A 12-year-old boy with fever and weight loss

CASE PRESENTATION

A 12-year-old boy was referred to a paediatric clinic for assessment of persistent fever, weight loss, and hematuria. His past medical history was significant for a complex chromosomal rearrangement, developmental delay, multiple renal and musculoskeletal abnormalities, and unrepaired structural heart disease, including a functionally bicuspid aortic valve, aortic regurgitation, and severe dilatation of the ascending aorta.

He initially presented to his primary care physician with 3 days of fever and an erythematous, maculopapular rash of the lower body. There were no respiratory symptoms, sore throat, or gastrointestinal symptoms. Physical examination revealed mild erythema of the right tympanic membrane. A presumed diagnosis of acute otitis media was made, and high-dose amoxicillin was prescribed.

Despite compliance with antibiotics, the patient remained febrile. He was seen in the emergency room for re-evaluation, 3 days after starting antibiotics. The family endorsed constitutional symptoms, including fatigue and documented weight loss over the last month. His tympanic membranes appeared normal. A series of investigations were completed (Table 1), and a diagnosis of a viral illness was made.

Table 1.

Results of investigations completed at initial presentation to the emergency department and subsequent clinic visit

Investigations	Initial (3 days after initiation of antibiotics)	Repeat (after completion of antibiotics)
CBC	Hgb 121	Hgb 126
	WBC 18.1*	WBC 9.3
	Plt 337	Plt 355
	Neuts15*	Neuts 7.0
	Lymph 2.1	Lymph1.7
Reticulocytes	--	212*
Electrolytes	Na 139	Na 139
	K 4.5	K 4.0
		Ca 2.3
		PO 1.71
Glucose	--	5.6
Creatinine	44	43
Urea	--	3.3
CK	--	52
Liver enzymes	AST 22	AST 15
	ALT 19	ALT 12
Albumin	45	43
Coagulation profile	--	INR 1.13
		PTT 41.0*
LDH	--	221
CRP	24.8*	15.2*
ESR	49	79
Complement levels	--	C3 1.83
		C4 0.40
ANA	--	Negative
Immunoglobulins	--	IgA 2.73
		IgG 14.68
ASO titers	--	737*
Urinalysis	Blood 3+	Blood 1+
	Leuks -	Leuks -
	Nitrites -	Nitrites -
	Protein -	Protein -
Cultures	Negative blood	Negative blood
	Negative urine	Negative throat
Chest x-ray	Normal	--
Abdominal ultrasound	--	Splenomegaly

Abnormal findings are indicated with an *.

ANA Antinuclear antibody; ASO Antistreptolysin O; CBC Complete blood count; CK Creatinine kinase; LDH Lactate dehydrogenase; CRP C-reactive protein; ESR Erythrocyte sedimentation rate.

He was subsequently seen in paediatric clinic and had defervesced 1 day after completing a 1-week course of antibiotics. He had been febrile for 12 days total. His weight loss and fatigue were ongoing. He had a persistent rash, but no other signs of Kawasaki disease. There was no lymphadenopathy or hepatosplenomegaly. He had a loud diastolic murmur in keeping with his known history of aortic regurgitation. The remainder of his physical exam was normal.

An additional test established the patient’s diagnosis.

DISCUSSION

Despite defervescence, a transthoracic echocardiogram (TTE) was requested. A large, 16 mm, mobile vegetation attached to the subaortic ridge was found (Figure 1 and Supplementary Video) and a diagnosis of subacute infective endocarditis (IE) was made.

Figure 1.

Diagnostic of infective endocarditis by TTE Parasternal long-axis view. On the left, diastole with aortic valve closed. One the right, systole with aortic valve opened. Large mobile vegetation attached to the subaortic ridge (echogenic mass).

Due to the size of the vegetation (>10 mm) and its location (left-sided heart), the patient underwent emergency cardiac surgery for resection of the vegetation and Ross’ intervention. His postoperative course was uneventful. Numerous blood cultures remained negative, but polymerase chain reaction (PCR) of the infected tissue identified Streptococcus oralis as the causative organism. Following cardiac surgery, he completed a 6-week course of intravenous antibiotics and made a complete recovery.

IE is rare in children but carries significant morbidity and mortality (1). Risk factors include congenital heart disease, indwelling central venous catheters, and rheumatic heart disease (2). The most common causative organisms in children are Staphylococcus aureus and viridans streptococci, as seen in our patient.

Subacute IE presents nonspecifically with fever, malaise, and weight loss for several weeks. Other findings may include a new or changing murmur, glomerulonephritis, hematuria, splenomegaly, a nonspecific rash, elevated inflammatory markers, and septic emboli resulting in extracardiac infection. Paediatric patients rarely have the classic stigmata of IE, such as Janeway lesions, Osler nodes, and splinter hemorrhages (2). Blood cultures are recommended for all paediatric patients with fever of unknown origin, and especially in those with a pathological heart murmur, history of heart disease, or previous IE (2). If the diagnosis of IE is suspected, three blood cultures of adequate blood volume for age and weight should be obtained. In acute IE, blood cultures should be collected within about one hour so that antibiotics may be initiated, but may be spaced further apart in subacute IE. Blood cultures in patients with IE may be persistently negative in approximately 5% of cases. The most common reason for this is recent or current antibiotic therapy, as was the case in our patient (2).

In children with suspected IE, with or without positive blood cultures, TTE is an important diagnostic tool, as highlighted in the modified Duke criteria. While TTE is more sensitive in children than in adults, the absence of vegetation or intracardiac abscess does not rule out IE. Serial echocardiograms and initiation of antibiotics should occur if there is strong clinical suspicion (2).

Our patient was diagnostically challenging for several reasons. He presented nonspecifically with fatigue, fever, and weight loss. The presence of weight loss in a child with unexplained fevers is a red flag for serious pathology and is what prompted a thorough diagnostic workup. While a diastolic murmur was noted, it was attributed to his known structural heart disease. Lastly, repeat blood cultures remained negative, likely from his recent antibiotic use.

Due to the variable presentation and significant mortality of IE, collaboration between paediatricians, cardiologists, and infectious disease specialists is recommended throughout diagnosis and management. Once a diagnosis is made, management includes a prolonged course of intravenous antibiotics, tailored to the causative organisms, if known. Surgical intervention is an important consideration in those with large vegetations, uncontrolled infection, prosthetic valve endocarditis, and heart failure (2). If surgical intervention is pursued, PCR of the extracted tissue can help identify causative organisms in culture negative IE.

PCR in this case identified Streptococcus oralis and highlights the importance of dental hygiene in children with valvulopathy. Recently, there has been a shift away from antibiotic prophylaxis before dental procedures and toward an emphasis on prevention of oral disease (2). Patients who are at risk of IE should receive education on the importance of oral health, including regular dental visits.

CLINICAL PEARLS

• Even in the presence of negative blood cultures, IE should be considered in children with persistent fever and/or elevated inflammatory markers, especially those with a history of structural heart disease.

• Weight loss in children with fever of unknown origin is always a red flag and should prompt a thorough diagnostic workup.

• Patients with known valvular heart disease should be counselled on the importance of dental hygiene, including regular dental visits, to prevent IE.

Informed consent: Written informed consent was obtained from the patient and his family.

Funding: There are no funders to report for this submission.

Potential Conflicts of Interest: All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.