EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Key words : Antifungal therapy, Aspergillus fumigatus, Solid-organ transplant

Invasive aspergillosis (IA) is a rare but serious complication in recipients of solid-organ transplant (SOT).¹ This condition is caused by Aspergillus, a prevalent mold transmitted through the inhalation of its spores (conidia), posing significant risks to SOT recipients.^1,2 Prediction of the transmissibility of fungal infections in donor-derived SOT remains a notable challenge. Our understanding primarily stems from reported case series and reviews, in which many cases infected with IA require explant; yet mortality has been reported despite such intervention.^1,3-7 The immunosuppression drugs essential for the survival of transplanted organs present a considerable challenge, as these can reactivate latent infections within the transplanted tissue. Previously published research, including case reports and reviews, has highlighted the complexity of IA management in SOT recipients. This report focuses on 3 unique cases of IA in patients who received kidney or liver transplants from the same deceased pediatric donor, marking the first documented instances of IA in SOT from a donor under 18 years of age.

Case 1
A 27-year-old male patient with kidney failure due to nephronophthisis received a left-sided kidney transplant from a 17-year-old deceased pediatric donor. The recipient’s renal functions were stable initially, and he was discharged on day 7. Monthly follow-ups remained within the normal range until posttransplant day 65, when he developed a low-grade fever and graft tenderness, accompanied by slightly elevated acute phase reactants. He was hospitalized and started on broad-spectrum antibiotics. On day 12 of hospitalization, blood culture result was positive for fungal infections, for which amphotericin B was added at conventional doses to his regimen. However, his condition worsened, with symptoms that included high-grade fever, decreased urine output, increased serum creatinine level (3.5 mg/dL), and graft site tenderness. Abdominal ultrasonography and subsequent computed tomography angiography revealed the development of exophytic, heterogeneously isohyperechoic mass-like lesions. A fine-needle biopsy confirmed the presence of IA. The patient underwent graft nephrectomy. His symptoms improved following the explant and rigorous antifungal therapy.

Case 2
Case 2 involved a 17-year-old male patient, with a medical history of kidney failure attributed to urethral stenosis, who underwent a right-sided kidney transplant from the same pediatric donor. Initially, his posttransplant recovery was stable, with a satisfactory estimated glomerular filtration rate exceeding 90 mL/min/1.73 m². The patient was discharged on day 7 with a postoperative immunosuppression regimen. His postoperative monthly follow-ups remained within the normal range until month 3, when he began to exhibit a low-grade fever, graft tenderness, and slightly elevated acute phase reactants. Consequently, the patient was hospitalized and started on broad-spectrum antibiotics following the collection of blood and urine cultures. On day 13 of hospitalization, his blood culture result was positive for a fungal infection, for which amphotericin B was added at conventional doses to his treatment. Subsequently, his condition worsened, characterized by a high-grade fever, decreased urine output, an increased serum creatinine level (3.2 mg/dL), and increased tenderness at the graft site. Abdominal ultrasonography and subsequent computed tomography angiography revealed the presence of multiple renal abscesses characterized by progressively enhanced walls and separations, alongside unenhanced alveolate areas in the transplanted kidney. A fine-needle biopsy confirmed the diagnosis of IA (Figure 1). Despite targeted antifungal therapy, the patient’s renal function continued to decline, ultimately leading to a graft nephrectomy. After graft nephrectomy, the patient’s condition substantially improved. He received a total of 28 days of treatment with amphotericin B. At the time of this writing, he remained on hemodialysis and has been awaiting another transplant.

Case 3
The third case involved a 28-year-old female patient with chronic liver failure who received a liver transplant from the same donor as the 2 previous cases. After the discovery of IA in 2 kidney recipients from this donor, contact was initiated with this third recipient, who had undergone liver transplant at another center. Her initial postoperative follow-ups were optimal until posttransplant day 45. She then presented with high fever and deteriorating liver function tests and was admitted to the intensive care unit (ICU) due to early liver graft failure and a diagnosis of sepsis. Detailed investigations revealed the presence of IA in the transplanted liver, which further complicated her clinical course. She started treatment with broad-spectrum antibiotics and amphotericin B at conventional doses for up to 30 days. Her condition improved, with a gradual decline in her bilirubin levels to reference levels, and the results of her blood culture were negative for infection. Fortunately, she did not require graft explant.

