Unusual Catheter-associated Aspergillus flavus Fungemia in an Immunocompetent Child: Pulmonary and Thrombotic Complications

To the Editors: Aspergillus flavus is a rare cause of catheter-related bloodstream infections, with most reported cases occurring in immunocompromised patients with underlying chronic conditions. While Aspergillus species are well-recognized opportunistic fungi, catheter-related Aspergillus fungemia is extremely uncommon, particularly in immunocompetent individuals. The detection of Aspergillus in blood cultures is also challenging due to the angioinvasive nature of the organism, which leads to sequestration within tissues, making fungemia a rare finding even in patients with invasive aspergillosis.1 Catheter-related Aspergillus infections have been reported in patients with hematologic malignancies, intestinal failure or immunosuppressive therapy. However, limited data exist on A. flavus fungemia in immunocompetent patients without predisposing conditions.1,2 To date, there have been no reported cases of catheter-related A. flavus fungemia in a completely immunocompetent pediatric patient without underlying chronic disease. Here, we present the first reported case of catheter-associated A. flavus fungemia in an immunocompetent child, complicated by both pulmonary involvement and an infected thrombus. This case highlights the importance of recognizing nontraditional risk factors for Aspergillus infections, the challenges in diagnosing A. fungemia and the need for individualized treatment approaches. A 13-year-old female was admitted to the pediatric intensive care unit (ICU) after sustaining multiple extremity fractures, maxillofacial fractures, thoracic trauma and abdominal trauma due to a fall from height. She underwent multiple surgical interventions and required a temporary central venous catheter (CVC) placement in the right femoral vein due to a prolonged ICU stay. On hospital day 18, broad-spectrum antibiotic therapy was initiated following the detection of gram-negative bacteria in blood cultures. Despite this, the patient developed a persistent fever of 39.0 °C. Clinical examination revealed borderline tachycardia with stable blood pressure and oxygen saturation. The patient was intubated and sedated. Local examination of the right femoral vein CVC site showed no signs of infection (no discharge, erythema or tenderness), and the catheter had been in place for 2 weeks. Laboratory investigations showed a white blood cell count of 14,600/mm³, absolute neutrophil count of 10,600/mm³, hemoglobin of 8.8 g/dL, platelet count of 519,000/mm³ and C-reactive protein of 211 mg/L. HIV serology was negative. Mold was detected in blood cultures for 3 consecutive days. Blood cultures obtained from both the CVC and peripheral blood grew A. flavus, confirmed by fungal culture from the catheter tip (>15 colonies). Serum galactomannan antigen and bronchoalveolar lavage galactomannan tests were negative. Antifungal susceptibility testing was not performed. A chest computed tomography (CT) revealed multiple bilateral pulmonary nodules, the largest measuring 7 mm. A comprehensive evaluation for disseminated fungal disease, including an ophthalmologic exam, echocardiography, brain CT and abdominal ultrasound (liver, spleen and kidneys), yielded normal results. Doppler ultrasonography detected a thrombus extending from the distal iliac vein to the saphenofemoral junction in the right lower extremity. Given these findings, the CVC was promptly removed, and voriconazole therapy was initiated at a loading dose of 6 mg/kg twice daily, followed by a maintenance dose of 4 mg/kg twice daily. Anticoagulation therapy was started to manage venous thrombosis. By treatment day 5, the fever had resolved, and inflammatory markers normalized. A coagulation workup including protein C, protein S, antithrombin III and activated protein C resistance was negative. Given the atypical and prolonged course of aspergillosis, an immunodeficiency workup was pursued in consultation with the immunology section, revealing normal lymphocyte enumeration, T memory panel, B-cell panel, B- and T-cell responses, total hemolytic complement activity and a normal dihydrorhodamine assay. Primary and secondary immunodeficiencies were ruled out. Blood cultures became sterile by day 4 of antifungal therapy. The patient was transferred out of the pediatric ICU within the first week of treatment. Voriconazole therapy was continued for 8 weeks, while anticoagulation therapy was maintained for an extended duration due to persistent thrombosis. A follow-up chest CT at 6 weeks showed a decrease in pulmonary nodule size, and Doppler ultrasound confirmed thrombus reduction. The patient was discharged in stable condition and remained well during follow-up. A. fungemia is an exceptionally rare condition in immunocompetent individuals, particularly in those without any underlying chronic disease. While Aspergillus species are well-known opportunistic pathogens in immunocompromised patients, their potential role in catheter-associated bloodstream infections in otherwise healthy individuals remains poorly understood.1–3 Aspergillosis