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Pyrexia of Unknown Origin in a Child: How to Approach?

Dhruv Gandhi, Ira Shah
Department of Pediatric Infectious Diseases, BJ Wadia Hospital for Children, Mumbai, India

Address for Correspondence: Dhruv Gandhi, 5B/13 Shyam Niwas, Breach Candy, Mumbai-400026, Maharashtra, India. Email: dhruvgandhi2610@gmail.com

Keywords: Fever of unknown origin, PUO, FUO, Infections, Malignancies, Histoplasmosis

Clinical Problem:
A 6-year-old boy presented in August 2024 with high-grade fever for 15 days. There was no nausea, vomiting, abdominal pain, loss of weight or appetite. On presentation, weight was 24 kg (between 75th-90th percentile according to Indian Academy of Pediatrics (IAP) charts) and height was 108 cm (between 10th-25th percentile according to IAP charts). On examination, pallor and bilateral inguinal lymphadenopathy (1 x 1cm) was present. Other general and systemic examinations were normal. Investigations are shown in Table 1. He was admitted and empirically started on intravenous cefotaxime. Routine urine examination was normal. Blood and urine cultures were negative. Non-contrast computerized tomography (NCCT) of the chest showed diffuse subtle centrilobular nodules in both lungs without hilar or mediastinal lymphadenopathy. Urine Xpert MTB/Rif and interferon-gamma release assay were negative. Malaria antigen test, dengue NS1, scrub typhus IgM, brucella IgM and HIV ELISA were negative. 2D-echocardiography did not show any vegetations or valvular abnormalities. Abdominal ultrasound showed mild hepatosplenomegaly with multiple liver and spleen lesions and bilateral bulky kidneys. Oral doxycycline was added. In view of persistent fever, lymphocyte subset analysis was advised which showed low B-cell counts. Total serum IgE was 53.89 IU/mL(normal: <90 IU/mL), serum IgA was 354 mg/dL(normal: 34-305 mg/dL) and serum IgM was 224 mg/dL(normal: 31-208 mg/dL). On day 10 of admission, urine histoplasma antigen was sent and was positive. All antibiotics were stopped and he was started on intravenous liposomal amphotericin-B(L-AMB)(3 mg/kg/day), to which he responded and became afebrile after 2 doses. He received L-AMB for 2 weeks followed by oral itraconazole 100 mg twice a day. Abdominal ultrasound on day 14 of L-AMB showed mild hepatosplenomegaly with complete resolution of liver lesions and reduction in size of splenic lesions. At the 1-month follow-up, abdominal ultrasound showed mild hepatosplenomegaly with no focal lesions in the liver or spleen. Urine histoplasma antigen became negative at 3 months of therapy.

Table 1. Investigations of the patient.

Parameters	At presentation	At follow-up	Reference Ranges
Hemoglobin (gm/dL)	10.8	12.2	11.5-15.5
White blood cell count (cells/cumm)	9670	6230	5000-13,000
Absolute neutrophil count (cells/cumm)	4846	2199	2000-8000
Absolute lymphocyte count (cells/cumm)	4520	2909	1000-5000
Platelets (10⁶ cells/cumm)	5.32	2.70	1.50-4.50
CRP (mg/dL)	67.4	-	-
ESR (mm/hr)	16	-	-
ALT (IU/L)	18	16.4	<41
AST (IU/L)	30	18	<41
ALP (IU/L)	237	-	51-332
Total bilirubin (mg/dL)	0.2	-	0.0-1.10
Direct bilirubin (mg/dL)	0.1	-	0.0-0.60
Indirect bilirubin (mg/dL)	0.1	-	0.10-0.80
BUN (mg/dL)	7	-	5-18
Serum creatinine (mg/dL)	0.51	0.69	0.3-0.59
Serum total protein (gm/dL)	7.3	-	6.00-8.30
Serum albumin (gm/dL)	3.7	-	3.80-5.40

Note : CRP- C-reactive protein, ESR- Erythrocyte sedimentation rate, ALT- Alanine aminotransferase, AST- Aspartate aminotransferase, ALP- Alkaline phosphatase, BUN- Blood urea nitrogen.