Fever of Unknown Origin in a 6-Year-old : The Pediatric Infectious Disease Journal

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Fever of Unknown Origin in a 6-Year-old

Nigam, Anmol MD*; Saucedo, Alex MD†,‡; Ingram, Evan MD; Chaparro, Juan D. MD†,‡,§; Ouellette, Christopher P. MD†,‡,§

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The Pediatric Infectious Disease Journal 42(2):p 172-174, February 2023. | DOI: 10.1097/INF.0000000000003686
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A 6-year-old female, previously healthy, presented with a 10-day history of fevers. Three weeks before her presentation, she reported sore throat (resolved at time of presentation), decreased appetite, and decreased urine output. After resolution of sore throat, she developed daily fevers of 10 days duration, poor urine output, constipation, and congestion without rhinorrhea. At presentation, the patient was without complaints of sore throat or neck stiffness, dental pain, cough, chest pain, shortness of breath, abdominal pain, vomiting, diarrhea, or arthralgias. Epidemiologic history was notable for recent mosquito bites, hiking in nearby woods, and living with 2 pet cats. Her dental hygiene was excellent with no history of caries.

Physical examination at presentation was remarkable for a well-appearing child, notable only for a macular, nonpruritic rash on her chest. Vital signs were unremarkable apart from tachycardia (122 bpm) in an afebrile state (36.8 C). Initial laboratory testing identified a significant leukocytosis (white blood cell count (WBC) 34,200 cells/µL), hemoglobin 9.4 g/dL, and thrombocytosis (platelet count 639,000 cells/µL), elevated C-reactive protein (5.9 mg/dL), and elevated sedimentation rate (90 mm/h). Serum lactate dehydrogenase and uric acid levels were within normal limits (637 U/L and 2.9 mg/dL, respectively). Given the presentation of fever of unknown origin (FUO) and accounting for epidemiologic factors, a broad infectious diagnostic workup was pursued, including serologic and polymerase chain reaction (PCR) assessment for Bartonella henselae, Toxoplasma gondii, arboviruses (La Crosse virus, West Nile virus), Epstein-Barr Virus (EBV), Adenovirus, Human Immunodeficiency Virus 1 and 2, Mycobacterium tuberculosis and Histoplasma capsulatum. Diagnostic testing results from above were all unremarkable with exception to an elevated complement fixation testing result to Histoplasma capsulatum (1:32). Blood cultures obtained on admission remained without growth. Consideration for multi-inflammatory syndrome in children (MIS-C) was evaluated although patient did not fulfill criteria. Echocardiography (ECHO) was obtained on hospital day (HD) no. 3 and was without coronary artery dilation, valvular abnormality, abnormal function, or effusion.

Although afebrile on admission, fevers persisted during hospitalization, and given persistence of fever and elevated inflammatory markers, the patient underwent positron emission tomography-computed tomography (PET/CT) on HD no. 5, which revealed a hypermetabolic mass in the anterior mediastinum with extension into the pericardial tissues (Figure 1A,B). Increased splenic avidity, as well as enlarged cervical, supraclavicular, and left common iliac lymph nodes with moderate avidity were observed. The PET/CT also revealed a calcified, nonmetabolically active nodule in the lung. With concern for potential malignancy, dedicated CT scans of neck, chest, abdomen, and pelvis were obtained and notable for bulky necrotic mediastinal lymphadenopathy as well as bilateral hilar lymphadenopathy, small pericardial effusion, and a nonspecific left lower lobe subpleural nodule with central calcification (Figure 1C). Shortly after this finding, her clinical status worsened, including persistent tachycardia as well as new requirement for supplemental oxygen. After obtaining repeat blood cultures, broad-spectrum antimicrobial therapy was initiated with IV vancomycin 17.5 mg/kg every 6 hours and IV ceftriaxone 75 mg/kg every 24 hours, and the patient was transferred to the pediatric intensive care unit (HD no. 7). She underwent repeat ECHO, which now noted a moderate pericardial effusion. She underwent pericardiocentesis, and while results were pending, liposomal amphotericin B 5mg/kg every 24 hours was initiated because of concern for potential histoplasmosis. Results from the pericardiocentesis revealed the diagnosis.