is a major cause of morbidity and mortality in immunocompromised patients, including those with prolonged neutropenia, hematologic malignancies, hematopoietic stem cell transplantation, solid organ transplantation, corticosteroid therapy, advanced AIDS and chronic granulomatous disease.3 However, the development of aspergillosis in completely immunocompetent individuals is exceedingly rare. In recent years, emerging risk factors for aspergillosis in patients with mild or no immunosuppression have been identified, including glucocorticoid therapy for chronic obstructive pulmonary disease, prolonged ICU stays and viral infections such as influenza or SARS-CoV-2. However, these risk factors are not fully established, and the development of aspergillosis in immunocompetent individuals remains an area of uncertainty.4 Our literature review identified 7 reported cases of catheter-related Aspergillus infections. All these cases occurred in patients with underlying chronic conditions, such as lymphoma, HIV, intestinal failure or acute lymphoblastic leukemia.2,5,6 In contrast, our case is unique as it represents the first reported pediatric case of catheter-associated A. flavus fungemia in an immunocompetent child without any underlying chronic disease. However, our patient had significant risk factors, including ICU admission due to trauma, multiple surgical interventions and the presence of a CVC. We believe that these factors contributed to Aspergillus colonization and subsequent fungemia. Nevertheless, a comprehensive immunological workup did not reveal any primary or secondary immunodeficiency, suggesting that even immunocompetent individuals can develop invasive aspergillosis under specific conditions. Among the 5 pediatric cases of catheter-associated bloodstream infection due to Aspergillus, only 2 involved A. flavus. Pulmonary involvement was reported in only one of these cases2 (Table 1). Our case is unique, as it represents the first pediatric case with both pulmonary involvement and an infected thrombus. A review of these cases showed that all patients underwent catheter removal and were treated with voriconazole or liposomal amphotericin B.2 Similarly, in our case, voriconazole was chosen as the primary antifungal therapy, and due to the presence of a thrombus, prolonged anticoagulation therapy was required. Given the presence of both an infected thrombus and pulmonary nodules, the antifungal treatment duration was extended. The decision to continue therapy for 8 weeks was guided by the need to ensure complete eradication of the infection and prevent potential complications such as persistent fungemia, thrombosis progression or pulmonary dissemination. This case highlights the importance of recognizing catheter-associated Aspergillus infections in immunocompetent individuals and considering nontraditional risk factors in such cases. Early recognition, prompt catheter removal and appropriate antifungal therapy are crucial for successful management. Table 1. - Pediatric Cases Diagnosed With Catheter-Related Bloodstream Infection in the Literature and Their Characteristics Are Presented2 Cases Age, (yr)/Sex Predisposing or Underlying Medical Condition(s) of Patients ISOLATE Identified Disease Process and Other Tissue Sites of Involvement Treatment Outcome 1 6/Female Acute lymphocytic leukemia Aspergillus fumigatus None Catheter removal, itraconazole 4 wk Survived 2 8/Male Acute lymphocytic leukemia Aspergillus niger Catheter exit site infection Catheter removal, amphotericin B (5 d), later itraconazole 2 wk Survived 3 10/Female B-type non-Hodgkin lymphoma A. fumigatus Developed secondary pulmonary aspergillosis Catheter removal, amphotericin B (1.25 mg/kg/day) ×36 d, itraconazole ×4 mo Survived 4 4/Male Acute lymphocytic leukemia A. flavus None Catheter removal, no antifungal therapy (patient nonneutropenic) Survived 5 13/Male Congenital ileal atresia A. flavus Developed secondary pulmonary aspergillosis Catheter removal, amphotericin B and later voriconazole (6 wk) Survived 6* 13/Female None A. flavus Developed secondary pulmonary aspergillosis and infected thrombus Catheter removal, voriconazole (8 wk) Survived *The sixth case is the one that we report. Ultimately, this case contributes to the expanding literature on catheter-related Aspergillus infections in immunocompetent hosts. It underscores the need to maintain a high index of suspicion for fungal bloodstream infections in patients with identifiable risk factors, even in the absence of traditional immunosuppression. Early catheter removal, timely initiation of antifungal therapy and careful monitoring for complications such as thrombosis and pulmonary involvement are essential for successful management. Our findings reinforce the importance of early recognition, aggressive intervention and an individualized approach to treatment duration, particularly in cases complicated by thrombosis and pulmonary involvement. Moving forward, clinicians should be aware that ICU admission, prior surgical interventions and the presence of a CVC can serve as significant risk factors for A. fungemia, even in otherwise healthy pediatric patients.