The 17-year-old, previously healthy donor had a history of severe accidents that had resulted in intracranial hemorrhage. The donor remained under ICU care for an extended period before declaration of brain death, after which his organs were procured for donation.

Invasive aspergillosis, primarily caused by Aspergillus fumigatus, may emerge as a substantial threat in SOT recipients, mainly due to the environmental ubiquity of the Aspergillus mold and the immunosuppressed state of these patients. In numerous reported cases, the source of IA is typically the lungs, or it involves dissemination from the skin to the target organs.⁸ In our 3 cases reported here, detailed investigations into the source of IA in recipients yielded negative results, except for exophytic-like growths in the transplanted organ. This led us to conclude the possibility of donor-derived IA. The risk of IA is exacerbated by factors such as contaminated sources, prolonged immunosuppression and ICU stays in donors, as well as breaches in aseptic techniques (typically seen in the commercial practice known as transplant tourism) during organ procurement and transplant.^2,9,10 In our cases, the donor had a history of prolonged ICU stay and immunosuppression, which aligned with previous similar scenarios reported in the literature. The related risk factors among the recipients included the extended immunosuppression therapy induced following the transplant.

The manifestations of IA vary widely, ranging from asymptomatic colonization to severe invasive disease, and this variability presents substantial challenges in diagnosis and management. Cases of suspected donor-derived IA have shown a broad variability in the timing of symptom onset; however, most cases are reported within 3 months after transplant.^3-7 Among our cases, the liver transplant recipient (case 3) was the first to present symptoms of IA, followed by the adult renal transplant recipient (case 1). Early monitoring of SOT recipients from the same donor could be beneficial for the timely diagnosis and treatment.

Initial symptoms of IA frequently include fever, failure of the transplanted organ, and localized tenderness, with the potential to progress to systemic involvement, including meningitis and endocarditis.^3-7 There are instances where localized Aspergillus infestation at the iliac artery was initially diagnosed as an aneurysm.⁶ The variability in the clinical presentation of IA complicates the diagnostic process. Reports of pseudoaneurysms of the iliac artery due to Aspergillus infection highlight the diverse manifestations of IA in transplant recipients, underscoring the need for a high index of suspicion and the use of advanced diagnostic tools for timely detection and intervention. In our cases, all 3 patients experienced low-grade fever that progressed to resistance to antipyretics.

The management of IA primarily relies on antifungal therapy, with amphotericin B being the initial treatment choice in most reported cases.^3-7 Alternatives such as voriconazole, itraconazole, and caspofungin are reserved for cases in which amphotericin B is contraindicated or ineffective due to resistance.^3-7 In our study, all 3 patients responded well to amphotericin B treatment at conventional doses for a prolonged period. Furthermore, the liver transplant recipient (case 3) was administered oral voriconazole as maintenance therapy. These therapeutic strategies highlight the importance of timely intervention in the treatment of IA, with some cases requiring personalized care plans.^3-7

Addressing IA in SOT recipients requires a comprehensive approach that includes tailored antifungal therapy and, when necessary, surgical interventions for localized infections or when pharmacotherapy is ineffective. Given the substantial risks of morbidity and mortality associated with IA, as well as the potential nephrotoxicity of antifungal agents (particularly for kidney transplant recipients), there is a vital need for careful monitoring, dosing adjustments, and the development of preventive strategies. Preventive measures encompass environmental controls, prophylactic antifungal therapy for patients at high risk, and diligent infection monitoring.

In conclusion, although IA remains a rare yet significant challenge in the management of SOT recipients, a detailed understanding of its epidemiology, clinical presentations, and treatment strategies is essential. Personalized care according to the individual risk profiles of transplant recipients is crucial for mitigation of this potentially fatal complication, and there remains a critical need for heightened clinical vigilance, especially for patients with unusual imaging findings, to ensure timely diagnosis and effective management.

Volume: 22 Issue: 10 October 2024 - Supplement - 5

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