A, B: PET/CT demonstrating mediastinal mass with mild mass effect on the trachea and avidity in the pericardial space. Chest CT (C) demonstrated bulky necrotic mediastinal lymphadenopathy and a stable, calcified lung nodule. PET/CT indicates positron emission tomography-computed tomography. 


Fluid analysis of the pericardiocentesis noted a WBC of 13,756 cells/mm3 (98% neutrophils) and red blood cell count of 2000 cells/mm3. Cytology of the fluid was without malignancy, however identified intracellular coccoid-like microorganisms. Bacterial aerobic, anaerobic, fungal, and acid-fast cultures from the pericardial fluid were without growth, as were repeat blood cultures. Broad-range PCR from the pericardial fluid detected Streptococcus intermedius (Streptococcus anginosus group) and Fusobacterium nucleatum (University of Washington). Biopsy of the anterior mediastinal mass was performed and noted inflammatory change without evidence of bacteria, fungi, or mycobacteria on routine stains. Broad-range PCR from the biopsy similarly detected Streptococcus intermedius and Fusobacterium nucleatum. PCR diagnostics from the pericardial fluid and mediastinal tissue were negative for other bacterial, fungal, and acid-fast pathogens. The calcified lung nodule was believed secondary to prior (resolved) histoplasma granulomatous lung disease, in part caused by these results, as well as a positive histoplasma complement fixation titer (1:32), negative Histoplasma antigen testing (blood and urine), and negative QuantiFERON Gold TB result. With these findings, the patient was treated as a suspected polymicrobial primary necrotizing mediastinitis with purulent pericarditis. Antibiotics were deescalated to IV ceftriaxone 75 mg/kg once daily and IV metronidazole 15 mg/kg every 8 hours for definitive therapy while inpatient. She was discharged on IV ceftriaxone until seen in follow up (completed 28 total days), where she was transitioned to oral amoxicillin/clavulanate 30 mg/kg every 8 hours. This was continued until normalization of inflammatory markers, for a total of 52 days of therapy. Postcompletion of therapy, she has remained well without complication or recrudescence of disease.

This case represents an extremely rare case of primary necrotizing mediastinitis and purulent pericarditis in the absence of a clear antecedent focus of infection, suggesting a new potential mode of clinical presentation. Typically, infectious mediastinitis is encountered as a complication of descending infection from odontogenic source, deep neck space infection, penetrating trauma, surgical procedures, or esophageal fistula/complications.1,2 Pathogens associated with mediastinitis are related to the mechanism of injury or infection: surgical causes are most frequently because of Staphylococcus sp., Gram-negative bacilli, and Streptococcus sp.,3 whereas deep neck space and oropharyngeal causes are related more frequently to Streptococcus sp., oral anaerobes (including Fusobacterium sp.), and occasionally Staphylococcus sp.4 Given the contiguous fascial planes and risk for direct extension, pericarditis may occur with mediastinitis with a similar microbial pathogenesis, although considerations for additional pathogens such as Mycobacterium tuberculosis in regions of endemicity are warranted.5

Streptococcus intermedius, a member of the Streptococcus anginosus group (SAG), has been implicated in a variety of invasive infections, including but not limited to intracranial abscesses secondary to complicated sinusitis, appendicitis, endocarditis, and rarely thoracic infections including mediastinitis and pericarditis.6 In review of the medical literature, only 5 cases of pediatric (age <18 years) mediastinitis or pericarditis caused by SAG have been reported.7–10 These patients presented frequently with FUO, and comorbid conditions including oropharyngeal infection or pericardial tumor.

Fusobacterium sp. are well known to cause invasive disease, recognized most commonly in septic jugular venous thrombophlebitis (Lemierre’s syndrome). F. nucleatum, as encountered in this case, has also been described to cause tissue invasive disease, including mediastinitis and pericarditis typically by odontogenic source or through esophageal perforation.11 In clinical practice, concomitant detection of SAG and anaerobic bacteria, such as Fusobacterium sp., during invasive infection is not infrequent, and documentation of streptococcal species with anaerobic bacteria in descending necrotizing acute mediastinitis has been described.12

In summary, our case represents a unique presentation of polymicrobial necrotizing mediastinitis and purulent pericarditis, in absence of a descending or traumatic focus of infection. Clinicians should be aware of this unusual presentation and the potential benefit of PET/CT for diagnosis in cases of FUO.


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