essential medications so as to rule out the possibility of drug fever. If the patient is on multiple medications, the elimination may be done one after the other.
2,3 In healthy-appearing children with PUO, the use of empirical antibiotics or steroids is not recommended. Empirical antibiotics may hinder the detection of common infectious etiologies of PUO and are thus recommended only if the infection or the pathogen is diagnosed or if there is a high clinical suspicion. Similarly, steroids for suspected autoimmune causes of PUO should only be started after confirmation of the diagnosis or if there is a high clinical suspicion for serious inflammatory conditions, and after ruling out malignancies. Further management of PUO will be specific to the underlying cause. Pediatric PUO has a relatively good prognosis even in cases with no identifiable cause.
2,3| References : |
- Pannu AK, Golla R, Kumari S et al. Aetiology of pyrexia of unknown origin in north India. Trop Doct. 2021 Jan;51(1):34-40.
- Trapani S, Fiordelisi A, Stinco M et al. Update on Fever of Unknown Origin in Children: Focus on Etiologies and Clinical Approach. Children (Basel). 2023 Dec 24;11(1):20.
- Antoon JW, Potisek NM, Lohr JA. Pediatric Fever of Unknown Origin. Pediatr Rev. 2015 Sep;36(9):380-90.
- Chien YL, Huang FL, Huang CM et al. Clinical approach to fever of unknown origin in children. J Microbiol Immunol Infect. 2017 Dec;50(6):893-8.
- Sumathisri R, Pandi K, Srinivasan S. Fever in the tropics: aetiology and clinical profile of fever of unknown origin in children-a prospective observational study in a tertiary care hospital in South India. Int J Contemp Pediatr. 2019 Jul 6;6(5):1834.
- Joshi N, Rajeshwari K, Dubey AP et al. Clinical spectrum of fever of unknown origin among Indian children. Ann Trop Paediatr. 2008 Dec;28(4):261-6.
- Surong N, Joseph D. Clinicoetiological profile of pyrexia of unknown origin in children 1-12 years of age in a tertiary care centre. Int J Contemp Pediatr. 2023 May 26;10(6):813-8.
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